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Mocroft, A., M. Bofill, M. Lipman, E. Medina, N. Borthwick, A. Timms, L. Batista, et al. "CD8+, CD38+ Lymphocyte Percent." Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 14, no. 2 (February 1997): 158–62. http://dx.doi.org/10.1097/00042560-199702010-00009.
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Petrovas, Constantinos, Yvonne M. Mueller, Ioannis D. Dimitriou, Susan R. Altork, Anupam Banerjee, Peter Sklar, Karam C. Mounzer, John D. Altman, and Peter D. Katsikis. "Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells." Blood 109, no. 6 (November 9, 2006): 2505–13. http://dx.doi.org/10.1182/blood-2006-05-021626.
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AbstractWhat governs the increased apoptosis sensitivity of HIV-specific CD8+ T cells is poorly understood. Here, we examined the involvement of mitochondria in this apoptosis. Remarkably higher mitochondrial mass (MM) was found in HIV-specific compared with CMV-specific CD8+ T cells from HIV+ patients and this could not be attributed to their different differentiation status. MMHigh phenotype characterized those CD8+ T cells from HIV+ patients that are sensitive to spontaneous and CD95/Fas-induced apoptosis. CD38 expression did not correlate with high MM, whereas Bcl-2 levels were significantly reduced in both CD38+ and CD38− HIV-specific CD8+ T cells. Although CD38+ HIV-specific CD8+ T cells were more susceptible to apoptosis, CD38 expression does not explain on its own the selective apoptosis sensitivity of HIV-specific CD8+ T cells, as CD38− HIV-specific CD8+ T cells were more apoptotic than CD38+ CMV-specific ones. Proapoptotic HIV-specific CD8+ T cells were CD38+Bcl-2LowMMHigh. Copolarization of mitochondria with CD95/Fas capping, very early in CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells, suggests that mitochondria act as an amplification step for this apoptosis. Thus, an extensive mitochondrial network contributes to apoptosis sensitivity of CD8+ T cells and, when this occurs together with reduced levels of Bcl-2 and chronic activation, determines the proapoptotic state of HIV-specific CD8+ T cells.
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Alvarez-Jimenez, Violeta, Jeanet Serafin-Lopez, Sergio Estrada-Parra, Iris Elvira Estrada-García, and Claudia Sandoval-Montes. "Analysis of extrinsic pathway mediators in CD8+CD38+ T cells of healthy donors stimulated with Mycobacterium tuberculosis antigens (99.20)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 99.20. http://dx.doi.org/10.4049/jimmunol.186.supp.99.20.
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Abstract CD38 is expressed in human T cells during early stages of activation and differentiation and can be used as a marker of prognosis for HIV. Currently, CD38 has raised interest since it has been found increased in patients with tuberculosis, however when the active phase is solved a decrease of CD38 in CD8 T lymphocytes is observed. Here we evaluated and determined the role of CD38 in human CD8 T lymphocytes stimulated with M. tuberculosis H37Rv soluble extracts (MTSE) and delipidized MTSE (dMTSE) in vitro. For this purpose, PBMC from healthy donors were incubated with PMA-ionomicyne, media, MTSE or dMTSE. After cultured, cells were harvested and stained with monoclonal antibodies conjugated to different fluorochromes. After kinetics experiments were performed and the expression of perforin, granzyme A, IFN-γ and CD38 in T CD8 cells was determined by flow cytometry. Expression of IFN-γ and perforin was statistically higher in T CD8+CD38+ in comparison with T CD8+CD38-. Remarkably, CD8+CD38+ T cells showed an increased cytotoxicity against macrophages pulsed with MTSE. These results suggest that the population of T CD8+ lymphocytes might have an effector functions in Ag specific dependance on CD38. This is the first report linking CTL activity to the CD38 molecule in tuberculosis.
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Ho, H. N., L. E. Hultin, R. T. Mitsuyasu, J. L. Matud, M. A. Hausner, D. Bockstoce, C. C. Chou, S. O'Rourke, J. M. Taylor, and J. V. Giorgi. "Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens." Journal of Immunology 150, no. 7 (April 1, 1993): 3070–79. http://dx.doi.org/10.4049/jimmunol.150.7.3070.
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Abstract CD38, a molecule with multilineage distribution but unknown function, and the MHC class II molecule HLA-DR (DR) have markedly elevated levels of expression on CD8+ cells of HIV-infected people. This study investigated the expression of CD38 and DR Ag on circulating HIV-specific CD8+ CTL in HIV-seropositive subjects. Purified CD8+ lymphocytes from 22 participants in the University of California at Los Angeles Multicenter AIDS Cohort Study were screened for CTL activity against autologous EBV-immortalized lymphoblast targets infected with vaccinia vectors that carried HIVIIIB gag, pol, and env genes. Sixty-seven percent (14 of 21), 64% (14 of 22), and 9% (2 of 22), respectively, of the subjects had HIV-specific CD8+ CTL activity against gag, pol, and env proteins. CD8+ cells from 11 of the subjects who had high CTL activity were then FACS-separated using three-color immunofluorescence sorting. Circulating DR-CD38- CD8+ cells had little activity. Highly purified DR+CD38+ CD8+ cells had higher HIV-specific CTL activity than other CD8+ cells. DR+CD38- or DR-CD38+ CD8+ cells also mediated significant activity, but only about half as much on a per cell basis as DR+CD38+ CD8+ cells. This is the first report that the CD38 molecule is expressed in vivo on Ag-specific CD8+ CTL, and confirms previous reports that DR is expressed on these cells. Both asymptomatic HIV-seropositive subjects (144 +/- 132/mm3) and AIDS patients (253 +/- 178/mm3) had markedly elevated levels of DR+CD38+ CD8+ cells compared with the levels in HIV-seronegative controls (7 +/- 3/mm3). However, the level of anti-HIV CTL activity was not correlated with the level of DR+CD38+ CD8+ cells, indicating that enumeration of this lymphocyte population by flow cytometry most likely will not be a useful surrogate for measuring functional CTL activity. Low levels of HIV-specific CTL activity, especially against gag, were correlated with lower CD4+ cells numbers, suggesting that the loss of CD8+ T cell cytotoxic activity against HIV that has been reported to occur with advancing HIV disease progression may reflect in part the extent of CD4+ cell immunodeficiency in HIV-infected subjects.
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Ríos-Olivares, Eddy, José W. Rodríguez, Luis A. Rodríguez, Madhavan Nair, and Robert Hunter. "Co-expression of apoptosis-related molecules on activated CD8+CD38+ T-cells is associated with HIV-1 disease progression (B213)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): LB44. http://dx.doi.org/10.4049/jimmunol.178.supp.b213.
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Abstract HIV-1 disease progression has been associated with a remarkable increase of CD8+CD38+ T-cells. It has been documented that a significant distribution of HIV-specific CD8+ T-cells resides in the CD8+CD38+ T-cell sub-population. The failure of HIV-specific CD8+CD38+ T-cells to control HIV-1 infection has been attributed to several mechanisms including apoptosis. However, the relationship between the CD38 expression and molecular events involved in CD8+ T-cell apoptosis is not well understood. We evaluated the expression of two membrane-associated apoptosis-related molecules: CXCR4 and CD95, and two cytoplasm-associated apoptosis-related molecules: Bcl-2 and active caspase-3 in 41 HIV-1 positive patients and 15 HIV-1 negative individuals. HIV-1 infection alters the level of expression of CD38, CD95, CXCR4, Bcl-2, and active caspase-3. A positive correlation was established between CD95, CXCR4, and active caspase-3 expression with low CD4 count and high plasma viremia and CD38 expression. The majority of activated CD8+CD38+ T-cells were apoptotic since they expressed active caspase-3 and the rest of these cells were susceptible to become apoptotic since they co-expressed CD95 and CXCR4. We suggest that one of the most likely HIV-mediated apoptosis mechanisms is via CD95 and CXCR4 induction through the caspase cascade despite Bcl-2 expression. This provides another explanation of why HIV-1 infection is not fully contained by HIV-specific CD8+CD38+ T-cells. Supported by NIH/RCMI Grant # G12-RR03035.
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Caselli, D., G. Comolli, A. Maccabruni, C. Klersy, and L. Minoli. "CD38/CD8 expression and HAART failure." Lancet 353, no. 9155 (March 1999): 840–41. http://dx.doi.org/10.1016/s0140-6736(05)76500-4.
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Ostendorf, L., P. Garantziotis, D. L. Wagner, P. Durek, F. Heinrich, P. Enghard, G. R. Burmester, et al. "POS0010 CD38+ MEMORY T CELLS ARE A FUNCTIONALLY DISTINCT SUBSET THAT IS EXPANDED IN SLE AND ASSOCIATED WITH LUPUS NEPHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 207.1–207. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3104.
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Background:We recently reported the beneficial clinical responses of the anti-CD38 monoclonal antibody daratumumab in two patients with systemic lupus erythematosus (SLE) [1]. While the primary rationale for its use was the depletion of autoantibody-producing long-lived plasma cells, daratumumab may promote additional therapeutic effects on CD38-expressing T cells, but their origin, lifestyle and role in lupus pathophysiology remains elusive.Objectives:To investigate the phenotype, transcriptional program, functional properties and clinical associations of CD4+ and CD8+CD38+ memory T cells in SLE compared to healthy controls (HC).Methods:CD38-expression on memory T cell subsets was measured by flow cytometry in 65 patients with SLE and 28 healthy controls. We investigated the functional capacity of CD38+ T cells using CFSE staining and intracellular cytokine staining after polyclonal stimulation. Additionally, we performed single-cell transcriptome and T-cell-receptor sequencing of 7 SLE patients and 7 matched healthy controls, including surface protein expression analysis using CITE-seq (RNA-barcoded) antibodies.Results:Compared to healthy controls, the frequency of CD38-expressing memory T cells in SLE was significantly increased in both CD4+ and CD8+ T cells. SLE patients with a previous or current lupus nephritis had significantly increased levels of CD8+CD38+ memory T cells compared to those without history of renal involvement. CD38+ memory T cells expressed increased levels of Ki-67 and displayed higher proliferative capacity upon polyclonal stimulation than their CD38- counterparts, both in SLE patients and HC, while they showed decreased ability to secrete IFN-γ, IL-2, GM-CSF and TNF-α. Single-cell transcriptome sequencing revealed that CD8+CD38+ memory T cells were enriched within terminally differentiated, cytotoxic CD8 T cells, and had reduced TCR repertoire diversity compared to their CD38- counterparts. CD8+CD38+ memory T cells from SLE patients had significantly higher expression of type I interferon associated genes, both compared to CD38- memory T cells from SLE patients and CD38+ cells from HCs.Conclusion:CD38+ memory T cells with increased proliferative capacity but altered effector functions are significantly expanded in peripheral blood of SLE and correlate with the lupus nephritis. Although the factors mediating their generation and their precise role in the disease pathophysiology remain to be investigated, CD38-expressing T cells may be useful as a future biomarker for lupus nephritis.References:[1]Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, et al. Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2020 Sep 17;383(12):1149–55.[2]Katsuyama E, Suarez-Fueyo A, Bradley SJ, Mizui M, Marin AV, Mulki L, et al. The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections. Cell Reports. 2020 Jan;30(1):112-123.e4.Acknowledgements:We thank our patients and healthy controls for making our research possible.Disclosure of Interests:None declared.
