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Yu, Esther Dawen, Alba Grifoni, Aaron Sutherland, Hannah Voic, Eric Wang, April Frazier, Natalia Jimenez-Truque, et al. "Balanced Cellular and Humoral Immune Responses Targeting Multiple Antigens in Adults Receiving a Quadrivalent Inactivated Influenza Vaccine." Vaccines 9, no. 5 (April 23, 2021): 426. http://dx.doi.org/10.3390/vaccines9050426.
Повний текст джерелаАнотація:
The role of T cell immunity has been acknowledged in recent vaccine development and evaluation. We tested the humoral and cellular immune responses to Flucelvax®, a quadrivalent inactivated seasonal influenza vaccine containing two influenza A (H1N1 Singapore/GP1908/2015 IVR-180 and H3N2 North Carolina/04/2016) and two influenza B (Iowa/06/2017 and Singapore/INFTT-16-0610/2016) virus strains, using peripheral blood mononuclear cells stimulated by pools of peptides overlapping all the individual influenza viral protein components. Baseline reactivity was detected against all four strains both at the level of CD4 and CD8 responses and targeting different proteins. CD4 T cell reactivity was mostly directed to HA/NA proteins in influenza B strains, and NP/M1/M2/NS1/NEP proteins in the case of the Influenza A strains. CD8 responses to both influenza A and B viruses preferentially targeted the more conserved core viral proteins. Following vaccination, both CD4 and CD8 responses against the various influenza antigens were increased in day 15 to day 91 post vaccination period, and maintained a Th1 polarized profile. Importantly, no vaccine interference was detected, with the increased responses balanced across all four included viral strains for both CD4 and CD8 T cells, and targeting HA and multiple additional viral antigens.
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Murphy, Juneann W., Fredda Schafer, Arturo Casadevall, and Adekunle Adesina. "Antigen-Induced Protective and Nonprotective Cell-Mediated Immune Components against Cryptococcus neoformans." Infection and Immunity 66, no. 6 (June 1, 1998): 2632–39. http://dx.doi.org/10.1128/iai.66.6.2632-2639.1998.
Повний текст джерелаАнотація:
ABSTRACT Mice immunized with two different cryptococcal antigen preparations, one a soluble culture filtrate antigen (CneF) in complete Freund’s adjuvant (CFA) and the other heat-killed Cryptococcus neoformans cells (HKC), develop two different profiles of activated T cells. CneF-CFA induces CD4+ T cells responsible for delayed-type hypersensitivity (DTH) reactivity and for amplification of the anticryptococcal DTH response, whereas HKC induce CD4+ and CD8+ T cells involved in anticryptococcal DTH reactivity and activated T cells which directly kill C. neoformans cells. The main purpose of this study was to assess the level of protection afforded by each of the two different T-cell profiles against challenge with viable C. neoformans cells, thereby identifying which activated T-cell profile provides better protection. CBA/J mice immunized with CneF-CFA had significantly better protective responses, based on better clearance of C. neoformans from tissues, on longer survival times, and on fewer and smaller lesions in the brain, than HKC-immunized mice or control mice similarly infected with C. neoformans. Both immunization protocols induced an anticryptococcal DTH response, but neither induced serum antibodies to glucuronoxylmannan, so the protection observed in the CneF-CFA immunized mice was due to the activated T-cell profile induced by that protocol. HKC-immunized mice, which displayed no greater protection than controls, did not have the amplifier cells. Based on our findings, we propose that the protective anticryptococcal T cells are the CD4+ T cells which have been shown to be responsible for DTH reactivity and/or the CD4+ T cells which amplify the DTH response and which have been previously shown to produce high levels of gamma interferon and interleukin 2. Our results imply that there are protective and nonprotective cell-mediated immune responses and highlight the complexity of the immune response to C. neoformans antigens.
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Bottino, C., G. Tambussi, S. Ferrini, E. Ciccone, P. Varese, M. C. Mingari, L. Moretta, and A. Moretta. "Two subsets of human T lymphocytes expressing gamma/delta antigen receptor are identifiable by monoclonal antibodies directed to two distinct molecular forms of the receptor." Journal of Experimental Medicine 168, no. 2 (August 1, 1988): 491–505. http://dx.doi.org/10.1084/jem.168.2.491.
Повний текст джерелаАнотація:
Two mAbs directed to the TCR-gamma/delta were analyzed for their pattern of reactivity with CD3+WT31- cell populations or clones. In normal individuals, the BB3 mAb reacted with approximately 2/3 of peripheral blood CD3+WT31- lymphocytes, whereas delta-TCS-1 stained approximately 1/3 of such cells. In addition, the sum of the percentages of BB3+ and delta-TCS-1+ cells approximated the percentages of peripheral blood CD3+WT31- lymphocytes in seven normal donors tested. Also, in peripheral blood-derived polyclonal CD3+WT31- populations, cultured in IL-2, cells reacting with one or another mAb accounted for the whole cell population. On the other hand, only delta-TCS-1-reactive cells, but not BB3+ cells, could be detected in unfractionated as well as in CD4-8-thymocyte populations. Analysis of peripheral blood-derived CD3+WT31- clones showed that 70% of 72 clones analyzed reacted with BB3 mAb, but not with delta-TCS-1 mAb. On the other hand, delta-TCS-1 mAb stained the remaining BB3- clones. Five clones expressing medium-low amounts of CD8 antigen were BB3- delta-TCS-1+. Both types of clones lysed the Fc gamma receptor-bearing P815 target cell in the presence of anti-CD3 mAb (but not of mAb directed against HLA-DR, CD7 molecules, or TCR-alpha/beta). In this cytolytic assay, BB3 mAb induced target cell lysis only by BB3+ clones, whereas delta-TCS-1 mAb was effective only with delta-TCS-1+ clones. The CD3-associated surface molecules expressed by BB3+ or delta-TCS-1+ clones were analyzed after cell surface iodination and immunoprecipitation with the corresponding anti-TCR mAb or with anti-CD3 mAb (in digitonin-containing buffer). In SDS-PAGE, molecules immunoprecipitated from 13 BB3+ clones displayed, under nonreducing conditions, a molecular weight of 80 kD (in some cases, a minor 38-kD band could be detected). Under reducing conditions, two major components of 44 and 41 kD (and a minor component of 38 kD) were detected. On the other hand, TCR molecules immunoprecipitated from 11 different delta-TCS-1+ clones appeared as a diffuse band of 41-44 kD, both under reducing and nonreducing conditions (under non-reducing condition, an additional 38-kD band was present). Therefore, BB3+ cells express a disulphide-linked form of TCR-gamma/delta whereas delta-TCS-1+ cells express a non-disulphide-linked form.(ABSTRACT TRUNCATED AT 400 WORDS)
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Garssen, J., H. Van Loveren, K. Kato, and P. W. Askenase. "Antigen receptors on Thy-1+ CD3- CS-initiating cell. In vitro desensitization with hapten-amino acid or hapten-Ficoll conjugates, versus hapten-protein conjugates, suggests different antigen receptors on the immune cells that mediate the early and late components of murine contact sensitivity." Journal of Immunology 153, no. 1 (July 1, 1994): 32–44. http://dx.doi.org/10.4049/jimmunol.153.1.32.
Повний текст джерелаАнотація:
Abstract In murine contact sensitivity (CS) models, cutaneous immune responses are caused by the activity of two different Ag-specific Thy-1+ CD5+ cells. These two different cell subsets act in an obligate sequence to mediate separate early and late components of CS that are accompanied respectively by skin swelling responses at 2 and 24 h after local challenge with the hapten. The early-acting CS-initiating cells are not conventional T cells inasmuch as they are surface negative for CD4, CD8, and CD3. In contrast to this non-MHC-restricted, CS-initiating cell, the classical late-acting CS effector T cell that is recruited locally is CD3+, CD4+, CD8-, and is MHC-restricted. In our study, we have conducted experiments in which a mixture of immune CS-initiating and CS-effector cells were desensitized by incubation in vitro at 37 degrees C with various hapten-amino acid and hapten-carrier conjugates, before i.v. transfer and subsequent ear challenge of normal recipient mice. Desensitization was achieved with multivalent complexes of the relevant hapten conjugated to a variety of unrelated nonmurine carrier proteins, and, in some instances, with monovalent hapten conjugated to amino acid. Because the CS-mediating cells were desensitized in a hapten-specific manner, but these same cells transferred CS reactivity that was hapten/MHC-class II specific, it was suggested previously that these results argued in favor of a two-receptor model for T cell recognition of Ag, one receptor for hapten and the other for MHC. Our study suggests that these findings need to be reinterpreted because CS reactions are mediated by two different, Thy-1+ Ag-specific cells that act in an obligate sequence. Our data suggest that the late-acting Ag/MHC-specific CS-effector T cells are not hapten-specific. In fact, desensitization with hapten alone has a locus of action solely on the Ag receptor of the first-acting Thy-1+ CS-initiating cells--which are therefore truly hapten-specific and which are required for local recruitment of the Ag/MHC-specific late CS-effector T cells.
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Rosat, Jean-Pierre, Ethan P. Grant, Evan M. Beckman, Christopher C. Dascher, Peter A. Sieling, Daphney Frederique, Robert L. Modlin, Steven A. Porcelli, Stephen T. Furlong та Michael B. Brenner. "CD1-Restricted Microbial Lipid Antigen-Specific Recognition Found in the CD8+ αβ T Cell Pool". Journal of Immunology 162, № 1 (1 січня 1999): 366–71. http://dx.doi.org/10.4049/jimmunol.162.1.366.
Повний текст джерелаАнотація:
Abstract It is generally accepted that TCR αβ+ CD8+ T cells recognize immunogenic peptides bound to MHC-encoded class I molecules. This recognition is a major component of the cellular response mediating immune protection and recovery from viral infections and from certain intracellular bacterial infections. Here, we report two human CD8+ TCR αβ+ T cell lines specific for Mycobacterium tuberculosis Ags presented in the context of CD1a or CD1c Ag-presenting molecules. These T cells recognize lipid Ags and display cytotoxicity as well as strong Th cell type I cytokine responses. By extending presentation by the CD1 system to the major TCR αβ+ CD8+ T cell pool, this system gains wider applicability beyond the double negative subset of T cells previously shown to have this reactivity. This implies that previous assumptions about the role of CD8+ T cells in microbial immunity may require revision as the relative proportions of CD1-restricted and MHC class I-restricted CD8+ T cells are further defined.
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Su, Charles, Shoichi Iida, Toyofumi Abe, and Robert Fairchild. "Endogenous memory CD8 T cells exhibit increased early proliferation in cardiac allografts subjected to prolonged ischemia (TRAN3P.880)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 202.19. http://dx.doi.org/10.4049/jimmunol.192.supp.202.19.
Повний текст джерелаАнотація:
Abstract Memory T cells induced to microbial infections provide protection to subsequent exposures but can have cross-reactivity with allogeneic MHC molecules. High numbers of memory T cells with donor reactivity in human and non-human primate recipients prior to transplant are associated with poorer allograft survival and resistance to costimulatory blockade strategies given to induce long-term graft survival. Rodent transplant models have failed to replicate the detrimental impact of endogenous memory T cells on allograft survival and tolerance induction, raising questions about the sufficiency of these models to study this component of alloimmunity. We have recently shown a direct association between increasing duration of cold ischemic storage and numbers of early graft infiltrating memory CD8 T cells that markedly up-regulate effector functions and directly mediate costimulatory blockade resistant rejection of cardiac allografts in a mouse model. Here we show that endogenous memory CD8 T cells exhibit increased early proliferation in grafts subjected to prolonged ischemia that is supported by memory CD4 T cells. Recipient depletion of CD4 T cells or treatment with MR1 (anti-CD40L) at transplant significantly decreased early memory CD8 T cell proliferation and extended survival of grafts subjected to prolonged cold ischemia. These studies provide novel insights into endogenous memory CD8 T cell mediated graft injury and the poor outcomes associated with cadaver donor grafts.
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Kim, Seon-Hee, Chungyong Han, Byoung S. Kwon та Beom K. Choi. "CD4 depletion potentiates anti-tumor immunity in adoptive immunotherapy by increasing IL-18Rαhi endogenous CD8+ T cells". Journal of Immunology 204, № 1_Supplement (1 травня 2020): 170.7. http://dx.doi.org/10.4049/jimmunol.204.supp.170.7.