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Tincati, Camilla, Giusi M. Bellistrì, Giuseppe Ancona, Esther Merlini, Antonella d’Arminio Monforte, and Giulia Marchetti. "Role ofIn VitroStimulation with Lipopolysaccharide on T-Cell Activation in HIV-Infected Antiretroviral-Treated Patients." Clinical and Developmental Immunology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/935425.
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We investigated the effect of LPSin vitrostimulation on T-cell activation in HIV-infected patients with different CD4+ recovery on HAART. PBMCs from 30 HIV-positive, HAART-treated, aviremic individuals with different CD4+ reconstitution (Low Responders: CD4+ < 350/μL; Intermediate Responders: CD4+ 350–599/μL; High Responders: CD4+ ≥ 600/μL) were cultured with LPS and the proportion of HLA-DR/CD38- and Ki67-expressing CD4+/CD8+ T-cells was measured (flow cytometry). Upon LPS stimulation, significantly higher CD4+ and CD8+HLA-DR+ cells were shown in LR and IR versus HIV-negative controls. While no differences in the proportion of LPS-stimulated CD4+CD38+ cells were recorded amongst HIV-positive subgroups, CD8+CD38+ cells were more elevated in patients with lower CD4+ recovery on HAART (i.e., LR and IR). Uponin vitroLPS stimulation, HLA-DR and CD38 expression on T-cells are differentially regulated. While HLA-DR induction reflects impaired CD4+ reconstitution on HAART, cell-surface CD38 expression is increased only on CD8+ T-cells, allowing to speculate that the sole induction of CD38 on CD4+ cells may not be sufficient to depict LPS-driven immune activation in HIV.
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Bai, Francesca, Camilla Tincati, Esther Merlini, Carlotta Pacioni, Elisabetta Sinigaglia, Giovanni Carpani, Antonella d’Arminio Monforte, and Giulia Marchetti. "Reduced Central Memory CD4+ T Cells and Increased T-Cell Activation Characterise Treatment-Naive Patients Newly Diagnosed at Late Stage of HIV Infection." AIDS Research and Treatment 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/314849.
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Objectives. We investigated immune phenotypes of HIV+ patients who present late, considering late presenters (LPs, CD4+ < 350/μL and/or AIDS), advanced HIV disease (AHD, CD4+ < 200/μL and/or AIDS), and AIDS presenters (AIDS-defining condition at presentation, independently from CD4+).Methods. Patients newly diagnosed with HIV at our clinic between 2007–2011 were enrolled. Mann-Whitney/Chi-squared tests and logistic regression were used for statistics.Results. 275 patients were newly diagnosed with HIV between January/2007–March/2011. 130 (47%) were LPs, 79 (29%) showed AHD, and 49 (18%) were AIDS presenters. LP, AHD, and AIDS presenters were older and more frequently heterosexuals. Higher CD8+%, lower CD127+CD4+%, higher CD95+CD8+%, CD38+CD8+%, and CD45R0+CD38+CD8+% characterized LP/AHD/AIDS presentation. In multivariate analysis, older age, heterosexuality, higher CD8+%, and lower CD127+CD4+% were confirmed associated with LP/AHD. Lower CD4+ and higher CD38+CD8+% resulted independently associated with AIDS presentation.Conclusions. CD127 downregulation and immune activation characterize HIV+ patients presenting late and would be studied as additional markers of late presentation.
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Lawrence Cheung, Chun Chau, Yong Hock Justin Seah, Juntao Fang, Nicole Orpilla, Justina Nadia Li Wen Lee, Han Chong Toh, Su Pin Choo, Kiat Hon Lim, Wai Meng David Tai, and Joe Yeong. "89 The immune marker LAG-3 increases the predictive value of CD38+ immune cells for survival outcome in immunotherapy-treated hepatocellular carcinoma." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A97—A98. http://dx.doi.org/10.1136/jitc-2021-sitc2021.089.
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BackgroundImmune check-point blockade (ICB) is one of the emerging therapeutic options for advanced hepatocellular carcinoma (HCC). However, low response rates amongst patients necessitates the development of robust predictive biomarkers that identify patients who likely benefit from ICB. Previously our group found that immunohistochemical scoring of CD38 in the tumour microenvironment predicts responsiveness to anti-PD-1/anti-PD-L1 immunotherapy in HCC.1 Recently BMS 4-gene inflammatory signature, comprising the 4 genes CD8, PD-L1, LAG-3 and STAT1, has been shown to be associated with better overall response to immunotherapy in various cancer types.2–4 In the present study, we examined the relationship between tissue expression of BMS 4-gene inflammatory signature and the responsiveness of HCC to immunotherapy, and whether BMS 4-gene inflammatory signature increases the predictive power of CD38.MethodsHCC tissue samples from 124 Asian patients that underwent conventional treatment and from 49 Asian patients that underwent ICB were analysed for CD8, PD-L1, LAG-3, STAT1, CD38 and CD68 tissue expression using immunohistochemistry and multiplex immunohistochemistry, followed by survival and statistical analysis.ResultsSurvival analysis of the 124 samples showed that high LAG-3 tissue expression was associated with shorter progression-free survival (PFS). On the other hand, immunohistochemical analyses on the 49 patient samples treated with ICB revealed that high LAG-3 density and high total LAG-3+CD8+ T cell proportion were associated with improved response to ICB (figure 1). However, CD8, PD-L1 and STAT1 levels did not significantly correlate with improved survival. The addition of total LAG-3+ cell proportion to total CD38+ cell proportion significantly increased the predictive value for both PFS (DeltaLRChi2=9.97; P=0.0016; table 1) and overall survival (OS) (DeltaLRChi2=8.84; P=0.0021; table 1), compared with total CD38+ cell proportion alone. Similarly findings were obtained after adding total LAG-3+CD8+ cell proportion to total CD38+ cell proportion (PFS: DeltaLRChi2=7.21; P=0.0072; OS: DeltaLRChi2=8.06; P=0.0045; table 1), compared with total CD38+ cell proportion alone. Lastly, when the total LAG-3+CD8+ cell proportion was added to total CD38+ and CD38+CD68+ cell proportion, the predictive value of the biomarker was significantly increased (PFS: DeltaLRChi2=6.10; P=0.0136; OS: DeltaLRChi2=6.18; P=0.0129; table 1). Ongoing works include further validation of the findings in various cohorts, and correlating with clinical outcome of the patients.Abstract 89 Table 1Log-likelihood of models with added predictive termsAbstract 89 Figure 1HCC patients‘ response to ICB in relation to LAG-3 density. (A) Kaplan-Meier curve showing the association between a high LAG-3 density and improved overall survival after treatment with ICB. (B) Kaplan-Meier curve showing the association between a high total LAG-3+CD8+ T cell proportion and improved overall survival after treatment with ICB. (C) Kaplan-Meier curve showing the association between a high LAG-3 density and improved progression-free survival after treatment with ICB. (D) Kaplan-Meier curve showing the association between a high total LAG-3+CD8+ T cell proportion and improved progression-free survival after treatment with ICB.ConclusionsHigh LAG-3 expression on tissue-infiltrating immune cells predicted greater response to ICB. LAG-3+ and LAG3+CD8+ cell proportion added predictive value to CD38+ cells for predicting survival outcome in immunotherapy-treated HCC. LAG-3 may be used in conjunction with CD38 to predict responsiveness to ICB in HCC.ReferencesNg HHM, Lee RY, Goh S, et al. Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma. J Immunother Cancer 2020;8.Hodi FS, Wolchok JD, Schadendorf D, et al. Abstract CT037: Genomic analyses and immunotherapy in advanced melanoma. AACR 2019.Lei M, Siemers NO, Pandya D, et al. Analyses of PD-L1 and Inflammatory Gene Expression Association with Efficacy of Nivolumab ± Ipilimumab in Gastric Cancer/Gastroesophageal Junction Cancer. Clinical Cancer Research 2021;27:3926–35.Sangro B, Melero I, Wadhawan S, et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol 2020.Ethics ApprovalThis study was approved by the Centralised Institutional Review Board of SingHealth (CIRB ref: 2009/907/B).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
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Cesano, Alessandra, Sophie Visonneau, Silvia Deaglio, Fabio Malavasi, and Daniela Santoli. "Role of CD38 and Its Ligand in the Regulation of MHC-Nonrestricted Cytotoxic T Cells." Journal of Immunology 160, no. 3 (February 1, 1998): 1106–15. http://dx.doi.org/10.4049/jimmunol.160.3.1106.
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Abstract Human CD38 is a type II transmembrane glycoprotein that regulates lymphocyte adhesion, proliferation, and cytokine production. The mAb Moon-1 recognizes a ligand for CD38 (CD38L) and specifically inhibits CD38-mediated cell adhesion. To analyze the role of CD38 and its ligand in MHC-nonrestricted T cell activation, we examined the effects of Moon-1 and the anti-CD38 mAb IB4 on the effector functions of the IL-2-dependent T cell line TALL-104 (CD3/TCR-αβ+, CD8+, CD56+) and of LAK cells (90% CD3+). TALL-104 cells were almost 100% reactive with both mAbs, whereas the reactivity of LAK cells for IB4 and Moon-1 ranged from 10 to 60% among different donors. From 78 to 94% of the cytotoxic CD8+/CD56+ LAK subset was CD38L+. Like mAb OKT3 (anti-CD3), and at variance with IB4, Moon-1 drastically enhanced the cytotoxicity of TALL-104 and CD8+ LAK cells against a resistant tumor target. Granule exocytosis did not appear to play a role in Moon-1-induced cytotoxicity. Moreover, neither IB4 nor Moon-1 induced [Ca2+]i mobilization in LAK and TALL-104 cells. Whereas stimulation of CD3 and CD38 resulted in a dramatic induction of cytokine (granulocyte-macrophage-CSF, IFN-γ, TNF-α, and TNF-β) release by both TALL-104 and LAK cells, ligation of CD38L was not followed by cytokine production in TALL-104 cells. Thus, cytotoxicity and cytokine release are independently regulated, at least in this system. These data demonstrate that CD38 and its ligand can regulate some T cell functions using signaling pathways distinct from those of CD3.