Повний текст джерелаАнотація:
Abstract Adoptive T cell therapy (ACT) requires lympho-depletion pre-conditioning to eliminate immune-suppressive elements to allow for the efficient engraftment of adoptively transferred tumor-reactive T cells. Because anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells to enhance anti-tumor immunity, combinations of anti-CD4 treatment and ACT have synergistic potential in cancer therapy. We designed a post-ACT conditioning regimen that involves weekly treatment with anti-CD4 (CD4post). Using murine melanoma, cyclophosphamide and tumor-reactive CD8+ T cell infusion were included to represent an ACT model. We evaluated anti-tumor effects and immunologic changes of T cells. CD4post in ACT markedly increased tumor suppression and survival. Remarkably, CD4post worked differently on ex vivo primed CD8+ T cells versus endogenous CD8+ T cells. CD4post substantially increased the proliferation of ex vivo primed CD8+ T cells, while increasing endogenous CD8+ T cell differentiation and effector function. Endogenous CD8+ T cells upregulated activation/exhaustion markers and exhibited a skewed TCR repertoire, implying that CD4post boosted tumor-reactivity. Accordingly, CD4post-experienced endogenous CD8+ T cells showed enhanced intra-tumoral infiltration and exhibited greater anti-tumor activity against melanoma in vitro. Importantly, enrichment of the IL-18Rαhi subset was critical for boosting anti-tumor responses, as IL-18Rα+ cell-depletion CD8+ T cells resulted in diminished anti-tumor activity. This study highlights the clinical relevance of CD4post to ACT and gives insights into the characteristics of the immunological components that drive the augmented cancer–immunity cycle in ACT.
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Kazemi, Pezhman, Mohammad Reza Nikudel, Mashalah Khamehchiyan, Paritosh Giri, Shima Taheri, and Simon Martin Clark. "Assessment of Alkali–Silica Reaction Potential in Aggregates from Iran and Australia Using Thin-Section Petrography and Expansion Testing." Materials 15, no. 12 (June 17, 2022): 4289. http://dx.doi.org/10.3390/ma15124289.
Повний текст джерелаАнотація:
The alkali–silica reaction can shorten concrete life due to expansive pressure build-up caused by reaction by-products, resulting in cracking. Understanding the role of the aggregate, as the main reactive component, is essential for understanding the underlying mechanisms of the alkali–silica reaction and thereby reducing, or even preventing, any potential damage. The present study aims to investigate the role of petrographic studies along with accelerated tests in predicting and determining the potential reactivity of aggregates, including granite, rhyodacite, limestone, and dolomite, with different geological characteristics in concrete. This study was performed under accelerated conditions in accordance with the ASTM C1260 and ASTM C1293 test methods. The extent of the alkali–silica reaction was assessed using a range of microanalysis techniques including optical microscopy, scanning electron microscopy, energy-dispersive X-ray analysis, and X-ray powder diffraction. The results showed that a calcium-rich aggregate with only a small quantity of siliceous component but with a higher porosity and water adsorption rate can lead to degradation due to the alkali–silica reaction, while dolomite aggregate, which is commonly considered a reactive aggregate, showed no considerable expansion during the conducted tests. The results also showed that rhyodacite samples, due to their glassy texture, the existence of strained quartz and quartz with undulatory extinction, as well as the presence of weathering minerals, have a higher alkali-reactivity potential than granite samples.
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Clutton, Genevieve Tyndale, Sallay Kallon, Ann Weideman, Yinyan Xu, Joanna Warren, Olivia Council, Damir Alzhanov, et al. "CD3 and CD8 coreceptor down-modulation are inversely associated with CD8 T cell functional avidity in humans." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 94.2. http://dx.doi.org/10.4049/jimmunol.204.supp.94.2.
Повний текст джерелаАнотація:
Abstract This study investigated the function of memory CD8 T cells in HIV-infected people durably suppressed on antiretroviral therapy (HIV+ cART). We assessed bulk and virus-specific memory CD8 T cells in HIV+ cART and HIV-seronegative individuals (HIV−) by flow cytometry. We observed a population of CD3+ CD8dim CD14− CD16− (CD8dim) T cells that was expanded as a percentage of total CD8 T cells in both HIV− and CMV-seropositive individuals. Bulk memory CD8dim T cells expressed significantly higher CD69 and less MHC Class I and CD127 ex vivo than CD8bright T cells, suggesting recent activation. CD8dim T cells expressed less GLUT1 and PGC-1α and took up less glucose (2-NBDG) and lipid (Bodipy) than CD8bright T cells, indicating relatively lower metabolic activity. Multimer reactivity was used to examine CMV-, EBV- and HIV-specific CD8 T cells ex vivo. Virus-specific populations were consistently CD8high. However, after peptide stimulation, antigen-specific CD8 T cells down-regulated CD3 and CD8. CMV-specific CD8 T cells down-regulated CD3 and CD8 more than HIV-specific cells. CD3 and CD8 downregulation were strongly correlated with the functional avidity of the response. A strong correlation between GLUT1 down-regulation and CD8 down-regulation was also observed, suggesting an association between CD8 expression and metabolic activity. These results suggest that the expanded CD8dim population in HIV+ cART individuals, who are >90% CMV-seropositive, may be driven by ongoing activation of high-avidity CMV-specific CD8 T cells. They also suggest that different virus-specific CD8 T cell populations differentially downregulate components of the TCR complex and metabolism after antigen stimulation, possibly to avoid excessive activation.
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Picker, Louis J., Andrew W. Sylwester, Bridget L. Mitchell, Cara Taormina, Christian Pelte, John Edgar, Florian Kern, et al. "T Cell Recognition of HCMV: Pan-Genome Analysis of Immunogenic Open-Reading Frames." Blood 104, no. 11 (November 16, 2004): 606. http://dx.doi.org/10.1182/blood.v104.11.606.606.
Повний текст джерелаАнотація:
Abstract Human Cytomegalovirus (HCMV) is among the largest and most complex of known viruses with 150–200nm virions enclosing a double stranded 230kb DNA genome capable of coding for >200 proteins. HCMV infection is life-long, and for the vast majority of immune competent individuals clinically benign. Disease occurs almost exclusively in the setting of immune deficiency, suggesting that the stable host-parasite relationship that characterizes these infections is the result of an evolutionarily “negotiated” balance between viral mechanisms of pathogenesis and the host immune response. In keeping with, and perhaps because of this balance, the human CD4+ T cell response to whole HCMV viral lysates is enormous, with median peripheral blood frequencies of HCMV-specific cells ~5–10 fold higher than for analogous preparations of other common viruses. Although certain HCMV ORFs have been identified as targets of either the CD4+ or CD8+ T cell response, the specificities comprising the CD4+ T cell response, and both the total frequencies and component parts of the CD8+ T cell response are unknown. Here, we used cytokine flow cytometry and ~14,000 overlapping 15mer peptides comprising all 213 HCMV ORFs encoding proteins >100 amino acids in length to precisely define the total CD4+ and CD8+ HCMV-specific T cell responses and the HCMV ORFs responsible for these responses in 33 HCMV-seropositive, HLA-disparate donors. An additional 9 HCMV seronegative donors were similarly examined to define the extent to which non-HCMV responses cross-react with HCMV-encoded epitopes. We found that when totaled, the median frequencies of HCMV-specific CD4+ and CD8+ T cells in the peripheral blood of the seropositive subjects were 4.0% and 4.5% for the total CD4+ or CD8+ T cell populations, respectively (which corresponds to 9.1% and 10.5% of the memory populations, respectively). The HCMV-specific CD4+ and CD8+ T cell responses included a median 12 and 7 different ORFs, respectively, and all told, 73 HCMV ORFs were identified as targets for both CD4+ and CD8+ T cells, 26 ORFs as targets for CD8+ T cells alone, and 43 ORFS as targets for CD4+ T cells alone. UL55, UL83, UL86, UL99, and UL122 were the HCMV ORFs most commonly recognized by CD4+ T cells; UL123, UL83, UL48, UL122 and UL28 were the HCMV ORFs most commonly recognized by CD8+ T cells. The relationship between immunogenicity and 1) HLA haplotype and 2) ORF expression and function will be discussed. HCMV-seronegative individuals were non-reactive with the vast majority of HCMV peptides. Only 7 potentially cross-reactive responses were identified (all by CD8+ T cells) to 3 ORFs (US32, US29 and UL116) out of a total of almost 4,000 potential responses, suggesting fortuitous cross-reactivity with HCMV epitopes is uncommon. These data provide the first glimpse of the total human T cell response to a complex infectious agent, and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.
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Federico, Lorenzo, Cara L. Haymaker, Marie-Andree Forget, Andrea Ravelli, Ankit Bhatta, Tatiana Karpinets, Ran Zhang, et al. "A preclinical study of tumor-infiltrating lymphocytes in NSCLC." Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): 161. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.161.
Повний текст джерелаАнотація:
161 Background: Multiple clinical studies have shown that adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) is remarkably effective in melanoma patients. Non-small cell lung cancer (NSCLC) shares similarities with melanoma in terms of mutational burden and sensitivity to immune checkpoint inhibitors. We therefore sought to test whether TIL ACT may represent a viable option for the treatment of NSCLC patients. We utilized tissue collected from patients enrolled on the prospective ImmunogenomiC prOfiling of Non-small cell lung cancer (ICON) study. Methods: TIL and tissue-infiltrating lymphocytes were expanded ex vivo from 97 freshly resected early-stage localized NSCLC tumors and 39 matched uninvolved lung tissues. Growth and functional characteristics of TIL were assessed via flow cytometry, TIL-tumor reactivity assays, and analysis of TCRβ sequencing data. Results: NSCLC showed an increased proportion of CD3+ lymphocytes within the tumor-infiltrating leukocyte component as compared to matched normal lung tissue. The TIL compartment included a suppressed CD8+ T cell subset expressing significantly higher levels of PD-1 and lacking cytolytic potential compared to T cells expanded from normal tissue. TIL contained a higher proportion of proliferating (Ki67+) CD8+CD103+ tissue-resident memory (TRM) cells expressing activation markers such as CTLA4, LAG3, PD1 and ICOS, and increased CD4+ Tregs. Despite a highly immunosuppressive environment, TIL expansion was achieved with a success rate of 68% (n = 97) but appeared hindered in patients undergoing neoadjuvant chemotherapy treatment prior to surgery (56.2%, n = 16 vs 72.5% success rate in therapy-naïve patients). In addition, expansion efficiency (number expanded and time of culture) of TIL and matched lung residing lymphocytes were significantly associated (r = 0.379, p = 0.017, n = 39). Importantly, expanded CD8+ TIL products were oligoclonal and showed reactivity toward autologous tumors. Conclusions: Although NSCLC TIL are functionally inhibited in vivo they can be successfully expanded ex vivo and demonstrate recognition of autologous tumor cells. These data suggest that TIL can potentially be used for adoptive T cell-based immunotherapy in NSCLC.
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Li, Han Xu, Xiang Cao, and Yong Xin Tang. "Study of Effect of Ternary-Component Blended Coal on Coal Gasification Reaction at High Temperature." Applied Mechanics and Materials 295-298 (February 2013): 3104–9. http://dx.doi.org/10.4028/www.scientific.net/amm.295-298.3104.
Повний текст джерелаАнотація:
Three typical Chinese individual coals which existed remarkable difference on coal ash chemical composition and ash fusion temperature were selected to carry out coal blending experiments to study the coal gasification reaction at high temperature by means of using ternary-component blended coal technique and TGA-DTA method. According to ternary-component blended coal with a certain proportion, ash chemical composition and coal-char/CO2 gasification reactivity were analyzed by X-ray fluorescence (XRF) and thermogravimetric analysis-derivative thermogravimetric analysis (TGA-DTG), respectively. The results show that the ash chemical components change because ternary-component blended coals change the mineral composition, and hence, the gasification reactivity can be affected as well. Moreover, in accordance with reactivity index R, it indicates that the order of gasification reactivity of three individual coals and four blended coal options is coal x > option B > option A > option D > option C > coal z >coal y. Meanwhile, a new mathematical model called per unit ash alkali index B* was established by using the ash chemical component dates, which has a good corresponding relationship with R for four blending coal options. Utilizing ternary-component blended coal technique could improve the high-temperature coal ash gasification reaction.
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Ge, Wei, Jun Chen, Fanfei Min, Shaoxian Song, and Hui Liu. "Potential Evaluation for Preparing Geopolymers from Quartz by Low-Alkali Activation." Materials 16, no. 4 (February 13, 2023): 1552. http://dx.doi.org/10.3390/ma16041552.
Повний текст джерелаАнотація:
Alkali fusion of granite sawdust at a high alkali dosage can significantly improve geopolymerization activity, but also result in a high alkali consumption and a poor geopolymer performance. In this work, quartz, the most inert component in granite sawdust, was selected to explore the effect of low-alkali activation on its reactivity and the compressive strength of geopolymer. It was found that the amount of activated quartz is mainly determined by the amount of alkali used for activation. The surface of a quartz particle can be effectively activated by an alkali fusion process at a low alkali dosage of 5%. The metakaolin-based geopolymer synthesized with quartz activated by an alkali dosage of 5% shows a high compressive strength of 41 MPa, which can be attributed to the enhanced interfacial interaction between quartz and the geopolymer gel, suggesting that low-alkali activation is a potential way to improve the geopolymerization ability of granite sawdust.
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Lochmann, Lubomír, and Jiří Trekoval. "Lithium - Heavier alkali metal exchange in organolithium compounds induced by alkoxides of heavier alkali metals and reactions occurring in this system." Collection of Czechoslovak Chemical Communications 53, no. 1 (1988): 76–96. http://dx.doi.org/10.1135/cccc19880076.