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Зыблева, С. В., and О. А. Сердюкова. "Peculiarities of the Immune Status of Patients with Atopic Dermatitis." Лабораторная диагностика. Восточная Европа, no. 4 (January 18, 2021): 413–19. http://dx.doi.org/10.34883/pi.2020.9.4.006.
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Цель. Выявление особенностей проявлений состояния иммунного статуса пациентов с атопическим дерматитом на основе комплексной оценки характеризующих его клинико-иммунологических показателей.Материалы и методы. Обследовано 155 пациентов с диагнозом «атопический дерматит», а также 64 здоровых добровольца, составивших группу сравнения.Оценены у них уровни лейкоцитов, эозинофилов, CD3+CD8+, CD19+, CD3+, CD3-CD16+CD56+, CD3+CD16+CD56+, CD3+CD4+, CD3+HLA-DR+, CD3+CD8+, HLADR+, CD3+CD4+HLADR+, CD3+CD38+, CD3+CD8+CD38+, CD3+CD4+CD38+, CD3+CD4+CD25+, CD3+CD4+CD25+highCD127+low, IgM, IgG, IgA,IgЕ, C3-компонент комплемента, C4-компонент комплемента.Результаты. У пациентов с атопическим дерматитом выявлено увеличение уровня Т-лимфоцитов преимущественно за счет субпопуляции Т-хелперов, рост CD3+-лимфоцитов, несущих маркеры ранней (CD38) и поздней (HLA-DR) активации. Обнаружено увеличение концентрации в сыворотке основных иммуноглобулинов M, G, E, С3- и С4-компонентов комплемента. Отмечено увеличение уровня активированных CD3+CD4+CD25+ (Т-хелперы активированные) и CD3+CD4+CD25+highCD127+low (Т-регуляторные) лимфоцитов. Выявлены более низкие (относительно группы сравнения) уровни общего количества лимфоцитов и субпопуляции натуральных киллеров.Выводы. Установлен многофакторный характер этиопатогенеза атопического дерматита со свойственными ему процессами сложного взаимодействия между иммунологическими и экзогенными компонентами организма. Механизмы нарушения иммунного гомеостаза у пациентов с атопическим дерматитом в фазе рецидива связаны с количественным и качественным изменениями иммунокомпетентных клеток, нарушениями их регуляторного и врожденного звеньев иммунитета. Purpose. Comprehensive assessment of clinical and immunological parameters in patients with atopic dermatitis.Materials and methods. We have examined 155 patients with atopic dermatitis. We have studied the levels of leukocytes, eosinophils, CD3+CD8+, CD19+, CD3+, CD3-CD16+CD56+, CD3+CD16+CD56+, CD3+CD4+, CD3+HLA-DR+, CD3+CD8+, HLADR+, CD3+CD4+HLADR+, CD3+CD38+, CD3+CD8+CD38+, CD3+CD4+CD38+, CD3+CD4+CD25+, CD3+CD4+CD25+highCD127+low, IgM, IgG, IgA, IgЕ, complementcomponent C3, complement component C4. The comparison group consisted of 64 healthy volunteers.Results. In patients with atopic dermatitis, the increase of the level of T-lymphocytes was revealed, mainly due to T-helpers subpopulation, the growth of CD3+ lymphocytes carrying markers of early (CD38) and late (HLA-DR) activation. We determined the increase of the concentration of the main classesofimmunoglobulins(IgM, IgG, IgE), complementcomponents C3 and C4 intheserum. Increase of the level of activated CD3+CD4+CD25+ (activated T-helpers) and CD3+CD4+CD25+highCD127+low (T-regulatory) lymphocytes was noted. The levels of the total number of lymphocytes and the natural killer subpopulation were found to be lower than in the comparison group.Conclusion. Thus, the etiopathogenesis of atopic dermatitis is multifactorial, and it is characterized by complex interactions between immunological and exogenous components. The mechanisms of failure of immune homeostasis in patients with atopic dermatitis in the relapse phase are associated with quantitative and qualitative changes in the immune-competent cells, disorders of their regulatory component and innate immunity component.
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Givens, Tara S., Brian K. DuChateau, Jonathan S. Boomer, Maxwell P. Westerman, Alice Gilman-Sachs, and Kenneth D. Beaman. "Regeneration and Tolerance Factor: a Correlate of Human Immunodeficiency Virus-Associated T-Cell Activation." Clinical Diagnostic Laboratory Immunology 6, no. 6 (November 1, 1999): 872–77. http://dx.doi.org/10.1128/cdli.6.6.872-877.1999.
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ABSTRACT Human immunodeficiency virus (HIV) infection causes extensive phenotypic alterations in lymphocytes. Cellular markers that are normally absent or expressed at low levels on quiescent cells are upregulated throughout the disease course. The transmembrane form of regeneration and tolerance factor (RTF) is expressed at negligible levels on resting T cells but is quickly upregulated following in vitro stimulation and activation. Recently, we reported that expression of RTF was significantly higher in cells from HIV-seropositive (HIV+) individuals than in cells from HIV-seronegative (HIV−) individuals. Because T cells from HIV+individuals express markers reflecting chronic activation, we hypothesized that these in vivo-activated cells would coexpress RTF. Flow cytometry was used to assess RTF expression on activated (CD38+ and HLA-DR+) CD4+ and CD8+ T cells. HIV+ individuals had higher percentages of RTF+ CD38+ (P< 0.0001) or RTF+ HLA-DR+ (P= 0.0001) CD4+ T cells than HIV− individuals. In HIV+ individuals, increased percentages of CD4+ T cells that were RTF+, RTF+CD38+, and RTF+ HLA-DR+ correlated inversely with the absolute number and percentage of CD4+ T cells and correlated positively with plasma β2-microglobulin concentrations. HIV+individuals had higher percentages of CD8+ T cells that were RTF+ CD38+ (P = 0.0001) or RTF+ HLA-DR+ (P = 0.0010). In HIV+ individuals, increased percentages of CD8+ T cells that were RTF+ HLA-DR+correlated inversely with the percentage of CD4+ T cells, and high percentages of CD8+ T cells that were RTF+ CD38+ correlated positively with plasma β2-microglobulin levels. These findings strongly suggest that increased RTF expression is a correlate of HIV-associated immune system activation.
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Stoeckler, J. D., H. A. Stoeckler, N. Kouttab, and A. L. Maizel. "1alpha,25-Dihydroxyvitamin D3 modulates CD38 expression on human lymphocytes." Journal of Immunology 157, no. 11 (December 1, 1996): 4908–17. http://dx.doi.org/10.4049/jimmunol.157.11.4908.
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Abstract B cells from chronically stimulated tonsils displayed high initial mean CD38 levels that declined during in vitro culture, despite ligation of CD40 and/or the Ag receptor in the presence of IL-4. Exposure to 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) restored the initial CD38 expression on these stimulated cells and up-regulated the Ag on stimulated CD38-/low cells. 1,25(OH)2D3 enhanced CD38 expression by four- to sixfold on CD8- and CD8+ peripheral blood T cells following PHA activation. The EC50 values for induction were 2 to 3 nM. Although all-trans-retinoic acid also induced CD38 expression on stimulated B and T cells, it was less effective than 1,25(OH)2D3. B cell CD38 expression was augmented less by 1,25(OH)2D3 than by IFN-alpha and IFN-gamma. However, T cell CD38 expression was induced more strongly by 1,25(OH)2D3 than by IFN-alpha, and was unaffected by IFN-gamma. The CD38 density on activated 1,25(OH)2D3-treated CD38-/low B and peripheral T cells was proportional to cell size, indicating that hormonal induction depended upon entry into the cell cycle. While IFNs induced CD38 rapidly in stimulated T and B lymphocytes, 1,25(OH)2D3 exerted its effects only after initial 1- to 3-day delays, suggesting a requirement for nuclear 1,25(OH)2D3 receptor up-regulation. In HL-60 cells, which constitutively express the nuclear receptors, 1,25(OH)2D3 rapidly induced CD38 Ag and ectoenzyme activity. The CD38 density on freshly isolated unfractionated tonsillar B lymphocytes and on the activated 1,25(OH)2D3-treated cultured cells was nearly identical for cells within the same size range, indicating that in vitro hormonal exposure reconstituted in vivo CD38 expression levels.
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Malickaitė, Radvilė, Laimutė Jurgauskienė, Stanislava Simanavičienė, Vytė Valerija Maneikienė, Rita Sudikienė, and Kęstutis Ručinskas. "Imuninė stebėsena širdies transplantacijoje: atmetimo reakcijos poveikis T limfocitų žymenų ekspresijai." Lietuvos chirurgija 8, no. 3 (January 1, 2010): 0. http://dx.doi.org/10.15388/lietchirur.2010.3.2103.
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Radvilė Malickaitė, Laimutė Jurgauskienė, Stanislava Simanavičienė, Vytė Valerija Maneikienė, Rita Sudikienė, Kęstutis Ručinskas Vilniaus universiteto Širdies ir kraujagyslių ligų klinikos Širdies chirurgijos centras, Santariškių g. 2, LT-08661 Vilnius El. paštas: Radvile.Malickaite@santa.lt Darbo tikslas: Nustatyti Vilniaus universiteto ligoninės Santariškių klinikų Širdies chirurgijos centre atliekamos širdies transplantacijos įtaką T limfocitų aktyvumo rodikliams, įvertinti imuninės stebėsenos tinkamumą ūminiam transplantato atmetimui prognozuoti. Ligoniai ir metodai: Retrospektyviai analizuotas dvidešimt vieno širdies recipiento imuninių rodiklių kitimas esant normaliai potransplantacinei būklei ir ūminiam transplantato atmetimui. Periferinio kraujo imunokompetentinių ląstelių CD3+CD103+, CD4+CD103+, CD8+CD103+, CD3+CD134+, CD4+CD134+, CD8+CD134+, CD8+CD57+ ir CD8+CD38+ procentas nustatytas tėkmės citometrijos būdu. Ūminis transplantato atmetimas vertintas pagal histologinius endomiokardinės biopsijos radinius. Rezultatai: Esant ūminio atmetimo epizodams, kai endomiokardo biopsijos įvertintos ≥ 2R (3A) laipsniu, reikšmingai didėja integrino CD103 (p < 0,0001), kostimuliacinio receptoriaus CD134 (p = 0,005), antigeno CD57 (p = 0,005) ir ląstelių paviršiaus glikoproteino CD38 (p = 0,015) ekspresija citotoksinių CD8+ limfocitų paviršiuje. Išvados: Imuninė periferinio kraujo limfocitų būklės stebėsena gali būti taikoma po transplantacijos skiriamam imunosupresiniam gydymui įvertinti numatant didelę ūminio atmetimo tikimybę. Reikšminiai žodžiai: kiaušidžių cistos, supiktybėjimo rizika, piktybiškumo rizikos indeksas, ultragarsinis tyrimas, Ca-125 antigenas, chirurginis gydymas Measuring T cell reactivity for predicting heart transplant rejection Radvilė Malickaitė, Laimutė Jurgauskienė, Stanislava Simanavičienė, Vytė Valerija Maneikienė, Rita Sudikienė, Kęstutis Ručinskas Vilnius University, Clinic of Cardiovascular Diseases, Centre of Heart sSurgery, Santariškių str. 2, LT-08661 Vilnius, Lithuania E-mail: Radvile.Malickaite@santa.lt Objective: We aimed to analyze alterations in peripheral blood T-cell subset activation compared with endomyocardial byopsy findings. Patients and methods: The study included in total twenty-one heart recipients grafted 1997–2007 at the Vilnius Heart sSurgery cCenter. T-cell activation markers CD3+CD103+, CD4+CD103+, CD8+CD103+, CD3+CD134+, CD4+CD134+, CD8+CD134+, CD8+CD57+ ir CD8+CD38+ were detected by two-color flow cytometry. Rejection was graded according to the ISHLT (the International Society of Heart and Lung Transplantation) grading system. Results: In case of ≥ 2R (3A) rejection episodes, a significant increase in the expression of integrin CD103 (p < 0.0001), co-stimulatory receptor CD134 (p = 0.005), antigen CD57 (p = 0.005) and surface glycoprotein CD38 (p = 0.015) on CD8+ T lymphocytes has been revealed. Conclusion: Immune monitoring performed on peripheral blood can be used for the assessment of immunosuppression therapy on transplant recipients’ immune response and for determining the risk of rejection. Key words: heart transplantation, acute rejection, and immune activation
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Tarbiah, Nesrin I., Nuha A. Alkhattabi, Abdullah J. Alsahafi, Hani S. Aljahdali, Husam M. Joharjy, Maryam H. Al-Zahrani, Aliaa M. Sabban, Rana A. Alghamdi, Maha J. Balgoon, and Reham A. Khalifa. "T Cells Immunophenotyping and CD38 Overexpression as Hallmarks of the Severity of COVID-19 and Predictors of Patients’ Outcomes." Journal of Clinical Medicine 12, no. 2 (January 16, 2023): 710. http://dx.doi.org/10.3390/jcm12020710.
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Background: By the end of 2019, the COVID-19 pandemic spread all around the world with a wide spectrum of clinical presentations ranging from mild to moderate to severe or critical cases. T cell subtype dysregulation is mostly involved in the immunopathogenic mechanism. The present study aimed to highlight the role of monitoring T cell subtypes and their activation (expression of CD38) in COVID-19 patients compared to healthy subjects and their role in predicting severity and patients’ outcomes. Materials: The study involved 70 adult COVID-19 confirmed cases stratified into three groups: a mild/asymptomatic group, a clinically moderate group, and a clinically severe/critical group. Flow cytometry analysis was used for the assessment of CD3+ cells for total T cell count, CD4+ cells for helper T cells (Th), CD8+ cells for cytotoxic T cells (Tc), CD4+CD25+ cells for regulatory T cells (T reg), and CD38 expression in CD4+ T cells and CD8+ T cells for T cell activation. Results: A statistically significant difference was found between COVID-19 cases and healthy controls as regards low counts of all the targeted T cell subtypes, with the lowest counts detected among patients of the severe/critical group. Furthermore, CD38 overexpression was observed in both CD4+ and CD8+ T cells. Conclusion: Decreased T cell count, specifically CD8+ T cell (Tc), with T cell overactivation which was indicated by CD38 overexpression on CD4+ and CD8+ T cells had a substantial prognostic role in predicting severity and mortality among COVID-19 patients. These findings can provide a preliminary tool for clinicians to identify high-risk patients requiring vigilant monitoring, customized supportive therapy, or ICU admission. Studies on larger patient groups are needed.
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Kumar, Sandeep, Sunil Kumar Singh, Navin Viswakarma, Gautam Sondarva, Rakesh Sathish Nair, Periannan Sethupathi, Matthew Dorman, et al. "Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8+ T cells." Journal for ImmunoTherapy of Cancer 8, no. 2 (August 2020): e000494. http://dx.doi.org/10.1136/jitc-2019-000494.
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BackgroundThe mitogen-activated protein kinases (MAPKs) are important for T cell survival and their effector function. Mixed lineage kinase 3 (MLK3) (MAP3K11) is an upstream regulator of MAP kinases and emerging as a potential candidate for targeted cancer therapy; yet, its role in T cell survival and effector function is not known.MethodsT cell phenotypes, apoptosis and intracellular cytokine expressions were analyzed by flow cytometry. The apoptosis-associated gene expressions in CD8+CD38+ T cells were measured using RT2 PCR array. In vivo effect of combined blockade of MLK3 and CD70 was analyzed in 4T1 tumor model in immunocompetent mice. The serum level of tumor necrosis factor-α (TNFα) was quantified by enzyme-linked immunosorbent assay.ResultsWe report that genetic loss or pharmacological inhibition of MLK3 induces CD70-TNFα-TNFRSF1a axis-mediated apoptosis in CD8+ T cells. The genetic loss of MLK3 decreases CD8+ T cell population, whereas CD4+ T cells are partially increased under basal condition. Moreover, the loss of MLK3 induces CD70-mediated apoptosis in CD8+ T cells but not in CD4+ T cells. Among the activated CD8+ T cell phenotypes, CD8+CD38+ T cell population shows more than five fold increase in apoptosis due to loss of MLK3, and the expression of TNFRSF1a is significantly higher in CD8+CD38+ T cells. In addition, we observed that CD70 is an upstream regulator of TNFα-TNFRSF1a axis and necessary for induction of apoptosis in CD8+ T cells. Importantly, blockade of CD70 attenuates apoptosis and enhances effector function of CD8+ T cells from MLK3−/− mice. In immune-competent breast cancer mouse model, pharmacological inhibition of MLK3 along with CD70 increased tumor infiltration of cytotoxic CD8+ T cells, leading to reduction in tumor burden largely via mitochondrial apoptosis.ConclusionTogether, these results demonstrate that MLK3 plays an important role in CD8+ T cell survival and effector function and MLK3-CD70 axis could serve as a potential target in cancer.
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Steel, Alan, Alison E. Cox, Mohamed H. Shamji, Laurence John, Mark Nelson, Don C. Henderson, Frances M. Gotch, Brian G. Gazzard, and Peter Kelleher. "HIV-1 Viral Replication below 50 Copies/ml in Patients on Antiretroviral Therapy is not associated with CD8+ T-cell Activation." Antiviral Therapy 12, no. 6 (August 2007): 971–76. http://dx.doi.org/10.1177/135965350701200613.
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Objectives To determine if the expression of CD38 on CD8+ T-cells could be used as a marker of viral replication <50 copies/ml in peripheral blood. Methods In a cross-sectional study of patients attending a single HIV clinic in London, an ultra-sensitive HIV RNA viral load assay, with a limit of detection of 3 copies/ml, was used to determine HIV-1 replication in plasma in 70 patients who had sustained viral suppression <50 copies/ml by bDNA assays. Immune activation using the expression of CD38 on CD8+ T-cells was also assessed in patients on antiretroviral therapy (ART) with sustained viral suppression, individuals with persistent low-level viraemia <400 copies/ml and subjects failing ART (viral load >400 copies/ml). Results There was no significant difference in the percentage of CD8+CD38++ T-cells between patients with <50 copies or <3 copies/ml. Immune activation was significantly increased in patients with persistent low-level viraemia and in subjects failing ART. CD4+ T-cell counts in patients on long-term successful ART are inversely associated with CD8+ T-cell activation. Conclusions T-cell activation in patients on long-term successful ART is not due to residual low-level viral replication in the blood compartment of HIV-1. CD8+ T-cell activation in this patient group appears to be associated with poor CD4+ T-cell recovery.
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Zybleva, S. V., and S. L. Zyblev. "Immunological cluster complexes in kidney transplantation." Medical Immunology (Russia) 24, no. 1 (March 10, 2022): 69–80. http://dx.doi.org/10.15789/1563-0625-icc-2212.