Повний текст джерелаАнотація:
Organolithium compounds of various types undergo an exchange reaction lithium-heavier alkali metal when treated with heavier alkali metal alkoxides. In the presence of a third reactive compound the exchange reaction gives rise to a compound of the third component substituted with the heavier alkali metal. Using this exchange reaction, organic derivatives of heavier alkali metals in the individual state can be easily prepared. The mechanism of such reactions is discussed, and the formation of lithium alkoxide is assumed to contribute significantly to the driving force of the reaction. Organic compounds of heavier alkali metals possess a considerably higher reactivity than organolithium compounds, and are therefore used as reactive intermediates in preparative chemistry, or as polymerization initiators in macromolecular chemistry. This review provides information about the scope and possibilities of this exchange reaction, which has been increasingly widely used in the recent years.
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Martínez Gómez, Julia, LinFa Wang, and Sylvie Alonso. "Deciphering the adaptive immune system of bats (VET2P.1131)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 147.3. http://dx.doi.org/10.4049/jimmunol.194.supp.147.3.
Повний текст джерелаАнотація:
Abstract Bats are natural reservoirs for several viruses, many of which cause morbidity and high mortality rates in other mammals, including humans but they generally don’t cause disease in bats. In fact, fruit bats have been found to be the principal suspect that initiated the latest 2014 West-Africa Ebola outbreak. How bats cope with such deadly viruses without getting sick remains unknown. Efforts are being increasingly devoted to dissect the bat’s immune system, however, due to the lack of reagents progress has been limited. Our group is focusing on characterizing bats adaptive immunity. The first step consists of generating a systematic knowledge on the various immune cell populations (T and B cells mainly). Subsequently, functional assays will be optimized to study how bats adaptive immunity reacts to viral infections. Screening of human and mouse antibodies against the main components of the bats adaptive immunity revealed poor cross-reactivity to T and B cell main surface markers (CD3, CD4, CD8, CD19). Combining flow cytometry and real-time PCR approaches, we have been able to characterize different T cell subset populations present in bats spleen and blood. Understanding how bats control viral infection can provide important insights into anti-viral strategies that may result in the development of new therapeutics for other mammals
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Lee, Justin S., Jason M. Goldstein, Jonathan L. Moon, Owen Herzegh, Dennis A. Bagarozzi, M. Steven Oberste, Heather Hughes, et al. "Analysis of the initial lot of the CDC 2019-Novel Coronavirus (2019-nCoV) real-time RT-PCR diagnostic panel." PLOS ONE 16, no. 12 (December 15, 2021): e0260487. http://dx.doi.org/10.1371/journal.pone.0260487.
Повний текст джерелаАнотація:
At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention (CDC) designed, manufactured, and distributed the CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel for SARS-CoV-2 detection. The diagnostic panel targeted three viral nucleocapsid gene loci (N1, N2, and N3 primers and probes) to maximize sensitivity and to provide redundancy for virus detection if mutations occurred. After the first distribution of the diagnostic panel, state public health laboratories reported fluorescent signal in the absence of viral template (false-positive reactivity) for the N3 component and to a lesser extent for N1. This report describes the findings of an internal investigation conducted by the CDC to identify the cause(s) of the N1 and N3 false-positive reactivity. For N1, results demonstrate that contamination with a synthetic template, that occurred while the “bulk” manufactured materials were located in a research lab for quality assessment, was the cause of false reactivity in the first lot. Base pairing between the 3’ end of the N3 probe and the 3’ end of the N3 reverse primer led to amplification of duplex and larger molecules resulting in false reactivity in the N3 assay component. We conclude that flaws in both assay design and handling of the “bulk” material, caused the problems with the first lot of the 2019-nCoV Real-Time RT-PCR Diagnostic Panel. In addition, within this study, we found that the age of the examined diagnostic panel reagents increases the frequency of false positive results for N3. We discuss these findings in the context of improvements to quality control, quality assurance, and assay validation practices that have since been improved at the CDC.
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Lundgren, Anna, Christina Trollmo, Anders Edebo, Ann-Mari Svennerholm, and B. Samuel Lundin. "Helicobacter pylori-Specific CD4+ T Cells Home to and Accumulate in the Human Helicobacter pylori-Infected Gastric Mucosa." Infection and Immunity 73, no. 9 (September 2005): 5612–19. http://dx.doi.org/10.1128/iai.73.9.5612-5619.2005.
Повний текст джерелаАнотація:
ABSTRACT Helicobacter pylori infects the stomach and duodenal mucosa. T cells are important components of the H. pylori-induced immune response, but little is currently known about how these cells are recruited to the infected mucosa. Here, we have characterized stomach and duodenal T cells isolated from H. pylori-infected and noninfected subjects with regard to subtype, expression of homing and chemokine receptors, and in vitro reactivity to H. pylori antigens. Higher numbers of CD4+ but similar numbers of CD8+ lamina propria T cells were isolated from stomach biopsies from H. pylori-positive compared to H. pylori-negative individuals. CD4+ T cells from infected stomach expressed increased levels of the homing receptor L-selectin and the chemokine receptor CCR4 compared to CD4+ T cells from uninfected stomach. Infected stomach mucosa also contained increased levels of the CCR4 chemokine ligand MDC/CCL22. In contrast, comparable numbers of CD4+ T cells with similar receptor expression were isolated from the duodenum of H. pylori-positive and H. pylori-negative individuals. In vitro proliferation of mucosal T cells was strongly enhanced by the addition of interleukin-2 (IL-2) and IL-7 to the cell cultures. Using this approach, H. pylori-specific T-cell responses were detected in stomach CD4+ T cells from H. pylori-positive but not H. pylori-negative individuals. Duodenal T cells from only a few individuals responded to H. pylori stimulation, and the responsiveness was not restricted to H. pylori-positive individuals, suggesting limited H. pylori specificity in the duodenum and possible cross-reactivity with antigens from other bacteria in this compartment. In conclusion, these results suggest that H. pylori-specific CD4+ T cells preferentially home to and accumulate in the infected stomach and that L-selectin and CCR4/MDC are important for this recruitment.
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Harinath, Adimulam, Jayeeta Bhattacharjee, Srinivas Anga, and Tarun K. Panda. "Dehydrogenative Coupling of Hydrosilanes and Alcohols by Alkali Metal Catalysts for Facile Synthesis of Silyl Ethers." Australian Journal of Chemistry 70, no. 6 (2017): 724. http://dx.doi.org/10.1071/ch16537.
Повний текст джерелаАнотація:
Cross-dehydrogenative coupling (CDC) of hydrosilanes with hydroxyl groups, using alkali metal hexamethyldisilazide as a single-component catalyst for the formation of Si–O bonds under mild condition, is reported. The potassium salt [KN(SiMe3)2] is highly efficient and chemoselective for a wide range of functionalized alcohols (99 % conversion) under solvent-free conditions. The CDC reaction of alcohols with silanes exhibits first-order kinetics with respect to both catalyst and substrate concentrations. The most plausible mechanism for this reaction suggests that the initial step most likely involves the formation of an alkoxide followed by the formation of metal hydride as active species.
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McMenamin, C., and P. G. Holt. "The natural immune response to inhaled soluble protein antigens involves major histocompatibility complex (MHC) class I-restricted CD8+ T cell-mediated but MHC class II-restricted CD4+ T cell-dependent immune deviation resulting in selective suppression of immunoglobulin E production." Journal of Experimental Medicine 178, no. 3 (September 1, 1993): 889–99. http://dx.doi.org/10.1084/jem.178.3.889.
Повний текст джерелаАнотація:
The immunological basis for atopy is currently ascribed to an inherent bias in the CD4+ T cell response to nonreplicating antigens presented at mucosal surfaces, resulting in dominance of the T helper 2 (Th2) interleukin 4 (IL-4)-producing phenotype, which favors IgE production. In contrast, the "normal" response to such antigens involves a predominance of interferon gamma (IFN-gamma)-producing Th1 clones. This difference has been suggested to be the result of active selection in atopics for Th2 (and hence against Th1) clones at the time of initial antigen presentation. In the study below, we demonstrate that the natural immune response to inhaled protein antigens, particularly in animals expressing the low immunoglobulin E (IgE) responder phenotype, includes a major histocompatibility complex (MHC) class I-restricted CD8+ T cell component, the appearance of which is associated with active suppression of IgE antibody production. Thus, continued exposure of rats to aerosolized ovalbumin (OVA) antigen elicits a transient IgE response, that is terminated by the onset of a state of apparent "tolerance" to further challenge, and this tolerant state is transferable to naive animals with CD8+ T cells. Kinetic studies on in vitro T cell reactivity in these aerosol-exposed rats demonstrated biphasic CD4+ Th2 responses which terminated, together with IgE antibody production, and coincident with the appearance of MHC class I-restricted OVA-specific IFN-gamma-producing CD8+ T cells. However, the latter were not autonomous in vitro and required a source of exogenous IL-2 for initial activation, which in CD(8+)-enriched splenocyte cultures could be provided by small numbers of contaminating OVA-specific CD4+ T cells. This represents the first formal evidence for the induction of an MHC class I-restricted T cell response to natural mucosal exposure to an inert protein antigen, and is consistent with a growing literature demonstrating sensitization of MHC class I-restricted CD8+ T cells by deliberate immunization with soluble proteins. We suggest that crossregulation of MHC class II-restricted CD4+ T cells via cytokine signals generated in parallel CD8+ T cell responses represents a covert and potentially important selection pressure that can shape the nature of host responses to nonreplicating antigens presented at mucosal surfaces.
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Saitoh, T., Y. Ikarashi, S. Ito, H. Watanabe, M. Fujiwara, and H. Asakura. "Depletion of CD8+ cells exacerbates organ-specific autoimmune diseases induced by CD4+ T cells in semiallogeneic hosts with MHC class II disparity." Journal of Immunology 145, no. 10 (November 15, 1990): 3268–75. http://dx.doi.org/10.4049/jimmunol.145.10.3268.
Повний текст джерелаАнотація:
Abstract Autoimmune diseases are known to be induced in some donor-recipient combinations of mice undergoing the graft-vs-host reaction (GVHR). In this paper, we report on the development of primary biliary cirrhosis (PBC)-like hepatic lesions and also on pancreatic insulitis in (B6 x bm12)F1 mice injected with B6 CD4+ T cells. At the sites of these lesions, cellular infiltration around ductal structure was observed. Immunohistochemical studies revealed that both CD4+ and CD8+ T cells were present in the lesions of the liver and pancreas. To clarify the role of the CD8+ T cells, which were probably of host origin, we used a mAb against the Lyt-2 molecule. Both the PBC-like hepatic lesions and pancreatic insulitis were exacerbated by eliminating CD8+ T cells from mice with MHC class II GVHR. Also, autoantibodies against the pyruvate dehydrogenase-E2 component, which has been recently found to contain an immunodominant site (autoepitope) for B cell reactivity in patients with PBC, were detected in the sera of these mice by ELISA and their presence was confirmed by immunoblotting procedures. Our findings suggest that similar mechanisms as in GVHR caused by MHC class II disparity are active in the development of PBC. It should also be noted that, in addition to the hepatic lesions, insulitis closely resembling that seen in the nonobese diabetic mouse was induced in our experimental system. The results suggest that our model provides a unique opportunity to study organ-specific autoimmune diseases. Because the effector in our experimental system was defined to be CD4+ T cells responding to Iabm12 Ag, our findings support the hypothesis that an excessive immune response directed against Ia Ag can produce autoimmune disease.
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Loeser, Stefanie, Karin Loser, Martijn S. Bijker, Manu Rangachari, Sjoerd H. van der Burg, Teiji Wada, Stefan Beissert, Cornelis J. M. Melief, and Josef M. Penninger. "Spontaneous tumor rejection by cbl-b–deficient CD8+ T cells." Journal of Experimental Medicine 204, no. 4 (April 2, 2007): 879–91. http://dx.doi.org/10.1084/jem.20061699.
Повний текст джерелаАнотація:
The concept of tumor surveillance implies that specific and nonspecific components of the immune system eliminate tumors in the early phase of malignancy. Understanding the biochemical mechanisms of tumor immunosurveillance is of paramount significance because it might allow one to specifically modulate spontaneous antitumor activity. We report that inactivation of the E3 ligase Casitas B cell lymphoma-b (Cbl-b) confers spontaneous in vivo rejection of tumor cells that express human papilloma virus antigens. Moreover, cbl-b−/− mice develop significantly fewer ultraviolet B (UVB)–induced skin malignancies and reject UVB-induced skin tumors. CD8+ T cells were identified as key players in the spontaneous tumor rejection response. Loss of Cbl-b not only enhances antitumor reactivity of CD8+ T cells but also occurs in the absence of CD4+ T cells. Mechanistically, cbl-b−/− CD8+ T cells are resistant to T regulatory cell–mediated suppression and exhibit enhanced activation and rapid tumor infiltration. Importantly, therapeutic transfer of naive cbl-b−/− CD8+ T cells is sufficient to mediate rejection of established tumors. Even up to 1 yr after the first encounter with the tumor cells, cbl-b−/− mice carry an “anticancer memory.” These data identify Cbl-b as a key signaling molecule that controls spontaneous antitumor activity of cytotoxic T cells in different cancer models. Inhibition of Cbl-b is a novel approach to stimulate long-lasting immunity against cancer.