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Laboratory tests are significant for the detection of immunopathological disorders in kidney transplantation. As a rule, the choice of tests is carried out individually and is based on the clinical characteristics and the presumptive diagnosis. Most often, in patients after kidney transplantation, atypical and not always standard changes in immunological parameters are observed, which is associated with a combination of many factors leading to different immune responses. All this served as the basis for typing immunological parameters in renal allograft recipients using one of the methods of system analysis – cluster analysis. Kidney transplantation was performed in 104 recipients. Immunological examination was performed on the 360th day after the surgery. The following groups of recipients were identified: KTR1 – with primary graft function on the 7th day and satisfactory graft function within a year, KTR2 – with renal graft dysfunction on the 7th day and within a year. By means of cluster analysis, immunotypes of regulatory complexes were detected and characterized in various courses of the post-transplant period. To assess the immune response in allogeneic kidney transplantation, a set of immune cells with a phenotype should be determined: CD3+CD4+CD25+highCD127+low, CD3+CD4-CD8-, CD3+CD4+CD69+, CD3+CD16+CD56+, CD19+CD5+, LIN-HLA-DR+CD11c-CD123+, CD3+CD8+CD69+, CD3+CD4+CD8+, CD3+CD8+CD38+, CD19+CD86+, CD19+IgD+CD27-, CD3-CD16+CD56+, CD3+CD38+, CD14+lowCD86+, LIN-HLA-DR+CD11c+CD123-. According to our data, the immunological cellular composition of the central point of clustering of the tolerogenic immunological complex is represented by regulatory CD3+CD4+CD25+highCD127+low and double-negative CD3+CD4-CD8-T lymphocytes. The composition of the central point of clustering of the hyperergic immunological complex is represented by the cooperation of CD3+CD8+CD69+ and CD3+CD4+CD8+ cells. The structure of the tolerogenic immune response in patients after kidney transplantation is based on intercellular interactions, which has a hierarchical system, the basis of which is represented by the cooperation of regulatory cells CD3+CD4+CD25+highCD127+low, CD3+CD4-CD8-, CD3+CD4+CD69+, CD3+CD16+CD56+, CD19+CD5+, LIN-HLA-DR+CD11c-CD123+. The hyperergic variant of the immune response in renal allograft transplantation is based on excessive activation of the following links of the immune response: CD3+CD8+CD38+, CD19+CD86+, CD3+CD38+, LIN-HLADR+CD11c+CD123-, CD19+IgD+CD27-, CD3-CD16+CD56+, CD3+CD8+CD69+ and CD14+lowCD86+. The detected immunotypes will make it possible to implement a personalized approach to the diagnosis and treatment of patients with various types of immune response in kidney transplantation.
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Siewe, Basile, Jack Stapleton, Jeffrey Martinson, Ali Keshavarzian, Nazia Kazmi, Patricia Demarais, Audrey French, and Landay Alan. "Selective Depletion of CD19+CD24hiCD38hiIL-10high Regulatory B cells (Bregs) in HIV-infected Aviremic Individuals (76.2)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 76.2. http://dx.doi.org/10.4049/jimmunol.188.supp.76.2.
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Abstract HIV-infection associated upregulation of IL-10 contributes to impaired antiviral effector T-cell functions promoting viral persistence. Bregs (CD19+CD24hiCD38hi) IL-10-mediated modulation of T-cell function has been reported in autoimmune disease but yet undefined during HIV infection. In this study, we confirmed high expression of IL-10 by Bregs in healthy controls (HC, n=16) and determined Breg frequency, T-cell immune activation (CD8+HLA-DR+CD38+, CD4+HLA-DR+CD38) and T-cell exhaustion (CD8+PD-1+) in aviremic (HIVavir, n=10) and viremic (HIVvir, n=15) HIV-infected individuals. We found a significant positive correlation between Breg frequency and viral load (r2=0.5166, p=0.0097); HIVavir-individuals exhibited a significant Bregs loss compared to HC (p=0.0004) and HIVvir-individuals (p=0.0122), despite no significant differences in total B-cell frequency. A significant positive correlation was observed between Breg frequency and immune activation (CD8+HLA-DR+CD38+, r2=0.6262, p=0.0041; CD4+HLA-DR+CD38+, r2=0.6298, p=0.0039) as well as T-cell exhaustion (r2=0.8853, p=0.0333). Additionally, we found a significant difference in Breg CD95 (Fas) expression between HIVavir and HIVvir-individuals (p=0.0119) yet no such difference between in HIVavir-individuals and HC. We hypothesize that, Bregs loss during HIV-infection may be due to Fas mediated apoptosis and that activated IL-10-secreting Bregs contribute to T cell impairment hence viral persistence in HIVvir individuals.
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Зыблева, С. В., and С. Л. Зыблев. "Cluster Analysis of Leukocyte Subpopulations in Kidney Transplantation." Гематология. Трансфузиология. Восточная Европа, no. 2 (November 8, 2021): 168–75. http://dx.doi.org/10.34883/pi.2021.7.2.005.
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Цель. Выявить варианты иммунного реагирования у пациентов при трансплантации почки на основе кластерного анализа, характеризующие течение посттрансплантационного периода. Материалы и методы. Обследовано 104 реципиента почечного трансплантата с терминальной стадией хронической болезни почек, которым выполнена трансплантация аллогенной почки, а также 90 здоровых добровольцев, составивших группу сравнения. Оценены уровни лейкоцитов с использованием метода проточной цитометрии по безотмывочной технологии с использованием моноклональных антител (Beckman Coulter и BD, США) CD4 PС7, CD8 FITC, CD3 PС5.5, CD3 FITC, CD45 PerCP, CD19 APC, CD56+ CD16 PE, CD3 PC5.5, HLA-DR APC, CD38 PE, CD4 FITC, CD3 PC5.5, CD8 APC, CD69 PE, CD127 PЕ, CD25 АРС CD154 PЕ, CD3 APCAF750, IgD FITC, CD27 PC5.5, CD5 APC-AF750, CD40РЕ, CD86 РЕ, CD14 PС7, CD64 FITC, CD86 PЕ LIN PE, CD123 PC7, Anti-HLADR APC-AF750 в объемах, рекомендуемых фирмой-производителем. Результаты и обсуждение. В результате проведенного исследования разработана система оценки иммунного статуса реципиента почечного трансплантата, обеспечивающая персонифицированный мониторинг, анализ и прогнозирование течения посттрансплантационного периода. Описаны виды регуляторных клеточных сетей и их синергический потенциал при трансплантации почки. В основе толерогенного иммунологического комплекса у пациентов после трансплантации почки лежат межклеточные взаимодействия, имеющие иерархическую систему, основа которой представлена кооперацией клеток CD3+CD4+CD25+highCD127+low, CD3+CD4-CD8-, CD3+CD4+CD69+, CD3+CD16+CD56+, CD19+CD5+ и LIN-HLA-DR+CD11c-CD123+. Воснове гиперергического иммунологического комплекса при почечной аллотрансплантации лежат избыточно активированные компоненты иммунного ответа: CD3+CD8+CD69+, CD3+CD4+CD8+, CD3+CD8+CD38+, CD19+CD86+, CD19+IgD+CD27-, CD3-CD16+CD56+, CD3+CD38+, CD14+lowCD86+, и LIN-HLA-DR+CD11c+CD123клетки. Выводы. Выделенные иммунофенотипы позволят осуществить персонифицированный подход к диагностике и лечению пациентов с различными вариантами иммунного реагирования при трансплантации почки. При выявлении иммунофенотипа, соответствующего толерогенному варианту иммунного ответа, терапию пациента в отдаленном посттрансплантационном периоде возможно проводить с учетом низкого иммунологического риска и минимизацией иммуносупрессивной нагрузки. Purpose. To identify the variants of immune response in patients with kidney transplantation on the base of cluster analysis that characterize the course of the post-transplant period. Materials and methods. We examined 104 kidney transplant recipients with end-stage chronic kidney disease, who underwent allograft transplantation, as well as 90 healthy volunteers, who made up the comparison group. Their leukocyte levels were assessed using no-wash flow cytometry with monoclonal antibodies (Beckman Coulter and BD, USA) CD4 PС7, CD8 FITC, CD3 PС5.5, CD3 FITC, CD45 PerCP, CD19 APC, CD56+ CD16 PE, CD3 PC5.5, HLA-DR APC, CD38 PE, CD4 FITC, CD3 PC5.5, CD8 APC, CD69 PE, CD127 PЕ, CD25 АРС CD154 PЕ, CD3 APC-AF750, IgD FITC, CD27 PC5.5, CD5 APC-AF750, CD40РЕ, CD86 РЕ, CD14 PС7, CD64 FITC, CD86 PЕ LIN PE, CD123 PC7, Anti-HLADR APC-AF750 in the volumes recommended by the manufacturer. Results and discussion. As a result of the conducted study, the system for assessing the immune status of a kidney transplant recipient was developed, which provides personalized monitoring, analysis, and prediction of the course of the post-transplant period. The types of regulatory cellular networks and their synergistic potential in kidney transplantation are described. The tolerogenic immunological complex in patients after kidney transplantation is based on intercellular interactions that have a hierarchical system, the base of which is represented by the cooperation of CD3+CD4+CD25+highCD127+low, CD3+CD4-CD8-, CD3+CD4+CD69+, CD3+CD16+CD56+, CD19+CD5+ and LIN-HLA-DR+CD11c-CD123+ cells. The hyperergic immunological complex in renal allotransplantation is based on over-activated components of the immune response: CD3+CD8+CD69+, CD3+CD4+CD8+, CD3+CD8+CD38+, CD19+CD86+, CD19+IgD+CD27-, CD3-CD16+CD56+, CD3+CD38+, CD14+lowCD86+, and LIN-HLA-DR+CD11c+CD123- cells. Conclusion. The detected immunotypes will let to implement the personalized approach to the diagnostics and treatment of patients with various types of immune response in kidney transplantation. If an immunophenotype corresponding to a tolerogenic variant of the immune response is identified, the patient’s therapy in the long-term post-transplant period can be carried out taking into account the low immunological risk and minimizing the immunosuppressive load.
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Crawford, Timothy, Frederick Hecht, Lishomwa Ndhlovu, and Jason Barbour. "Activated CD8+ T cells exhibit blunted effector functions in early HIV-1 disease (P3035)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 55.18. http://dx.doi.org/10.4049/jimmunol.190.supp.55.18.
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Abstract Elevated, persistent CD8+ T cell activation is a hallmark of HIV-1 infection. CD8+ T cell activation is measured by expression of CD38 and HLA-DR antigens on CD8+ T cells from the blood. How CD8+ T cell activation state may define impairments to CD8+ T cell function remains unclear. ERK1/2 signaling is critical for multiple T cell functions, and interruption of this pathway due to immune activation and inflammation may blunt CD8+ T cell function. We previously demonstrated that a major proportion of activated (CD38+HLA-DR+) CD8+ T cells from recently HIV-1-infected antiretroviral-treatment-naïve adults are refractory to phosphorylation of the ERK1/2 kinases (p-ERK1/2-refractory). Here we hypothesized that p-ERK1/2-refractory CD8+ T cells would exhibit reduced effector function compared to CD8+ p-ERK1/2-responsive cells. We combined single-cell phospho-kinase flow cytometry with intracellular cytokine staining into a single assay (PFICS), to examine IFN-γ and perforin responses in CD8+ T cells by ERK1/2 signaling ability. On a per cell basis, p-ERK1/2-refractory cells produced less IFN-γ in response to polyclonal or HIV-1 Gag peptide stimulation (% IFN-γ+ cells was 5.5-fold lower, p=0.006 for polyclonal and 1.5-fold lower, p=0.048 for Gag) and expressed reduced levels of perforin (2.1 and 1.6-fold lower perforin MFI). Blunted CD8+ T effector functions, secondary to ERK1/2 signaling deficits concentrated within activated CD8+ T cells, may contribute to HIV immunodeficiency.