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Ma, Yiwei, Yuwei Lu, Keith Petrofsky, Roger Ruan, and Chi Chen. "Metabolomics Profiling Revealed Double-Edged Metabolic Effects of Functionalized Wheat Bran in Mouse." Current Developments in Nutrition 5, Supplement_2 (June 2021): 346. http://dx.doi.org/10.1093/cdn/nzab037_056.
Повний текст джерелаАнотація:
Abstract Objectives Wheat bran is rich in bioactive components, mainly dietary fiber, micronutrients, and phytochemical contents. However, the health-promoting effects of wheat bran is restricted by the high-degree crosslinking of dietary fiber and low bioavailability of phytochemicals. The present study aims to improve the functions of wheat bran by increasing the levels of soluble fiber and free ferulic acid from optimized processing to examine the metabolic effects of consuming functionalized wheat bran (FWB) in mice. Methods Control wheat bran (CWB) was processed by an optimized combination of milling, high pressure pulverization, and alkali treatment, leading to dramatic increases of soluble fiber and free ferulic acid. Three groups of male mice were fed the control AIN93G diet, and two modified AIN93G diets containing 10% of CWB and 10% FWB, respectively, for 7 days. The effects of CWB and FWB on the mouse metabolome were determined through the LC-MS based metabolomics analysis of feces, liver, serum, and urine samples. Results The processing dramatically improved the function-associated physicochemical properties of wheat bran, including the increases of soluble fiber content and viscosity by milling and high-pressure pulverization and the elevation of free ferulic acid by alkali treatment. FWB feeding elevated microbial SCFAs production, promoted the excretion of bile acids and cholesterol in feces, modified the lipidome in the liver, decreased triacylglycerols and cholesterol in serum, and increased the levels of ferulic acid and microbial metabolites in urine. On the other hand, FWB feeding resulted in the increases of free amino acids in feces and the decreases of essential amino acids, choline and its metabolites in the liver. Conclusions The optimized processing dramatically increased the soluble fiber and free ferulic acid contents of wheat bran, resulting in improved hypocholesterolemic and antioxidant functions of FWB. However, the bioavailability of nutrients, including essential amino acids and choline, and the homeostasis of lipidome could be negatively affected by FWB diet. These double-edged metabolic effects warrant further investigations on how to achieve the balance between the functionalization of bioactive components and the disruption of nutrient bioavailability in wheat bran processing. Funding Sources NIFA project MIN-18–125.
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Hergenrother, William L., Ashley S. Hilton, and Chenchy J. Lin. "Model Reaction of Polysulfide with Olefin." Rubber Chemistry and Technology 77, no. 4 (September 1, 2004): 646–61. http://dx.doi.org/10.5254/1.3547842.
Повний текст джерелаАнотація:
Abstract A model polysulfide, t-butyl polysulfide (TBPS) and an olefin, cyclododecene (CDD), were used to study the reactivity of polysulfanes in silica filled rubbers. The TBPS has a similar sulfur rank and distribution as bis (3-triethoxysilylpropyl) tetrasulfide (TESPT) without the complication of reactivity of the triethoxysilyl group that would cause a loss of soluble components of the reactants and products by hydrolytic coupling. Thermal reaction between the polysulfide and olefin was investigated by following the TBPS loss in the CDD solution at 171 °C as a function of time. The loss of TBPS and the formation of reaction products during heating were followed, identified and quantified using HPLC. These include attachment of t-butyl sulfide group from the TBPS to CDD, coupling between CDD, and redistribution of the sulfur rank. It was found that after six minutes, less than 2 weight % of the sulfur in the TBPS was utilized to couple CDD molecules. Since these thermal conditions are more severe than what a rubber compound is normally subjected to, this sulfur coupling would not be expected to give a vulcanization problem during mixing. The model reaction was also followed in the presence of added peroxide or typical vulcanization ingredients. The strongest catalytic effect was seen with N-cyclohexyl-2-benzothiazolesulfenamide and zinc oxide.
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xu, Huifang. "Surface Characters of Interfaces and Twin Domains: TEM and AFM Study of a Feldspar Crystal." Microscopy and Microanalysis 3, S2 (August 1997): 1265–66. http://dx.doi.org/10.1017/s1431927600013210.
Повний текст джерелаАнотація:
Alkali feldspar, a framework silicate (K, Na)(Si3Al)04, is a common component in ceramic materials. The feldspar crystals commonly display exsolution lamellae, twins, and modulated structures. The boundaries between neighboring domains may cause stain energy. The domain structures cause heterogeneities both inside crystals and on crystal surfaces in aspects of structure, composition, and surface microtopography. Reactivity at domain boundary positions is different from the neighboring areas. More and more studies show the effects of microtopography on the surface reactivity. It is important to reveal the surface characters or microtopography of domain structures in crystals, and their effects on local reactivity.Results from transmission electron microscopy (TEM) characterization show it contains exsolution lamellae (both K-rich and Na-rich lamellae) and twin domains in the Na-rich lamellae (Fig. 1A). Its SAED pattern shows reflections from both K-rich and Na-rich lamellae (Fig. B). Splitted reflections result from the Na-rich lamellae wiht twin domains related by (010) mirror plane, i.e., albite twin law.
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Malkani, A. S., J. Li, N. J. Oliveira, M. He, X. Chang, B. Xu, and Q. Lu. "Understanding the electric and nonelectric field components of the cation effect on the electrochemical CO reduction reaction." Science Advances 6, no. 45 (November 2020): eabd2569. http://dx.doi.org/10.1126/sciadv.abd2569.
Повний текст джерелаАнотація:
Electrolyte cations affect the activity of surface-mediated electrocatalytic reactions; however, understanding the modes of interaction between cations and reaction intermediates remains lacking. We show that larger alkali metal cations (excluding the thickness of the hydration shell) promote the electrochemical CO reduction reaction on polycrystalline Cu surfaces in alkaline electrolytes. Combined reactivity and in situ surface-enhanced spectroscopic investigations show that changes to the interfacial electric field strength cannot solely explain the reactivity trend with cation size, suggesting the presence of a nonelectric field strength component in the cation effect. Spectroscopic investigations with cation chelating agents and organic molecules show that the electric and nonelectric field components of the cation effect could be affected by both cation identity and composition of the electrochemical interface. The interdependent nature of interfacial species indicates that the cation effect should be considered an integral part of the broader effect of composition and structure of the electrochemical interface on electrode-mediated reactions.
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Schwartz, Jennifer A., Ilia Prado, Johnathan Misamore, Deborah Weiss, Jesse Francis, Ranajit Pal, Maria Huaman, et al. "An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques." Clinical and Vaccine Immunology 23, no. 7 (May 18, 2016): 618–27. http://dx.doi.org/10.1128/cvi.00115-16.
Повний текст джерелаАнотація:
A promising concept for human immunodeficiency virus (HIV) vaccines focuses immunity on the highly conserved transition state structures and epitopes that appear when the HIV glycoprotein gp120 binds to its receptor, CD4. We are developing chimeric antigens (full-length single chain, or FLSC) in which gp120 and CD4 sequences are flexibly linked to allow stable intrachain complex formation between the two moieties (A. DeVico et al., Proc Natl Acad Sci U S A 104:17477–17482, 2007, doi:10.1073/pnas.0707399104; T. R. Fouts et al., J Virol 74:11427–11436, 2000,doi:10.1128/JVI.74.24.11427-11436.2000). Proof of concept studies with nonhuman primates show that FLSC elicited heterologous protection against simian-human immunodeficiency virus (SHIV)/simian immunodeficiency virus (SIV) (T. R. Fouts et al., Proc Natl Acad Sci U S A 112:E992–E999, 2016,doi:10.1073/pnas.1423669112), which correlated with antibodies against transition state gp120 epitopes. Nevertheless, advancement of any vaccine that comprises gp120-CD4 complexes must consider whether the CD4 component breaks tolerance and becomes immunogenic in the autologous host. To address this, we performed an immunotoxicology study with cynomolgus macaques vaccinated with either FLSC or a rhesus variant of FLSC containing macaque CD4 sequences (rhFLSC). Enzyme-linked immunosorbent assay (ELISA) binding titers, primary CD3+T cell staining, and temporal trends in T cell subset frequencies served to assess whether anti-CD4 autoantibody responses were elicited by vaccination. We find that immunization with multiple high doses of rhFLSC did not elicit detectable antibody titers despite robust responses to rhFLSC. In accordance with these findings, immunized animals had no changes in circulating CD4+T cell counts or evidence of autoantibody reactivity with cell surface CD4 on primary naive macaque T cells. Collectively, these studies show that antigens using CD4 sequences to stabilize transition state gp120 structures are unlikely to elicit autoimmune antibody responses, supporting the advancement of gp120-CD4 complex-based antigens, such as FLSC, into clinical testing.
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Capitini, Christian M., Martin Guimond, Crystal L. Mackall, and Terry J. Fry. "GVHD Abrogates T Cell Responses to Dendritic Cell Vaccines but Not Vaccine-Induced Proliferation." Blood 110, no. 11 (November 16, 2007): 1802. http://dx.doi.org/10.1182/blood.v110.11.1802.1802.
Повний текст джерелаАнотація:
Abstract BACKGROUND: Allogeneic bone marrow transplant (BMT) is a potent form of immunotherapy against hematopoietic and potentially solid tumors, but relapse of malignancy and Graft versus Host Disease (GVHD) remain a major cause of morbidity and mortality. Dendritic cell (DC) vaccines represent a potential strategy to enhance the potency and efficacy of the Graft versus Tumor (GVT) effect without exacerbating GVHD, but little is known regarding the impact of the allogeneic BMT environment on vaccine responses. Previous work in our lab has shown that DC can effectively expand tumor-antigen specific T cells following minor-mismatched allogeneic transplantation, resulting in delay of tumor growth. However, GVHD completely abrogates these responses. We hypothesized that the mechanism behind the loss of DC vaccine responses was through diminished T cell proliferation in the setting of GVHD. METHODS: We established a minor histocompatibility antigen mismatched BMT model by transplanting B6 x C3H.SW (F1) thymectomized mice with either CD45.1+ B6 (allogeneic) or CD45.1+/45.2+ F1 (syngeneic) T cell-depleted bone marrow on day 0, followed by a donor lymphocyte infusion at day 14 to induce GVHD. On day 28, we adoptively transferred transgenic CD8+ (CD45.2, V beta 8.3+) or CD4+ (CD45.2, V beta 6+) T cells that only recognize components of the HY antigen to avoid cross-reactivity with allogeneic antigens. The T cells were labeled with CFSE prior to transfer to explore the impact of vaccine-induced proliferation in the presence or absence of GVHD. RESULTS: In the allogeneic BMT setting, both CD8+ and CD4+ HY-transgenic T cells given with a DC vaccine begin proliferating 5 days (CD8+ 40%, CD4+ 65% divided) after adoptive transfer. The syngeneic BMT vaccinated control mice show similar kinetics (CD8+ 38%, CD4+ 65% divided), suggesting GVHD does not decrease T cell proliferation. Interestingly, although HY transgenic T cells do not normally undergo homeostatic peripheral expansion (HPE) during lymphopenia, the CD4+ T cells proliferate in lymph nodes even in the absence of a vaccine (50% divided), but this was not observed in the respective syngeneic BMT unvaccinated control mice (0% divided). CONCLUSIONS: DC vaccines represent a strategy to improve the efficacy of the GVT response following allogeneic BMT, however, GVHD can abrogate DC vaccine responses. The negative impact of GVHD on vaccine responses does not appear to result from impaired DC vaccine-driven proliferation. Indeed, even in the absence of a vaccine, non-alloreactive CD4+ T cells proliferate via a mechanism that appears to be distinct from HPE. This data provides important insights towards optimizing antigen-specific vaccines administered in the allogeneic BMT setting.
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Kotsiou, Eleni, Joe Robinson, Amber Rogers, Daisy Melandri, Amy Baker, Anabel Ramirez Aragon, Sidra Nawaz, et al. "193 The Achilles VELOSTM Process 2 boosts the dose of highly functional clonal neoantigen-reactive T cells for precision personalized cell therapies." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A205. http://dx.doi.org/10.1136/jitc-2021-sitc2021.193.