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Puspitawati, Ira, and Umi S. Intansari. ", DALAM KEADAAN (STATUS) IMUNOLOGIS DAN KLINIS PENGOBATAN ANTIRETROVIRAL PENDERITA HIV/AIDS CD38 LIMFOSIT CD8 + , TAMPANG (PROFIL) CD4 +." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 16, no. 1 (March 17, 2018): 32. http://dx.doi.org/10.24293/ijcpml.v16i1.994.
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ABSTRACTThe relationship between immune activation and pathogenesis of Human Immunodeficiency Virus (HIV) infection is unproven. It has been hypothesized that state that HIV-induced activation enhances the magnitude of HIV replication other study shown that viralreplication impaired immune activation. One of the best immune activation marker is CD38 expression on CD8because it has thestrongest significant prognostic markers. It was previously shown that increased CD8+ T-cell activation has predictive value for diseaseprogression but the relation is still controversial. One hypothesis state that HIV-induced activation enhances the magnitude of HIVreplication, other said that viral replication impaired immune activation. To know the profile of immunology and clinical state of HIV/AIDS patients by determining the CD38 molecule expression on CD8+ profiles and clinical state.Crosssectonal, observasional study was done. Twenty nine HIV/AIDS patients who routinely had medical check up and having routine +cells as an activation marker, CD4+antiretroviral therapy at Sardjito hospital and 8 healthy people as normal controls were involved in this study. The count of CD4 +cells counts had significantnegative correlation with WHO stage (p = 0.012). Expression of CD38 molecule on CD8absolute counts and expression of CD38 molecule on CD8 cells were measured using flowcytometry. The CD4+cells of HIV/AIDS patients were highercompared to normal controls, 209.29 ± 76.56, 109.61 + 32.29 respectively (p < 0.05). That expression was not correlated with CD4 + +counts and CD4incrementafter therapy was statistically significant (p = 0.003). The CD4+increment. It might be caused by the time of measurement was not at the begining of diseases. The CD4 + count was negatively correlated with the WHO stage. Expression ofCD38 molecule on CD8+ cells of HIV/AIDS patients were significantly higher compared to normal controls but it wasn’t correlated withthe CD4++ number and CD4+increment after therapy.
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Drent, Esther, Richard Groen, Willy A. Noort, Jeroen Lammerts van Bueren, Paul W. H. I. Parren, Jurgen H. Kuball, Zsolt Sebestyen, et al. "CD38 Chimeric Antigen Receptor Engineered T Cells As Therapeutic Tools for Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 4759. http://dx.doi.org/10.1182/blood.v124.21.4759.4759.
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Abstract Chimeric Antigen Receptors (CARs) are engineered constructs consisting of an antibody-derived antigen recognition domain linked to intracellular T cell signaling domains. Cytotoxic T cells transduced to express tumor-reactive CARs are highly promising tools for immunotherapy of cancer. The CD38 molecule, with its high and homogenous expression on Multiple Myeloma (MM) tumor cells, is considered a suitable target for antibody therapy of MM. Prompted by this, we evaluated the feasibility and efficacy of targeting MM cells with CD38-CAR-transduced T cells (CD38-CAR T cells). To this end, we generated three different retroviral CAR constructs based on human CD38 antibodies as antigen recognition domain, CD3zeta and 41BB (CD137) as signaling domains and transduced them into PBMCs of a healthy donor. After in vitro selection and expansion, all CD38-CAR T cells, either unsorted or CD4/CD8 sorted, effectively lysed MM cell lines in a dose-, and CD38 expression-dependent manner, with a better efficacy for the CD8+ fraction. CD38-CAR T cells also effectively eradicated primary MM cells in the bone marrow mononuclear cells derived from MM patients, indicating their clinical relevancy. Although CD38-CAR T cells also displayed cytotoxic activity against the CD38+ fraction of mature monocytes and NK cells and to a lesser extent CD38+ B and T cells, they did not affect the outgrowth of CD34+ cells into various myeloid lineages. In addition,CD38-CAR T cell activity was effectively controllable by transducing them with a caspase 9-based inducible suicide gene. More interestingly, we discovered that the CD38-CAR T cells were themselves devoid of CD38 surface expression, indicating that CD38 was not essential for T cell expansion and function. Finally, in a novel in vivo xenotransplant model (UM9 cell line), in which myeloma cells were grown in a humanized bone marrow microenvironment, i.v. as well as intra tumor administration of CD38-CAR T cells established significant anti-tumor effects, proving that CD38-CAR endowed cytotoxic T lymphocytes, even with no CD38 expression, can efficiently migrate, infiltrate and eliminate human MM tumors growing in their natural niche. These results demonstrate the feasibility and potency of CAR mediated targeting of CD38+ MM cells. Optimization of CD38-CAR and suicide-gene control of CD38 CAR T cellsmay provide next steps towards safe clinical implementation of CD38-CAR T cell immune therapy. Disclosures Drent: Genmab BV: Guest employee (unpaid) Other. Lammerts van Bueren:Genmab : Employment. Parren:Genmab: Employment, Equity Ownership. van de Donk:Genmab BV: Research Funding; J&J: Research Funding; Celgene: Research Funding. Martens:Genmab BV: Research Funding; J&J: Research Funding; Celgene: Research Funding. Lokhorst:Celgene: Research Funding; J&J: Research Funding; Genmab: Research Funding. Mutis:Celgene: Research Funding; J&J: Research Funding; Genmab BV: Research Funding.
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Ostendorf, L., P. Enghard, P. Durek, F. Heinrich, M. F. Mashreghi, G. R. Burmester, A. Radbruch, F. Hiepe, and T. Alexander. "AB0138 INCREASED CD38 EXPRESSION LEVELS ON IMMUNE CELL SUBSETS IN SYSTEMIC LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1369.2–1370. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6531.
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Background:Plasma Cells (PCs) are implicated in the pathogenesis of Systemic Lupus erythematosus (SLE) and their targeting proved a promising treatment modality. As there is a monoclonal therapeutic antibody targeting CD38 licensed for clinical use in multiple myeloma, plasma cell depletion via CD38 seems to represent a promising path in SLE treatment. While CD38 Is highly expressed on plasmacells, it is present on the surface of subsets of T and B lymphocytes as well as myeloid cells.Objectives:Here we aim to identify the differential expression of CD38 on peripheral blood leukocytes in SLE compared to healthy controls (HC) investigate the function of CD38+ T lymphocytesMethods:We performed flow cytometry to investigate the expression of CD38 on peripheral blood mononuclear cells of SLE patients (n=36) and HCs (n=20). We additionally analyzed the expression of T lymphocytes within the urine of patients with lupus nephritis as well as the skin of SLE patients. We investigated the inflammatory potential of CD38 positive memory T lymphocytes after stimulation and performed single-cell RNA sequencing analyses.Results:CD38 Expression is increased on certain immune cell subsets: Plasmablasts and unswitched Memory B cells, as well as plasmacytoid dendritic cells and CD16+ non-classical monocytes. We observed a drastic increase CD38 in both memory CD4 and CD8 T lymphocytes in SLE patients. These cells were mostly effector T cells (and not regulatory T cells) and expressed other markers of T cell activation and proliferation. We found an enrichment of CD38+ memory T cells in the urine of patients with lupus nephritis. After polyclonal stimulation of T cells, CD38+ produced less inflammatory cytokines. Preliminary single-cell sequencing results indicate that CD38+ CD8+ T-lymphocytes have decreased clonal diversity and that these cells express genes associated with exhaustion and type 1 interferon response.Conclusion:Increased CD38 expression on various lymphocyte subsets provides an additional rationale for investigating CD38-directed therapies in SLE. Targeting CD38 could not only deplete plasma cells but also has the potential to target interferon alpha producing plasmacytoid dendritic cells and modulate inflammatory T cell functions.Disclosure of Interests:Lennard Ostendorf: None declared, Philipp Enghard: None declared, Pawel Durek: None declared, Frederik Heinrich: None declared, Mir-Farzin Mashreghi: None declared, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Andreas Radbruch: None declared, Falk Hiepe: None declared, Tobias Alexander: None declared
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Bean, Andrew G. D., Dale I. Godfrey, Walter G. Ferlin, Leopoldo Santos-Argumedo, R. Michael E. Parkhouse, Maureen C. Howard, and Albert Zlotnik. "CD38 expression on mouse T cells: CD38 defines functionally distinct subsets of αβ TCR+CD4−CD8−thymocytes." International Immunology 7, no. 2 (1995): 213–21. http://dx.doi.org/10.1093/intimm/7.2.213.
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Kassu, Afework, Aster Tsegaye, Beyene Petros, Dawit Wolday, Ermias Hailu, Tesfaye Tilahun, Binyam Hailu, et al. "Distribution of Lymphocyte Subsets in Healthy Human Immunodeficiency Virus-Negative Adult Ethiopians from Two Geographic Locales." Clinical Diagnostic Laboratory Immunology 8, no. 6 (November 1, 2001): 1171–76. http://dx.doi.org/10.1128/cdli.8.6.1171-1176.2001.