Повний текст джерелаАнотація:
BackgroundAdoptive transfer of ex-vivo expanded tumor-infiltrating lymphocytes (TIL) has shown promise in the clinic. However, the non-specific expansion of TIL and the lack of understanding of the active component of TIL has resulted in poor correlation between clinical response and dose as well as poor understanding of response and resistance mechanisms. The VELOSTM manufacturing process generates a precision and personalized treatment modality by targeting clonal neoantigens with the incorporation of an antigen-specific expansion step to enrich the product for these specificities. Achilles has developed a second generation manufacturing process (VELOSTM Process 2) to boost the neoantigen-reactive cell dose while maintaining key qualitative features associated with function. Here we report the in-depth characterization of clonal neoantigen-reactive T cells (cNeT) products expanded using the two VELOSTM processes.MethodsMatched tumors and peripheral blood from patients undergoing routine surgery were obtained from patients with primary NSCLC or metastatic melanoma (NCT03517917). TIL were expanded from tumor fragments and peptide pools corresponding to the clonal mutations identified using the PELEUSTM bioinformatics platform were synthesized. cNeT were expanded by co-culture of TIL with peptide-pulsed autologous dendritic cells, with an optimized cytokine cocktail and co-stimulation for Process 2. Neoantigen reactivity was assessed using our proprietary potency assay with peptide pool re-challenge followed by intracellular cytokine staining. Single peptide reactivities were identified using ELISPOT and flow cytometric analysis for in-depth phenotyping of cNeT was performed.ResultsCD3+ T cells displayed higher fold expansion in Process 2 (median 77.4) compared to Process 1 (median 3.8)(n=5). Both processes showed similar CD3+ T cell content (median Process 1=91.3%, Process 2=96.9% n=5) and contained both CD4+ and CD8+ T cells showing reactivity to clonal neoantigens. Proportion of cells responding to neoantigen re-challenge was similar across both processes (median Process 1=19.9% and Process 2=18.2%) leading to higher reactive dose when coupled with higher T cell doses in Process 2. Phenotypically T cells were predominantly effector memory for both processes and Process 2 had lower frequencies of terminally differentiated T cells.ConclusionsAchilles’ proprietary potency assay enables the optimization of new processes that deliver high cNeT doses to patients by detecting the active drug component. We have generated proof of concept data that supports the transfer of the VELOSTM Process 2 to clinical manufacture for two first-in-human studies for the treatment of solid cancers.Ethics ApprovalThe samples for the study were collected under an ethically approved protocol (NCT03517917)
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Nessim, Christine K., Adel M. Michael, Yasmin M. Fayez, and Hayam M. Lotfy. "Novel Stability-Indicating Chemometric-Assisted Spectrophotometric Methods for the Determination of Chlordiazepoxide and Clidinium Bromide in the Presence of Clidinium Bromide’s Alkali-Induced Degradation Product." Journal of AOAC INTERNATIONAL 101, no. 3 (May 1, 2018): 714–22. http://dx.doi.org/10.5740/jaoacint.17-0096.
Повний текст джерелаАнотація:
Abstract Two simple and accurate chemometric-assisted spectrophotometric models were developed and validated for the simultaneous determination of chlordiazepoxide (CDZ) and clidinium bromide (CDB) in the presence of an alkali-induced degradation product of CDB in their pure and pharmaceutical formulation. Resolution was accomplished by using two multivariate calibration models, including principal component regression (PCR) and partial least-squares (PLS), applied to the UV spectra of the mixtures. Great improvement in the predictive abilities of these multivariate calibrations was observed. A calibration set was constructed and the best model used to predict the concentrations of the studied drugs. CDZ and CDB were analyzed with mean accuracies of 99.84 ± 1.41 and 99.81 ± 0.89% for CDZ and 99.56 ± 1.43 and 99.44 ± 1.41% for CDB using PLS and PCR models, respectively. The proposed models were validated and applied for the analysis of a commercial formulation and laboratory-prepared mixtures. The developed models were statistically compared with those of the official and reported methods with no significant differences observed. The models can be used for the routine analysis of both drugs in QC laboratories.
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Lam, Tin Sing, Marian van de Meent, J. H. Frederik Falkenburg, and Inge Jedema. "Immune Surveillance By Autoreactive Helper But Not Cytolytic T Cells Is a Common Phenomenon In Patients With Acute Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 1044. http://dx.doi.org/10.1182/blood.v122.21.1044.1044.
Повний текст джерелаАнотація:
Abstract The presence of immune surveillance as a mechanism to prevent the development of malignancies and/or to eradicate small numbers of developing tumor cells has been described by many researchers in the past. The development of an overt malignancy may therefore be seen as failure of immune surveillance. In previous studies we demonstrated the existence of autoreactive CD4 T cells showing HLA-restricted reactivity against myeloid cells as a common phenomenon in healthy individuals. These autoreactive T cells show a profound cytokine response, but do not exert significant cytotoxic effects. To investigate whether such autoreactive T cell responses could play a role in immune surveillance against myeloid malignancies, we investigated the functional reactivity and cell lineage specificity of autologous T cell responses mounted against mature acute myeloid leukemia (AML) blasts. T cells were isolated using the pan T isolation kit and magnetic bead separation (MACS) from peripheral blood of patients with AML in remission after induction chemotherapy and labeled with the fluorescent dye PKH26. These T cells were stimulated with autologous AML blasts at a 1/2 responder to stimulator ratio and cultured for 14 days in medium containing heat-inactivated human serum and 1 ng/mL IL7 and 0.01 ng/mL IL-15 (Miltenyi). At day 14, proliferating CD4 and CD8 T cells comprising 7.3% +/- 2.5% and 0.8 +/- 0.5% of the total T cell populations, respectively, were isolated single cell/well using flowcytometric cell sorting based on PKH dilution. T cell clones were expanded and tested against a panel of autologous and HLA-matched or HLA-mismatched allogeneic target cells, comprising AML blasts, EBV-LCL, monocytes, monocyte-derived dendritic cells (DCs), B cells and primary skin fibroblasts. The isolated CD4 clones produced interferon-gamma (IFNg) and/or interleukin 4 (IL-4) in response to stimulation with autologous AML blasts. This cytokine production could be blocked using pan-HLA-class-II and allele-specific blocking antibodies. HLA-DR, -DP, as well as –DQ restricted clones were found and these clones displayed an oligoclonal T cell receptor V-beta (TCR-VB) usage. Interestingly, these clones exerted also reactivity against autologous EBV-LCL, monocytes, DCs, HLA-class II expressing (IFNg pretreated) fibroblasts and to a lesser extend against autologous B cells, as well as to the same target cell populations (including AML blasts) obtained from allogeneic third party individuals that were matched for the HLA-molecules presenting the T cell epitopes. These results indicate recognition of common antigens, not restricted to the malignant cell populations. No reactivity was observed against HLA-mismatched target cells. In addition, a limited number of CD8 clones was isolated that showed a similar HLA-restricted cytokine production profile. Similar experiments were performed in serumfree X-vivo15 medium to exclude recognition of serum components. In contrast to the profound cytokine response, none of the isolated clones exerted substantial cytotoxicity against one of the targets. Some CD8 clones exerted a maximum of 17% lysis at a 10/1 effector to target ratio against AML blasts. Since no direct cytotoxicity by the autoreactive T cells could be demonstrated, we investigated whether crosstalk between the autoreactive T cells and the AML blasts may render the AML cells more sensitive to subsequent immune attack. The expression of costimulatory markers (CD40, CD80 and CD86) and adhesion (ICAM-1 /CD54) on the AML blasts was significantly increased after co-incubation with the autoreactive T cells. Similar AML responsive autoreactive T cell clones were obtained using T cells from HLA-matched healthy donors as responder cells, illustrating that these autoreactive T cells are part of the normal T cell repertoire and were not induced by the high dose chemotherapy that the patients had been subjected to. In conclusion, we here demonstrate that the presence of autoreactive helper T cells is a common phenomenon in patients with AML. We hypothesize that the large burden of myeloid cells at presentation of AML may result in the amplification of an autoreactive AML directed CD4 T cell response. This response does not result in a direct effective anti-AML immune surveillance, but the immune-modulatory effect on the AML phenotype upon crosstalk may pave the way for other immunological interventions. Disclosures: No relevant conflicts of interest to declare.
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Arndt, Claudia, Anja Feldmann, Stefanie Koristka, Irene Michalk, Marc Cartellieri, Slava Stamova, Malte von Bonin, Martin Bornhäuser, Gerhard Ehninger, and Michael Bachmann. "Redirection of Immune Effector Cells by Bispecific Antibody Systems for the Treatment of Acute Myeloid Leukemia." Blood 118, no. 21 (November 18, 2011): 1528. http://dx.doi.org/10.1182/blood.v118.21.1528.1528.
Повний текст джерелаАнотація:
Abstract Abstract 1528 Acute myeloid leukemia (AML) is the most common diagnosed cancer affecting the myeloid line of immune cells in adults. Although chemotherapy initially leads to a remission of the disease in 60–80% of the cases, an enormous number of these patients (50–80%) relapse. Hence, new adjuvant therapeutic strategies for the elimination of minimal residual disease (MRD) are needed. One novel attractive approach is based on recombinant bispecific antibodies (bsAb). BsAb are able to mediate a direct cross-link between T cells and tumor cells. This in turn leads to a polyclonal, MHC- and TCR-independent activation of CD4+ and CD8+ T cells for the effective killing of the recognized target cells. A front runner in this field is the bsAb blinatumomab with dual specificity for CD3 and CD19 which is already used successfully in first clinical trials for the treatment of B-cell lymphomas. The development of a novel bsAb is usually very time-consuming and includes a series of individual optimization steps to achieve optimal reactivity with lowest possible side effects. The aim of the present work was therefore to establish a novel, more flexible, less time-consuming, modular cell targeting system and to compare its efficiency and sensitivity with classical bsAb. For the immunotargeting of AML by recombinant antibodies we selected the transmembrane glycoprotein CD33, because 90% of the AML patients have CD33-positive blasts irrespective of the underlying AML-subtype. We developed (i) a novel fully humanized bsAb with dual specificity for CD3 and CD33 and in addition (ii) a novel modular cell targeting system which consists of two different recombinant antibody components (figure 1). The first component (targeting module) is an exchangeable linker module composed of an anti-CD33 single-chain fragment variable (scFv) and a peptide epitope (E). The second component (universal effector module) is a bsAb with antigen binding specificity for the CD3-complex on T cells and for the peptide epitope of the scFv-based linker module. Together both molecules are able to form protein complexes similar to bsAb. Figure 1: Schematic representation of (i) the direct cross-linking system and (ii) the modular cell targeting system Figure 1:. Schematic representation of (i) the direct cross-linking system and (ii) the modular cell targeting system The functionality of both immunotargeting systems was examined by performing chromium (51Cr) release assays. As target cells both AML blasts from patients and artificially overexpressing CD33-positive tumor cells were used. Both the direct targeting system consisting of a classical novel humanized anti-CD33-anti-CD3 bsAb and the modular cell targeting system efficiently killed CD33-positive targets cells down to picomolar concentrations (figure 2). Figure 2: Tumor cell lysis mediated by classical bsAb and the modular cell targeting system was determined by performing a chromium release assay. For this purpose, CD33-positive, 51Cr loaded target cells were incubated with PBMCs as effector cells. Co-cultivation occurred either in the presence or absence of recombinant Ab by using an effector to target cell ratio of 10: 1 and different amounts of recombinant Abs. Figure 2:. Tumor cell lysis mediated by classical bsAb and the modular cell targeting system was determined by performing a chromium release assay. For this purpose, CD33-positive, 51Cr loaded target cells were incubated with PBMCs as effector cells. Co-cultivation occurred either in the presence or absence of recombinant Ab by using an effector to target cell ratio of 10: 1 and different amounts of recombinant Abs. Compared to the classical bsAb the novel modular cell targeting has a series of advantages: Just by replacing the targeting module the system can be easily modified for retargeting of T cells against other tumor antigens. Moreover, using linker modules with dual specificities enables a multi-specific targeting which may improve the targeting specificity and thereby might increase the success of an immunotherapy. Taken together, here we present for the first time two novel fully functional humanized, recombinant Ab-based systems for the immunotargeting of CD33+ AML blasts by CD3+ T cells. The obtained data indicate that both the direct cross-linking anti-CD3-anti-CD33 bsAb and the modular cell targeting system hold great potential as an adjuvant cancer immunotherapy for the elimination of MRD in AML-patients. Disclosures: No relevant conflicts of interest to declare.
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Cramer, EM, G. Berger, and MC Berndt. "Platelet alpha-granule and plasma membrane share two new components: CD9 and PECAM-1." Blood 84, no. 6 (September 15, 1994): 1722–30. http://dx.doi.org/10.1182/blood.v84.6.1722.1722.
Повний текст джерелаАнотація:
Abstract CD9 (p24) and PECAM1 (CD31) antigens are well-defined components of the platelet plasma membrane. Both are integral glycoproteins (GPs) implicated in the adhesive and aggregative properties of human platelets. In the present report, we have investigated their subcellular localization using immunoelectron microscopy. The monospecificity of the two polyclonal antibodies used was confirmed by immunoblotting. On normal resting platelets, immunolabeling for CD9 and PECAM1 was found lining the plasma membrane and the luminal face of the open canalicular system. Some labeling was also consistently found on the alpha-granule limiting membrane. This was confirmed by double labeling experiments in which fibrinogen and von Willebrand factor (vWF) were used as alpha-granule markers. CD9 and PECAM-1 were found lining the membrane of the same granules that contained fibrinogen and vWF in their matrix. CD9 and PECAM-1 thus appear to have an intracellular distribution identical to GPIIb-IIIa, a major aggregation platelet receptor. To rule out a cross-reactivity of the two polyclonal antibodies with GPIIb/IIIa, we studied PECAM1 and CD9 expression on the platelets from a patient with type I Glanzmann's thrombasthenia whose platelets are devoid of GPIIb/IIIa. The same pattern of labeling was observed for both antigens as for normal platelets. Normal platelets were further observed after stimulation by agonists that either fail to induce (ADP) or induce granule secretion (thrombin). After treatment with ADP, platelets changed shape and centralized their granules; the plasma membrane immunolabeling remained unchanged; and gold particles were still found decorating the periphery of the centralized alpha- granules. After thrombin treatment, alpha-granules fused with the platelet membrane and secretion occurred. A significant increase of labeling was then observed on the platelet surface. From these results we conclude that the alpha-granule membrane contains two additional receptors in common with the plasma membrane. This suggests that alpha- granule membrane receptors may originate from a dual mechanism: direct targeting from the Golgi complex in megakaryocytes (for alpha-granule- specific receptors such as P-selectin) or by endocytosis from the plasma membrane (for proteins distributed in the two compartments).
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Cramer, EM, G. Berger, and MC Berndt. "Platelet alpha-granule and plasma membrane share two new components: CD9 and PECAM-1." Blood 84, no. 6 (September 15, 1994): 1722–30. http://dx.doi.org/10.1182/blood.v84.6.1722.bloodjournal8461722.
Повний текст джерелаАнотація:
CD9 (p24) and PECAM1 (CD31) antigens are well-defined components of the platelet plasma membrane. Both are integral glycoproteins (GPs) implicated in the adhesive and aggregative properties of human platelets. In the present report, we have investigated their subcellular localization using immunoelectron microscopy. The monospecificity of the two polyclonal antibodies used was confirmed by immunoblotting. On normal resting platelets, immunolabeling for CD9 and PECAM1 was found lining the plasma membrane and the luminal face of the open canalicular system. Some labeling was also consistently found on the alpha-granule limiting membrane. This was confirmed by double labeling experiments in which fibrinogen and von Willebrand factor (vWF) were used as alpha-granule markers. CD9 and PECAM-1 were found lining the membrane of the same granules that contained fibrinogen and vWF in their matrix. CD9 and PECAM-1 thus appear to have an intracellular distribution identical to GPIIb-IIIa, a major aggregation platelet receptor. To rule out a cross-reactivity of the two polyclonal antibodies with GPIIb/IIIa, we studied PECAM1 and CD9 expression on the platelets from a patient with type I Glanzmann's thrombasthenia whose platelets are devoid of GPIIb/IIIa. The same pattern of labeling was observed for both antigens as for normal platelets. Normal platelets were further observed after stimulation by agonists that either fail to induce (ADP) or induce granule secretion (thrombin). After treatment with ADP, platelets changed shape and centralized their granules; the plasma membrane immunolabeling remained unchanged; and gold particles were still found decorating the periphery of the centralized alpha- granules. After thrombin treatment, alpha-granules fused with the platelet membrane and secretion occurred. A significant increase of labeling was then observed on the platelet surface. From these results we conclude that the alpha-granule membrane contains two additional receptors in common with the plasma membrane. This suggests that alpha- granule membrane receptors may originate from a dual mechanism: direct targeting from the Golgi complex in megakaryocytes (for alpha-granule- specific receptors such as P-selectin) or by endocytosis from the plasma membrane (for proteins distributed in the two compartments).
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D’Elia, Angela, Marina Clausi, Ana Fernández-Jiménez, Angel Palomo, Giacomo Eramo, Rocco Laviano, and Daniela Pinto. "Alkali-Activated Binary Binders with Carbonate-Rich Illitic Clay." Polymers 15, no. 2 (January 10, 2023): 362. http://dx.doi.org/10.3390/polym15020362.
Повний текст джерелаАнотація:
This work deals with the investigation of alkaline binders obtained from binary mixtures of carbonate-rich illitic clay from deposits in southern Italy and two industrial by-products with very different total composition and calcium content, i.e., blast furnace slag and type F fly ash, respectively. To improve the reactivity, the selected clay was ground in a ball miller and heated to 700 °C. The binary mixtures were alkali activated with NaOH solution at 4 M and 8 M, and the activated pastes were cured at room temperature and relative humidity >90% in a climatic chamber. Heat flow, total heat and compressive strength (2, 7 and 28 days) were determined. The hardened pastes were characterized by X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDX). Results show that the main reaction product in all samples is a gel or mixture of C-A-S-H/(N, C)-A-S-H type gel depending on the calcium content in the precursors. The paste, made up of a 1:1 weight proportion of carbonate-rich illitic clay and blast furnace slag, showed the formation of a more compact matrix than that observed in each individually activated component, achieving the considerable mechanical strength value of 45 MPa after 28 days, which suggests a very positive interaction between the two calcium-rich solid precursors. The binary mixture of carbonate-rich illitic clay and F fly ash showed relatively low compressive strength (below 15 MPa), which has been related to the poor reaction potential of fly ash regarding the alkali activation at room temperature. The modification of curing parameters is expected to improve the reaction of carbonate-rich illitic clay/fly ash blend. The clay activation method used in this study has been demonstrated to be suitable for larger scale industrial pre-treatment set-ups.
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Arif Satria Hardika, Rita Ervina, and Eviana Norahmawati. "Relationship between tumor infiltrating lymphocyte CD8+ stromal and intratumoral with grading, Estrogen Receptors (ER) and Progesterone Receptors (PR) expression in invasive breast carcinoma of no special type at Dr. Saiful Anwar General Hospital Malang." GSC Biological and Pharmaceutical Sciences 21, no. 2 (November 30, 2022): 163–71. http://dx.doi.org/10.30574/gscbps.2022.21.2.0409.
Повний текст джерелаАнотація:
Invasive breast carcinoma of no special type (IBC of NST) is a group of malignant epithelial neoplasms of the breast glands with the highest incidence of cancer in women. Tumor infiltrating lymphocytes (TIL) CD8+ is considered a group of T cells that play a role in the reactivity of specific immunity against cancer cells. TIL CD8+ group is a component that plays a role in specific adaptive immunity. TIL CD8+ infiltration in stromal tumor is related to a favorable prognosis and can predict the therapy outcome in patients. This study aims to determine the relationship between TIL CD8+ stromal and intratumoral with grading, ER and PR expression in the IBC of NST. The design of this study is analytical observational using 44 paraffin block samples in patients with IBC of NST at the Anatomical Pathology Department of Dr. Saiful Anwar Malang General Hospital by measuring TIL CD8+ expression on stromal and intratumoral, associated with grading and ER and PR expression. The results of this research showed that there is no significant relationship between histopathological grading with TIL (TIL CD8+ stromal p = 0.264, TIL CD8+ intratumoral p = 0.820), ER expression with TIL (TIL CD8+ stromal p = 0,297, TIL CD8+ intratumoral p = 0,145) and PR Expressions with TIL (TIL CD8+ stromal p = 0.240, TIL CD8+ intratumoral p = 0,003). In conclusion, there is no relationship between TIL CD8+ stromal and intratumoral with grading, expression of ER and PR in patients with IBC of NST.
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Salkova, E., M. Flajshans, and C. Steinbach. "Immunohistochemical mapping of thymic microenvironment in sterlet (Acipenser ruthenus)." Veterinární Medicína 65, No. 7 (July 10, 2020): 301–8. http://dx.doi.org/10.17221/181/2019-vetmed.
Повний текст джерелаАнотація:
In this study, we describe the immunohistochemical characterisation of the thymus, the main lymphoid organ, in sturgeon. The wide range cytokeratin, vimentin, S-100 protein, LCA (CD45) and CD3 were selected as the immunohistochemical markers to map the thymus in juvenile sterlet (Acipenser ruthenus). The epithelial cells and Hassall’s corpuscles were labelled with a wide range cytokeratin. The fibroblasts and connective tissue within the thin fibrous capsule on the thymic surface expressed vimentin positivity. The stromal reticular cells were S-100 protein positive. The Leukocyte Common Antigen LCA (CD45) was negative on the thymic lymphocytes. The CD3 was negative on the thymic lymphocytes with cross-reactivity on the non-targeted structures. In conclusion, the commercially available antibodies against the wide range cytokeratin, vimentin and S-100 protein can be used to differentiate components of the sturgeon thymus, while the LCA (CD45) and CD3 application failed. We suggest that further studies are needed to generate fish specific antibodies.
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Maugeri, Norma, Ana C. Kempfer, Virgilio Evangelista, Chiara Cerletti, Giovanni de Gaetano, and Maria A. Lazzari. "Enhanced Response to Chemotactic Activation of Polymorphonuclear Leukocytes from Patients with Heart Valve Replacement." Thrombosis and Haemostasis 77, no. 01 (1997): 071–74. http://dx.doi.org/10.1055/s-0038-1655909.
Повний текст джерелаАнотація:
SummaryArtificial surfaces activate blood components. Since anticoagulant and antiplatelet therapy fail to abolish thromboembolic complications in patients with mechanical heart valve replacement (MHVR), other mechanisms might contribute to switch on a thrombotic event. We therefore investigated the reactivity to chemotactic activation of PMN from patients with MHVR. PMN responses were analyzed in 3 groups: 130 patients with MHVR and oral anticoagulant therapy, with or without aspirin, 57 patients on a comparable antithrombotic regimen, but without MHVR and 50 healthy subjects. In vitro studies showed that the release of cathepsin G and elastase from fMLP-stimulated PMN was significantly higher in the MHVR group, the leukocyte content of α1-antitrypsin (an inhibitor of both enzymes) being similar in all three groups. CD1 lb expression after stimulation with fMLP was also significantly higher on PMN from MHVR patients than from control patients or healthy volunteers, while PMN CD 11b basal expression was similar in all three groups. This increased PMN response in vitro in the absence of an obvious activation in vivo, may reflect a modified reactivity of circulating PMN passing through the artificial valves. Increased reactivity to local stimuli might allow PMN to participate in thrombus formation, despite conventional antithrombotic therapy.
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Shao, Yan, Chris Salim, and Hirofumi Hinode. "Hydrothermal Synthesis of Zeolites from Lake Sludge." Advanced Materials Research 785-786 (September 2013): 1117–20. http://dx.doi.org/10.4028/www.scientific.net/amr.785-786.1117.
Повний текст джерелаАнотація:
Sludge tends to accumulate easily in lake due to the closed water system and the pollutants contained inside could cause serious environmental problems. The sludge accumulation is mainly solved by dredging the lake, although the general disposal method of the dredged sludge by landfilling remains a problem due to formation of soft-ground and limited space. In this study, the conversion of the dredged sludge into adsorbent material that can be used for water treatment was tried. Using hydrothermal treatment in alkali medium, lake sludge which main components are silica and alumina could be converted into zeolite. The effects of various treatment conditions (NaOH concentration, alkali solution volume to dry sludge weight L/S ratio, Si/Al molar ratio, reaction temperature) were investigated. The adsorption abilities of synthesized zeolites were evaluated by measuring the cation exchange capacity (CEC) value and adsorption capacity towards heavy metals in aqueous solution (Pb, Cd). Soluble elements in sludge such as silica and alumina tend to dissolve at higher temperature and form zeolite. Zeolite type Na-P1 which was synthesized at silica/alumina (Si/Al) ratio of 2.5 and reaction temperature of 120°C showed the highest CEC value. The synthesized zeolites showed some adsorption ability towards heavy metals in aqueous solution (Pb2+ (Xm=55.3mg/g) and Cd2+ (Xm=40.9mg/g)).
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Dey, Souvik, Erika Sutanto-Ward, Katharina L. Kopp, James DuHadaway, Arpita Mondal, Dema Ghaban, Inés Lecoq, et al. "Peptide vaccination directed against IDO1-expressing immune cells elicits CD8+ and CD4+ T-cell-mediated antitumor immunity and enhanced anti-PD1 responses." Journal for ImmunoTherapy of Cancer 8, no. 2 (July 2020): e000605. http://dx.doi.org/10.1136/jitc-2020-000605.