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ABSTRACT Immunological values for 562 factory workers from Wonji, Ethiopia, a sugar estate 114 km southeast of the capital city, Addis Ababa, Ethiopia, were compared to values for 218 subjects from Akaki, Ethiopia, a suburb of Addis Ababa, for whom partial data were previously published. The following markers were measured: lymphocytes, T cells, B cells, NK cells, CD4+ T cells, and CD8+ T cells. A more in depth comparison was also made between Akaki and Wonji subjects. For this purpose, various differentiation and activation marker (CD45RA, CD27, HLA-DR, and CD38) expressions on CD4+ and CD8+ T cells were studied in 60 male, human immunodeficiency virus-negative subjects (30 from each site). Data were also compared with Dutch blood donor control values. The results confirmed that Ethiopians have significantly decreased CD4+ T-cell counts and highly activated immune status, independent of the geographic locale studied. They also showed that male subjects from Akaki have significantly higher CD8+ T-cell counts, resulting in a proportional increase in each of the CD8+ T-cell compartments studied: naı̈ve (CD45RA+CD27+), memory (CD45RA−CD27+), cytotoxic effector (CD45RA+CD27−), memory/effector (CD45RA−CD27−), activated (HLA-DR+CD38+), and resting (HLA-DR−CD38−). No expansion of a specific functional subset was observed. Endemic infection or higher immune activation is thus not a likely cause of the higher CD8 counts in the Akaki subjects. The data confirm and extend earlier observations and suggest that, although most lymphocyte subsets are comparable between the two geographical locales, there are also differences. Thus, care should be taken in extrapolating immunological reference values from one population group to another.
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Burns, M., L. Ostendorf, A. Grützkau, F. Hiepe, T. Alexander, and H. Mei. "POS0420 DYSREGULATED CD38 EXPRESSION ON PERIPHERAL BLOOD IMMUNE CELL SUBSETS IN SLE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 439.1–439. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3883.
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Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by pathogenic antinuclear autoantibodies, which are secreted by autoreactive plasma cells. Among novel plasma cell-depleting strategies, CD38 has been identified as promising target. The monoclonal anti-CD38 antibody daratumumab is approved for treatment of multiple myeloma and provided a therapeutically relevant depletion of plasma cells in patients with SLE1.Objectives:Beyond plasma cells, CD38 is widely expressed across innate and adaptive immune cells and additional cellular targets of anti-CD38 treatment, especially in patients with SLE, are largely unknown. Therefore, this study aimed to systematically characterize the expression of CD38 in peripheral blood leukocytes to identify potential target cells of CD38-directed therapies that may contribute to or limit therapeutic benefits in SLE.Methods:We analyzed the expression of CD38 on peripheral blood leukocytes in two different cohorts, comprising a total of 56 SLE patients and 39 healthy controls, by flow and mass cytometry. CD38 expression levels across major immune cells were analyzed for changes between controls and SLE, as well as for correlation across immune cell lineages, and with clinical and serological disease parameters.Results:We detected increased CD38 expression levels on circulating NK cells, plasmacytoid dendritic cells, CD4+ and CD8+ memory T cells, as well as IgD-CD27- and marginal zone-like B cells in SLE compared to healthy controls. In myeloid and NK cells, CD38 expression was associated with an activated cellular phenotype, reflected by co-expression of molecules such as HLA-DR, CD11c or Syk. In the B cell compartment, IgA- plasmablasts and plasma cells expressed more CD38 than their IgA+ counterparts. Also, HLA-DRhigh plasmablasts showed higher CD38 expression compared to HLA-DRlow plasma cells. The strongest differences in CD38 expression between controls and SLE were found in CD8+ central and effector memory T cells. Additionally, we detected an expansion in CD38high and CD38int cells in the T cell memory compartment, with some patients showing distinctly increased expression values. We observed a high intra-individual correlation of CD38 expression across immune cell lineages, yet without correlation of CD38 expression levels with clinical activity (SLEDAI-2K), serological markers of SLE or the type I interferon surrogate marker CD169 (SIGLEC-1).Conclusion:Our data indicate that not only pathogenic plasma cells are potential target cells of CD38-targeting antibodies. The highly dysregulated CD38 expression across innate and adaptive immune cells in SLE could be of pathophysiological importance with respect to the potential efficacy and side effects of such therapies. Since CD38 expression did not correlate with disease activity, it may be assumed that it is not a response protein solely induced and modulated by type I interferons. Nevertheless, our comprehensive characterization of CD38 expression in the immune system might have important implications for personalized approaches with emerging CD38-directed therapeutics.References:[1]Ostendorf, L. et al. Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N. Engl. J. Med. 383, 1149–1155 (2020).Disclosure of Interests:None declared
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D’Abramo, Alessandra, Maria Antonella Zingaropoli, Alessandra Oliva, Claudia D’Agostino, Samir Al Moghazi, Giulia De Luca, Marco Iannetta, Claudio Maria Mastroianni, and Vincenzo Vullo. "Immune Activation, Immunosenescence, and Osteoprotegerin as Markers of Endothelial Dysfunction in Subclinical HIV-Associated Atherosclerosis." Mediators of Inflammation 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/192594.
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HIV-infected patients have a significantly greater risk of cardiovascular disease. Several markers including osteoprotegerin have been shown to be involved in the development and progression of atherosclerosis. We investigated the relationship between T-cell phenotype, osteoprotegerin, and atherosclerosis evaluated by carotid intima-media thickness (c-IMT) in 94 HIV+ patients on suppressive antiretroviral therapy with Framingham score <10%. As for the control group, 24 HIV-negative subjects were enrolled. c-IMT was assessed by ultrasound. CD4+/CD8+ T-cell activation (CD38+ HLADR+) and senescence (CD57+ CD28−) were measured by flow cytometry. IL-6 and OPG levels were measured by ELISA kit. c-IMT was higher in HIV+ than in controls. Among HIV+ patients, 44.7% had pathological c-IMT (≥0.9 mm). CD8+ T-cell activation and senescence and OPG plasma levels were higher in HIV+ patients than in controls. Subjects with pathological c-IMT exhibited higher CD8+ immune activation and immunosenescence and OPG levels than subjects with normal c-IMT. Multivariate analysis showed that age, CD8+ CD38+ HLADR+, and CD8+ CD28− CD57+ were independently associated with pathological c-IMT. Several factors have been implicated in the pathogenesis of atherosclerosis in HIV patients. Immune activation and immunosenescence of CD8+ T cell together with OPG plasma levels might be associated with the development and progression of early atherosclerosis, even in the case of viral suppression.
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Kitadate, Akihiro, Hiroki Kobayashi, Yoshiaki Abe, Kentaro Narita, Daisuke Miura, Masami Takeuchi, and Kosei Matsue. "CD38 Expression Levels on Myeloma Cells and the Frequency of Circulating CD38-Positive Treg Cells Are Associated with the Response to Daratumumab in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 1883. http://dx.doi.org/10.1182/blood-2018-99-113737.
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Abstract Background: CD38 is highly expressed on plasma cells and is a good target for multiple myeloma (MM) therapies. Daratumumab (DARA), a humanized antibody to CD38, has emerged as a promising treatment for MM. DARA targets CD38-expressing myeloma and non-plasma cells, including CD38-positive (CD38+) regulatory T (Treg) cells. To investigate the mechanism of action of DARA, we analyzed baseline CD38 expression levels and lymphocyte subsets, including CD38+ Treg cells, before and after DARA treatment. Methods: This study comprised 32 patients with relapsed/refractory MM, who were treated with DARA at our Center and were followed up for more than one cycle of the drug. Peripheral blood and bone marrow samples were analyzed before and during treatment. Using flow cytometric analysis, CD38 expression (mean fluorescence intensity (MFI)) and lymphocyte subsets (CD4/CD8 T cells, natural killer (NK) cells, and Treg cells) were evaluated. Treg cells were identified as a fraction of the CD4+CD25highCD127dim population. Results: The median age of the patients was 78 years (range, 53-92 years). Twenty-two patients (69%) had received more than three prior therapies. Patients received a median of four prior lines of therapy (range, 2-11 prior therapies). All patients were refractory to their last line of therapy, and 89% were refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). Eight patients (25%) received a PI-based DARA-containing regimen, 21 (66%) received an IMiD-based DARA-containing regimen, and 3 (9%) received other DARA-containing regimens. Twenty patients (63%) had a partial response (PR) or better (responders), whereas 12 patients (37%) did not respond to the drug (non-responders). The pretreatment levels of CD38 MFI were significantly higher in responders than in non-responders (p < 0.0005). Before treatment, the absolute number of CD38+ Treg cells was significantly higher in responders (median, 12.3 cells/µL; range, 5.1-37.3 cells/µL) than in non-responders (median, 4.5 cells/μL; range, 1.1-12.8 cells/µL, p = 0.001), but absolute Treg cell numbers were not associated with DARA response. CD38+ Treg cells were depleted in all treated patients, but CD38-negative Treg cell numbers remained relatively stable after DARA treatment. The absolute CD8+ T-cell numbers were significantly increased after DARA treatment (236.1 ± 146.2 vs. 388.6 ± 183.4/μL, p = 0.002). In addition, the absolute HLA-DR+ activated T-cell numbers were also significantly increased (p = 0.002). However, the increased numbers of CD8+ and HLA-DR+ T cells were not associated with clinical responses. The numbers of CD56+ NK cells were immediately depleted in all treated patients. As a control, we also examined the changes in lymphocyte subsets in patients treated with elotuzumab, the first approved monoclonal antibody for MM treatment. However, there was no change in CD38+ Treg and total Treg cell numbers. Next, to investigate the role of CD38+ Treg cells in disease progression, we analyzed the frequencies of Treg cells in healthy volunteers and in patients with monoclonal gammopathy of undetermined significance, smoldering MM, newly diagnosed MM, and relapsed MM. The CD38+ Treg cells were significantly higher in the relapsed MM group than in the other disease or control groups, suggesting that CD38+ Treg cells may play an important role in the progression of MM. Finally, we investigated the CD38 expression and frequency of CD38+ Treg cells in durable responders. Among 20 responders, 13 patients showed a long-lasting response (>6 months) or deepening response (defined as durable responders). The absolute number of CD38+ Treg cells was significantly higher in the durable responders (p = 0.009). On the other hand, the CD38 MFI of myeloma cells was not associated with a durable response. Conclusions: Pretreatment levels of the CD38 MFI could be a predictive marker for the early response to DARA treatment. Moreover, the frequency of CD38+ Treg cells present before treatment could also serve as a durable-response marker. These results suggest that the depletion of CD38+ Treg cells could contribute to some immunological mechanism of DARA. This study provides evidence to support multiple mechanisms of action for DARA, including antibody-dependent cell-mediated cytotoxicity and immunomodulatory effects. Disclosures No relevant conflicts of interest to declare.
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Lischke, Timo, Kira Heesch, Valéa Schumacher, Michael Schneider, Friedrich Haag, Friedrich Koch-Nolte, and Hans-Willi Mittrücker. "CD38 Controls the Innate Immune Response against Listeria monocytogenes." Infection and Immunity 81, no. 11 (August 26, 2013): 4091–99. http://dx.doi.org/10.1128/iai.00340-13.