Повний текст джерелаАнотація:
BackgroundThe tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which subverts T-cell immunity at multiple levels, is itself subject to inherent T-cell reactivity. This intriguing deviation from central tolerance has been interpreted as counterbalancing IDO1-mediated immunosuppression. Based on this hypothesis, clinical studies employing an IDO1 peptide-based vaccine approach for cancer treatment have been initiated, but there remains a pressing need to further investigate the immunological ramifications of stimulating the anti-IDO1 T-cell response in this manner.MethodsCT26 colon carcinoma tumors were evaluated for expression of IDO1 protein by western blot analysis, immunofluorescence microscopy and flow cytometry. Mouse IDO1-derived peptides, predicted to bind either major histocompatibility complex (MHC) class I or II of the H2d BALB/c strain, were emulsified in 50% Montanide for prophylactic or therapeutic vaccine treatment of CT26 tumor-bearing mice initiated either 7 days prior to or following tumor cell injection, respectively. In some therapeutic treatment experiments, administration of programmed cell death protein 1-binding antibody (anti-PD1 antibody) or epacadostat was concurrently initiated. Tumor size was determined by caliper measurements and comparative tumor growth suppression was assessed by longitudinal analyses of tumor growth data. For adoptive transfer, T cells from complete responder animals were isolated using paramagnetic beads and fluorescence-activated cell sorting.ResultsThis study identifies mouse MHC class I-directed and II-directed, IDO1-derived peptides capable of eliciting antitumor responses, despite finding IDO1 expressed exclusively in tumor-infiltrating immune cells. Treatment of established tumors with anti-PD1 antibody and class I-directed but not class II-directed IDO1 peptide vaccines produced an enhanced antitumor response. Likewise, class I-directed and II-directed IDO1 peptides elicited an enhanced combinatorial response, suggesting distinct mechanisms of action. Consistent with this interpretation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component consistent with antigen spread.ConclusionsThe in vivo antitumor effects demonstrated with IDO1-based vaccines via targeting of the tumor microenvironment highlight the utility of mouse models for further exploration and refinement of this novel vaccine-based approach to IDO1-directed cancer therapy and its potential to improve patient response rates to anti-PD1 therapy.
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van Rooij, Nienke, John B. A. G. Haanen, Marit van Buren, Daisy Philips, Mireille Toebes, Bianca Heemskerk, Laura van Dijk, et al. "Use of tumor exome analysis to reveal neo-antigen-specific T-cell reactivity in ipilimumab-responsive melanoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9085. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9085.
Повний текст джерелаАнотація:
9085 Background: Evidence for T cell mediated regression of human cancer in particular melanoma following immunotherapy is strong. Anti-CTLA4 treatment has been approved for treatment of metastatic melanoma and blockade of PD-1 has shown encouraging results. However, it is unknown which T cell reactivities are involved in cancer regression. Reactivity against non-mutated tumor self-antigens has been analyzed in patients treated with Ipilimumab or with autologous TILs, but the size of these responses are modest. Therefore, T cell recognition of patient-specific mutant epitopes may be a potentially important component. Animal model data recently suggested that analysis of T cell reactivity against patient-specific neo-antigens may be feasible through exploitation of cancer genome data. However, human data have thus far been lacking. Methods: To address this we have used MHC class I peptide exchange technology allowing production of very large collections of pMHC complexes, together with a pMHC "combinatorial coding" strategy for parallel detection of dozens of different T cell populations within a single sample. Results: From a melanoma patient responding to ipilimumab treatment, we identified tumor specific mutations via exome sequencing of tumor material. The exome contained 1,075 non-synonymous mutations. Possible MHC epitopes covering these mutations were predicted based on; 1) predicted to bind the patient’s MHC; 2) predicted to be cleaved by the proteasome; 3) genes of which the mutated peptides arose had evidence of RNA expression. The analysis yielded 1,952 epitopes restricted to the HLA-A and HLA-B. To screen for T cell reactivity against these epitopes we used the pMHC combinatorial coding approach. We found T cell reactivity against 2 neo-antigens, including a dominant T cell response against a mutant epitope of the ATR gene product. Analysis of PBMC samples collected before and during Ipilimumab therapy showed that this particular response increased strongly after treatment from 0.06% to 0.28% of CD8 T cells after being stable in magnitude for 10 months. Conclusions: These data provide the first demonstration of cancer exome-guided analysis to dissect the effects of melanoma immunotherapy.
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Neale, Alex R., and Laurence J. Hardwick. "Stable Formulations for the Lithium and Sodium Metal Interfaces in Alkali Metal-Oxygen Batteries." ECS Meeting Abstracts MA2022-01, no. 3 (July 7, 2022): 496. http://dx.doi.org/10.1149/ma2022-013496mtgabs.
Повний текст джерелаАнотація:
The high reactivity of both positive and negative interfacial regions in metal-oxygen (M-O2) batteries leads to a variety of parasitic degradation reactions that reduce reversibility on charge/discharge and can lead to rapid cell failure. To reversibly access the high theoretical specific energies these chemistries promise (3456 and 1602 Wh·kg-1 for Li-O2 and Na-O2, respectively), reducing charging overpotentials and the design of new electrode and electrolyte materials with improved stabilities are key targets. Considering the M|electrolyte interface, where decomposition reactions and dendrite formation generates severe safety concerns as well as reduced cycling stabilities, surface protection of the alkali metal anode by pre-treatment techniques or additive formulation has been among the more successful methodologies.1 In this work, we present a formulation strategy targeting enhanced cycling stabilities of the metal anode in M-O2 cells. Initially demonstrated in the Li-O2 chemistry, we report on an in-depth investigation into the electrochemical performance and the spectroscopic and diffusional properties of ternary ionic liquid (IL)-molecular solvent blend electrolytes.2 By introduction of the IL and exploring a wide formulation range (Figure 1a), we attain significant enhancements in the stability of practically-relevant electrolyte materials that otherwise fail rapidly at alkali metal anodes (Figure 1b), achieving the highest Coulombic efficiencies for Li plating/stripping in this solvent. The optimized formulations consequently displayed enhanced performances in Li-O2 full cells and ex situ characterization of Li surfaces also revealed the suppression of dendrite formation and important changes in the solid electrolyte interphase as a result of modulating solvent reactivity. Using Raman spectroscopy and diffusional analyses, we relate this closely to the local solvation environments involving the reactive solvent component in optimized formulations and, therefore, elucidate critical solvent/Li-salt ratios for improved stability. By understanding key shifts in Raman spectra relating to solvation effects in concentrated Li formulations, and how this modulates cycling performances, we further demonstrate the applicability of this relationship and formulation strategy to the Na-O2 battery chemistry. Therein, the Na metal interface is comparably more reactive and, therefore, presents greater stability challenges, with decomposition reactions in non-optimized formulations more rapidly causing plating and stripping at the anode to fail. However, we demonstrate the plating/stripping of Na (Figure 1c) and cycle lifetime in Na-O2 cells can be hugely improved by applying the above strategy and understandings of critical solvation interactions to equivalent formulations based on Na-salts. Y. Yu, G. Huang, J.-Z. Wang, K. Li, J.-L. Ma, and X.-B. Zhang, Adv. Mater. (Weinheim, Ger.), 32 (38), 2004157 (2020). A. R. Neale, R. Sharpe, S. R. Yeandel, C.-H. Yen, K. V. Luzyanin, P. Goddard, E. A. Petrucco, and L. J. Hardwick, Adv. Funct. Mater., 31 (27), 2010627 (2021). Figure 1. (a) Ternary plot highlighting the changes in stability of Li/Na metal anode cycling as a function of the studied formulation ranges and example voltage profiles of symmetric (b) Li|Li cells and (c) Na|Na cells with non-optimized (navy/purple) and optimized (orange) electrolyte formulations. Figure 1
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Mao, Qingqing, Jieyao Yuan, Lei Wang, Makayla Maher, and Chi Chen. "Novel Urinary Metabolites of Aldehydic Lipid Oxidation Products From Heated Soybean Oil Revealed by Aldehyde Abatement and Metabolomic Fingerprinting." Current Developments in Nutrition 6, Supplement_1 (June 2022): 310. http://dx.doi.org/10.1093/cdn/nzac053.051.
Повний текст джерелаАнотація:
Abstract Objectives Heated cooking oils are a constitutive component of contemporary human diets and a common ingredient in animal feed. Aldehydes, as the most reactive lipid oxidation products (LOPs) in heated oils, are widely considered as a contributor to the adverse health effect associated with heated oil consumption. Aldehydes-derived metabolites in biofluids are valuable for monitoring the exposure of the aldehydes from heated oils, but the efforts for their identification were hampered by the high reactivity of aldehydes as well as the chemical complexity caused by the coexistence of other LOPs in heated oils. To address this challenge, this study investigated the aldehydes-derived metabolites through the metabolomic fingerprinting of mouse urine samples from feeding heated oils with and without aldehyde abatement. Methods The heated soybean oil (HSO) was prepared by heating the control soybean oil (CSO) at 185°C for 6 h with constant air flow (50 ml/min). Both HSO and CSO were then mixed with the silica gel with piperazine side chain to remove their aldehyde content, producing the silica gel-treated HSO (HSO-si) and the silica gel-treated CSO (CSO-si), respectively. The urine, serum, fecal samples were collected from the C57BL/6 mice fed with 4 diets containing CSO, CSO-si, HSO, HSO-si, and then analyzed by the liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis. Results The silica gel treatment dramatically reduced the aldehyde contents in HSO. Novel urinary metabolites formed by the reactions between 2,4-decadienal and lysine were identified through the metabolomic comparison between the HSO samples and the samples from 3 other treatment groups. Conclusions The identification of novel urinary metabolites of aldehydic LOPs warrants further biochemical examination on the chemical and metabolic processes responsible for their formation. These metabolites could become the biomarkers for monitoring the exposure of aldehydes in humans and animals. Funding Sources The research is partially supported by the NIFA project MIN-18–125.
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Wang, Qing, Xin Rui Wang, Hai Cao, Zhao Yang Ding, and De Yong Kong. "Study on the Mechanical Properties and Heavy Metal Ions Immobilization Capability of Solidified Body for MSWI Fly Ash with Geopolymer." Materials Science Forum 1036 (June 29, 2021): 301–8. http://dx.doi.org/10.4028/www.scientific.net/msf.1036.301.
Повний текст джерелаАнотація:
In this study, municipal solid waste incineration fly ash (hereinafter called MSWI fly ash) was used as a main raw material, and it was prepared into a solidified body for MSWI fly ash with geopolymer by a single-component chemical alkali excitation method. The results were shown that when the content of MSWI fly ash was 50%, SiO2/Al2O3 was between 3.51-4.04, and Na2O/Al2O3 was between 0.24-0.30, with the increasing of SiO2/Al2O3 and Na2O/Al2O3, the 28d compressive strength of the solidified body showed a trend of increasing first and then decreasing, the maximum 28d compressive strength was 17.7MPa. When SiO2/Al2O3 was 4.04 and Na2O/Al2O3 was 0.30, the minimum leaching concentrations of Pb2+ and Cd2+ were 0.018mg/L and 0.027 mg/L. When the content of MSWI fly ash was increasing, the 28d compressive strength of the solidified body gradually decreased, and the heavy metal ions leaching concentration gradually increased. The result of XRD and FTIR indicated that the MSWI fly ash was involved in the polymerization reaction, and the heavy metal ions in MSWI fly ash were also chemically solidified into the geopolymer structure.
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Haddon, David, Justin Jarrell, Chih-Long Liu, Jordan Price, Stephanie Tangsombatvisit, Grace Credo, Guangyu Xu, Madoo Varma, Emily Baechler, and Paul Utz. "Silicon-based peptide microarrays for epitope mapping of serum autoantibodies from patients with systemic lupus erythematosus with single-amino acid resolution (P4030)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 42.16. http://dx.doi.org/10.4049/jimmunol.190.supp.42.16.
Повний текст джерелаАнотація:
Abstract We have developed a silicon-based peptide microarray with >5,700 features, corresponding to 891 unique peptides derived from the U1-70 protein, a well-known target of autoantibodies in systemic lupus erythematosus (SLE). U1-70 is a component of the U1-small nuclear ribonucleoprotein (U1-snRNP) complex, which is one of five snRNPs that comprise the spliceosome. The peptides on the microarray represent every possible overlapping peptide, up to 21 amino acids in length, spanning amino acids 110 to 170 within the U1-70 RNA binding domain. The microarray includes regions of U1-70 targeted by SLE patient autoantibodies, although the precise epitopes are not known. Additionally, the region includes a peptide (131-150) that our lab recently identified as a target of autoreactive CD4+ T cells. We have validated the microarray using commercial anti-U1-70 antibodies, and have shown that this array is capable of sensitive and specific determination of their minimal epitopes. We went on to evaluate a cohort of SLE (n=24) patients and identified two minimal reactive epitopes, peptides 116-121 (n=3) and 143-148 (n=1), of their U1-70 autoantibodies. Further analysis of a larger SLE cohort (n=80) by peptide ELISA revealed additional patients with reactivity to peptides 116-121 (1/80) and 143-148 (5/80). Currently we are correlating reactivity to these peptides with patient clinical information in an effort to better understand the development and function of anti-U1-70 autoantibodies in SLE.
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Sido, Bernd, Jutta Braunstein, Raoul Breitkreutz, Christian Herfarth, and Stefan C. Meuer. "Thiol-Mediated Redox Regulation of Intestinal Lamina Propria T Lymphocytes." Journal of Experimental Medicine 192, no. 6 (September 18, 2000): 907–12. http://dx.doi.org/10.1084/jem.192.6.907.
Повний текст джерелаАнотація:
Intestinal lamina propria T lymphocytes (LP-Ts) have a markedly low proliferative potential both in vivo and in vitro. Here, we have identified that the capacity of antigen-presenting cells to release cysteine upon receptor–ligand interactions represents a critical parameter for proliferation of LP-Ts. The availability of cysteine is limiting for the intracellular production of glutathione, which in turn is essential for cell cycle progression. When cysteine is provided either directly or by addition of the reducing agent 2-mercaptoethanol to cystine-containing culture medium, proliferation of LP-T is fully restored. Importantly, coculture with peripheral blood monocytes that easily take up cystine, reduce cystine, and secrete cysteine also restores reactivity of LP-Ts to T cell receptor/CD3 stimulation. In marked contrast, lamina propria macrophages lack this capacity to elaborate cysteine, and thereby secure physiological unresponsiveness to antigen exposure in the intestinal microenvironment. The well-documented local recruitment of blood monocytes in inflammatory bowel disease (IBD) may thus represent an important parameter underlying hyperresponsiveness of T cells, an essential component of the pathogenesis of IBD.
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Radenkova-Saeva, Julia, Rositza Kostadinova, Antoaneta Michova, and Bogdan Petrunov. "Pulmonary complications related to heroin overdose and some changes in immune reactivity." Open Medicine 5, no. 4 (August 1, 2010): 508–12. http://dx.doi.org/10.2478/s11536-010-0022-9.
Повний текст джерелаАнотація:
AbstractTo examine the clinical spectrum of complications in pulmonary system and changes of some parameters of humoral and cell mediated immunity related to heroin overdose. The study includes 16 patients who are long-term heroin abusers with acute heroin and mixed with other psychoactive drugs intoxications with an average age of 21,5 ± 5.04 years (12 men and 4 woman). All patients were hospitalized in the Clinic of Toxicology, MHATEM “N.I.Pirogov”, Sofia. We have used clinical, clinico-laboratory, immunological, chimicotoxicological, instrumental methods. In severe intoxications with heroin and other psychoactive drugs, we observed pulmonary system complications, i.e. pneumonia, aspiration of gastric contents, noncardiogenic pulmonary edema (NCPE) and acute respiratory distress syndrome (ARDS.). Of the 16 patients in our study, 3 patients died due to complications. Some changes in the immune reactivity observed in the study were (1) statistically significant lower mean levels of IgG and (2) tendency to lower mean levels of IgA, IgM and complement components — C3 in the studied patients in comparison with the values in healthy people. The changes were more demonstrative in the group with pulmonary complications compared to the group without pulmonary complications. We observed that the CD4 lymphocytes were significantly less in the studied patients; in addition, a lower level of CD56-bearing lymphocytes (natural killer /NK/ cells) was observed in comparison to healthy controls. The results show that the mixture of acute heroin with other psychoactive drugs leads to complications in the pulmonary system and changes of some parameters of cell-mediated and humoral immunity.
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Luo, Guo, Aditya Ambati, Ling Lin, Mélodie Bonvalet, Markku Partinen, Xuhuai Ji, Holden Terry Maecker, and Emmanuel Jean-Marie Mignot. "Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy." Proceedings of the National Academy of Sciences 115, no. 52 (December 12, 2018): E12323—E12332. http://dx.doi.org/10.1073/pnas.1818150116.
Повний текст джерелаАнотація:
Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide–specific CD4+ T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA273–287 (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17–31 and C-amidated but not native version of HCRT54–66 and HCRT86–97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA273–287-tetramers, suggesting molecular mimicry. This public CDR3β uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-α/β CDR3 motifs of HCRT54–66-NH2 and HCRT86–97-NH2 tetramers were extensively shared: notably public CDR3α, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-α/β CDR3 sequences found in pHA273–287, NP17–31, and HCRTNH2 tetramer-positive CD4+ cells were also retrieved in single INF-γ–secreting CD4+ sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
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Ramadan, Abdulraouf, Jilu Zhang, Mohammad Abu Zaid, Heather O'Leary, Reuben Kapur, Helmut Hanenberg, Jie Sun, Hal E. Broxmeyer, Mark H. Kaplan, and Sophie Paczesny. "IL-33/ST2 Triggering of IL-9-Secreting T Cells Alters the Balance of Fatal Immunity and Tumor Immunity." Blood 126, no. 23 (December 3, 2015): 231. http://dx.doi.org/10.1182/blood.v126.23.231.231.
Повний текст джерелаАнотація:
Abstract Treatment of acute myeloid leukemia (AML) has changed little over the last several decades and prognosis remains very poor. Allogeneic hematopoietic cell transplantation (allo-HCT) is one potentially curative option for relapsed or high-risk AML. The immunotherapeutic activity of allo-HCT is known as the graft-vs-leukemia (GVL) activity. However, GVL activity is often accompanied by T-cell reactivity to allo-antigens in normal host tissues, which leads to graft-versus-host disease (GVHD), another major cause of death after HCT with relapse. Therefore, there is a great unmet need to improve the current process of allo-HCT through increasing the GVL activity and decreasing GVHD. We have shown that an elevated plasma level of soluble (s)ST2 in HCT patients is a risk factor for severe GVHD (Vander Lugt et al, N Engl J Med, 2013) and that ST2 blockade reduces sST2-producing T cells while maintaining protective membrane (m)ST2-expressing T cells during GVHD (Zhang et al, Sci Transl Med, 2015). In addition, the interleukin (IL)-9-producing CD4 T helper (Th)9 and CD8 cytotoxic T (Tc)9 cell subsets (together T9 cells) have higher antitumor activity than Th1 and Tc1 cells in melanoma models (Lu et al, J Clin Invest, 2012 and Lu et al, ProcNatl Acad Sci, 2014). We hypothesized that activation of the ST2/IL-33 pathway in T9 cells will both alleviate GVHD and increase GVL. In our laboratory, we have shown that T9 cells express a high level of mST2 and that differentiation of total T cells into T9 cells in the presence of IL-33 (T9IL-33 cells) increases expression of mST2 (Figure 1A) and PU.1 (Figure 1B), a transcription factor that promotes IL-9 production on both CD4 and CD8 T cells. Adoptive transfer of T9IL-33 cells with bone marrow cells in a murine model of HCT resulted in less severe GVHD compared to transfer of T9IL33 cells generated from ST2-/- or IL-9-/- T cells (Figure 1C). Ex-vivo analysis of target organs such as gut showed a decrease in T9IL-33 interferon (IFN)g-producing T cells that was abolished in mice receiving T9IL-33 cells derived from ST2-/- or IL-9-/- T cells (not shown). Furthermore, T9IL-33 cells revealed higher anti-leukemic activity in vitro when cultured with a B cell lymphoma line (A20) or retrovirally transduced MLL-AF9 leukemic cells in cytolytic assays (not shown). In vivo GVL experiments with MLL-AF9 induced leukemia, and adoptive transfer of T9IL-33 cells resulted in increased survival compared to transfer of T9IL-33 cells generated from ST2-/- or IL-9-/- T cells (Figure 1D). Human T9 cells are poorly explored. We demonstrated that differentiation of human T9 cells in the presence of IL-33 enhanced IL-9 production by CD4 and CD8 T cells (Figure 2A). T9IL-33 cells also upregulated the expression of the cytolytic molecules granzymes A and B compared to T9 cells (Th9IL-33: 33.6%±4%, vs. Th9: 15.69%±2.53% p=0.021), (Tc9IL-33: 57.6%±4.7%, vs. Tc9: 34.61%±3.4% p=0.018), as well as demonstrated higher in vitro anti- leukemic cytolytic activity when incubated with MOLM14, an aggressive AML tumor cell line expressing FLT3/ITD mutations (Figure 2B). Transcriptome analysis of T9IL-33 cells from wild-type and ST2-/- T cells showed upregulation of molecules implicated in anti-leukemic activity (granzymes A and B, CD8α, IL-15, IL-15rα, IFNα, and IL-1α) on both CD4 and CD8 T cells (Figure 2C), and such upregulation was confirmed at the protein level (Figure 2D). Furthermore,investigations into the possible mechanism of activation using transwell assays revealed that both soluble factors and cell contact between Th9IL-33 and Tc9IL-33 T cells were required for maximum killing (not shown). We next investigated the possible mechanism of action and hypothesized that CD8α might be the contact-dependent component. CD8α blockade with neutralizing antibody during human T9IL-33 differentiation reduced the cytotoxicity of both murine T9IL-33 and human T9IL-33 cells (Figure 2E). Altogether, our observations suggest that adoptive transfer of T9IL-33 cells represents a promising cellular therapy following HCT. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Paczesny: Viracor laboratories: Patents & Royalties: "Methods of detection of graft-versus-host disease" (US- 13/573,766).
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Sutmuller, Roger P. M., Leonie M. van Duivenvoorde, Andrea van Elsas, Ton N. M. Schumacher, Manon E. Wildenberg, James P. Allison, Rene E. M. Toes, Rienk Offringa, and Cornelis J. M. Melief. "Synergism of Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Depletion of Cd25+ Regulatory T Cells in Antitumor Therapy Reveals Alternative Pathways for Suppression of Autoreactive Cytotoxic T Lymphocyte Responses." Journal of Experimental Medicine 194, no. 6 (September 17, 2001): 823–32. http://dx.doi.org/10.1084/jem.194.6.823.
Повний текст джерелаАнотація:
Therapeutic efficacy of a tumor cell–based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte–associated antigen (CTLA)-4 pathway or the CD25+ regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25+ Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2180–188–specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8+ T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25+ Treg cells indicates that CD25+ Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.
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Barilo, A. A., S. V. Smirnova, and M. V. Smolnikova. "AGE-DEPENDENT INDEXES OF IMMUNITY IN THE PATIENTS WITH PSORIATIC ARTHRITIS." Medical Immunology (Russia) 21, no. 1 (January 24, 2019): 69–76. http://dx.doi.org/10.15789/1563-0625-2019-1-69-76.
Повний текст джерелаАнотація:
Psoriatic arthritis is a chronic progressive systemic inflammatory disease of joints and spine, which leads to the development of erosive arthritis, bone resorbtion, multiple enthesitis and spondylitis. Severe clinical course, resistance to therapy, high prevalence of disability, increased mortality of patients determine a need for further study of the disease. Psoriatic arthritis is a multifactorial disease including immune pathogenic factors representing a complex process of interaction between cellular and humoral components of immune system. The most important way of activating epidermal cells and synovial membrane proliferation in psoriatic arthritis is an imbalance of proinflammatory and anti-inflammatory cytokines. It is noted that the features of clinical course in psoriasis are age-dependent. The study of immune response indices in different age groups allows to reveal distinct progression features of the psoriatic pathology.The purpose of this study was to compare concentrations of proinflammatory and anti-inflammatory cytokines, cellular and humoral immunity, and to conduct a comparative analysis in young and adult patients with psoriatic arthritis.The study included a group of patients with psoriatic arthritis (n = 101) who were divided by their age: group 1, from 18 to 44 years (n = 43); group 2, over 44 years (n = 58). The control groups (3 and 4) included virtually healthy people (n = 103) matched for sex and age with the patients. Populational and subpopulation profiling of blood lymphocytes was performed by flow-cytometry using monoclonal antibodies to CD3, CD4, CD8, CD16, CD19 (LLC “Sorbent”, Moscow, Russia). Phagocytic activity of peripheral blood neutrophils was assessed microscopically by uptake of latex particles. Concentrations of IgA, IgM, and IgG immunoglobulins, circulating immune complexes, cytokines (IL-4, IL-6, IL-10, TNFα) in blood serum was determined by enzyme-linked immunosorbent assay. Statistical evaluation of the results obtained was performed using applied “Statistica 6.0” software.In all the age subgroups of patients with psoriatic arthritis, we have revealedstatistically significant differences against controls, i.e., increased relative and absolute number of CD3-CD16+lymphocytes in peripheral blood, higher concentration of CIC-C1q, with decreased concentrations of IgA, IgM, IgG in blood serum. The analysis of the main cellular and humoral indicators of immunity in psoriatic arthritis patients revealed a statistically significant differences for psoriatic arthritis in young and adulthood. E.g., the serum concentration of IL- 10 was statistically significantly lower in psoriatic arthritis at a young age in comparison with adult psoriatic arthritis. Phagocytic number and IgG concentration in serum were statistically significantly lower in adults with psoriatic arthritis adulthood than in young patients.In conclusion, The revealed changes in immunological indices in psoriatic arthritis in young and adult patients indicate to differences against healthy controls, as well as intergroup differences. Previous studies have not revealed statistically any significant differences in immunological parameters between young and adult patients with psoriatic arthritis in, thus suggesting a presence of immune disorders associated with psoriatic pathology, but not with the age of patients. However, changes of immunological reactivity are observed with increasing age of patients with psoriatic arthritis and development of severe clinical forms, and they can be considered as markers of psoriatic disease progression, such as increased concentrations of IL-10 and lower IgG amounts in blood serum, a decreased phagocytic number.