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ABSTRACTCD38, adenosine-5′-diphosphate-ribosyl cyclase 1, is a multifunctional enzyme, expressed on a wide variety of cell types. CD38 has been assigned diverse functions, including generation of calcium-mobilizing metabolites, cell activation, and chemotaxis. Using a murineListeria monocytogenesinfection model, we found that CD38 knockout (KO) mice were highly susceptible to infection. Enhanced susceptibility was already evident within 3 days of infection, suggesting a function of CD38 in the innate immune response. CD38 was expressed on neutrophils and inflammatory monocytes, and especially inflammatory monocytes further upregulated CD38 during infection. Absence of CD38 caused alterations of the migration pattern of both cell types to sites of infection. We observed impaired accumulation of cells in the spleen but surprisingly similar or even higher accumulation of cells in the liver. CD38 KO and wild-type mice showed similar changes in the composition of neutrophils and inflammatory monocytes in blood and bone marrow, indicating that mobilization of these cells from the bone marrow was CD38 independent.In vitro, macrophages of CD38 KO mice were less efficient in uptake of listeria but still able to kill the bacteria. Dendritic cells also displayed enhanced CD38 expression following infection. However, absence of CD38 did not impair the capacity of mice to prime CD8+T cells againstL. monocytogenes, and CD38 KO mice could efficiently control secondary listeria infection. In conclusion, our results demonstrate an essential role for CD38 in the innate immune response againstL. monocytogenes.
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Yagi, Mary Jane, Fo-Nian Chu, Jian Dong Jiang, Joyce Wallace, Patricia Mason, Yuan Liu, Joyce Carafa, and J. George Bekesi. "Increases in soluble CD8 antigen in plasma, and CD8+ and CD8+CD38+ cells in human immunodeficiency virus type-1 infection." Clinical Immunology and Immunopathology 63, no. 2 (May 1992): 126–34. http://dx.doi.org/10.1016/0090-1229(92)90004-8.
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Chandele, Anmol, Jaturong Sewatanon, Sivaram Gunisetty, Mohit Singla, Nattawat Onlamoon, Rama S. Akondy, Haydn Thomas Kissick, et al. "Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India." Journal of Virology 90, no. 24 (October 5, 2016): 11259–78. http://dx.doi.org/10.1128/jvi.01424-16.
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ABSTRACT Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR + CD38 + and HLA-DR − CD38 + effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLA-DR + CD38 + subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue. IMPORTANCE Dengue is becoming a global public health concern. Although CD8 T cells have been implicated both in protection and in the cytokine-mediated immunopathology of dengue, how the balance is maintained between these opposing functions remains unknown. We comprehensively characterized CD8 T cell subsets in dengue patients from India and Thailand and show that these cells expand massively and express phenotypes indicative of overwhelming antigenic stimulus and tissue homing/cytotoxic-effector functions but that a vast majority of them fail to produce IFN-γ in vitro . Interestingly, the cells were fully capable of producing the cytokine when stimulated in a T cell receptor (TCR)-independent manner but failed to do so in TCR-dependent stimulation. These results, together with transcriptomics, revealed that the vast majority of these CD8 T cells from dengue patients become cytokine unresponsive due to TCR signaling insufficiencies. These observations open novel avenues for understanding the mechanisms that fine-tune the balance between CD8-mediated protective versus pathological effects.
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Perfetto, Stephen P., John D. Malone, Clifton Hawkes, Gilbert McCrary, Bob August, Susan Zhou, Robin Garner, Matthew J. Dolan, and Arthur E. Brown. "CD38 expression on cryopreserved CD8+ T cells predicts HIV disease progression." Cytometry 33, no. 2 (October 1, 1998): 133–37. http://dx.doi.org/10.1002/(sici)1097-0320(19981001)33:2<133::aid-cyto7>3.0.co;2-k.
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Huang, Nick, Brandon Wyman, Emma Cravo, Thomas Winans, Gourav Choudhary, Zachary Oaks, Manuel Duarte, et al. "Rab4A inactivation in T cells blocks mTOR activation, pro-inflammatory lineage development, and disease pathogenesis in lupus-prone mice." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 115.6. http://dx.doi.org/10.4049/jimmunol.202.supp.115.6.
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Abstract Introduction Expression of Rab4A is increased in T cells of patients and mice with SLE. Overexpression of Rab4A forms a positive feedback loop with mTOR that can be blocked with therapeutic efficacy in SLE. To determine the impact of this gene on disease development, the triple-congenic lupus-prone Sle1.2.3 mouse strain (TC) have been backcrossed with C57Bl/6 wild-type (WT) mice that carry floxed Rab4AQ72L (TC-FL) alleles or lack Rab4A in T cells (TC-KO). Methods Proteinuria was assessed by the Bradford assay. Splenocytes were examined by flow cytometry. Autoantibody production was measured by ELISA. Results TC mice had increased proteinuria over age and sex-matched WT controls. Deletion of Rab4A in T cells reduced proteinuria ≥ 50% in female TC-KO mice relative to TC-FL mice at 21 or 40 weeks of age. Similar trends were noted in male mice. The production of antinuclear and antiphospholipid antibodies was reduced in TC-KO mice as compared to TC-FL and parental TC controls. Immunophenotyping unveiled a 45% depletion of CD4+ T cells and 50% expansion of CD8+ T cells in female TC-KO mice relative to TC-FL controls. CD38 expression was reduced on CD4+ T cells of TC-KO mice by 51% and 48% relative to TC and TC-FL controls. CD38 expression was also reduced on CD8+ T cells but not on CD19+ B cells. mTORC1 activity was reduced by 36% in CD4 T cells, but not in CD8 T cells or B cells of TC-KO mice. Along these lines, overexpression of Rab4A activated mTORC1, reduced expression of CD4, and increased expression of CD38 in Jurkat cells. Conclusion These findings reveal an opposite influence of Rab4A on endosomal recycling of CD4 and CD38 that facilitates mTORC1 activation and thus causes pro-inflammatory T-cell lineage specification and triggers autoimmunity in SLE.
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Kovacs, Andrea A. Z., Naoko Kono, Chia-Hao Wang, Daidong Wang, Toni Frederick, Eva Operskalski, Phyllis C. Tien, et al. "Association of HLA Genotype With T-Cell Activation in Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus–Coinfected Women." Journal of Infectious Diseases 221, no. 7 (November 10, 2019): 1156–66. http://dx.doi.org/10.1093/infdis/jiz589.
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Abstract Background Global immune activation and HLA alleles are each associated with the pathogenesis of human immunodeficiency virus (HIV) and hepatitis C virus . Methods We evaluated the relationship between 44 HLA class I and 28 class II alleles and percentages of activated CD8 (CD8+CD38+DR+) and CD4 (CD4+CD38+DR+) T cells in 586 women who were naive to highly active antiretroviral therapy. We used linear generalized estimating equation regression models, adjusting for race/ethnicity, age, HIV load, and hepatitis C virus infection and controlling for multiplicity using a false discovery rate threshold of 0.10. Results Ten HLA alleles were associated with CD8 and/or CD4 T-cell activation. Lower percentages of activated CD8 and/or CD4 T cells were associated with protective alleles B*57:03 (CD8 T cells, −6.6% [P = .002]; CD4 T cells, −2.7% [P = .007]), C*18:01 (CD8 T cells, −6.6%; P < .0008) and DRB1*13:01 (CD4 T cells, −2.7%; P < .0004), and higher percentages were found with B*18:01 (CD8 T cells, 6.2%; P < .0003), a detrimental allele. Other alleles/allele groups associated with activation included C*12:03, group DQA1*01:00, DQB1*03:01, DQB1*03:02, DQB1*06:02, and DQB1*06:03. Conclusion These findings suggest that a person’s HLA type may play a role in modulating T-cell activation independent of viral load and sheds light on the relationship between HLA, T-cell activation, immune control, and HIV pathogenesis.
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Kandilarova, Snezhina M., Atanaska I. Georgieva, Anastasiya P. Mihaylova, Marta P. Baleva, Valentina K. Atanasova, Diana V. Petrova, Georgi T. Popov, and Elissaveta J. Naumova. "Immune Cell Subsets Evaluation as a Predictive Tool for Hepatitis B Infection Outcome and Treatment Responsiveness." Folia Medica 59, no. 1 (March 1, 2017): 53–62. http://dx.doi.org/10.1515/folmed-2017-0008.
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AbstractBackground: The patient’s immune response is one of the major factors influencing HBV eradication or chronification, and it is thought to be responsible for the treatment success.Aim: Our study aimed to investigate whether cellular defense mechanisms are associated with the course of HBV infection (spontaneous recovery [SR] or chronification [CHB]) and with the therapeutic approach.Patients and methods: A total of 139 patients (118 with CHB, 21 SR) and 29 healthy individuals (HI) were immunophenotyped by flowcytometry. Fifty-six patients were treatment-naïve, 20 were treated with interferons and 42 with nucleoside/ nucleotide analogues.Results: Deficiency of T lymphocytes, helper-inducer (CD3+CD4+), suppressorcytotoxic (CD8+CD3+) and cytotoxic (CD8+CD11b-, CD8+CD28+) subsets, activated T cells (CD3+HLA-DR+, CD8+CD38+) and increased CD57+CD8- cells, elevated percentages of B lymphocytes and NKT cells were observed in CHB patients compared with HI. In SR patients, elevated CD8+CD11b+, NKT and activated T cells were found in comparison with controls. The higher values of T cells and their subsets in SR patients than in CHB patients reflect a recovery of cellular immunity in resolved HBV infection individuals. In both groups of treated patients, reduced T lymphocytes, CD3+CD4+ and CD8+CD38+ subsets were found in comparison with HI. Higher proportions of cytotoxic subsets were observed in treated patients compared with treatment-naïve CHB patients, more pronounced in the group with interferon therapy.Conclusion: Our data demonstrate that cellular immune profiles may be of prognostic value in predicting the clinical course of HBV infection, and the determination of the therapeutic response.
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Giraldo, Nicolas, Natalia Bolaños, Adriana Cuellar, Nubia Roa, Zulma Cucunubá, Victor Velasco, Fernando Rosas, Concepción Puerta, and John González. "Proliferative dysfunction in chronically activated T lymphocytes from chagasic patients (70.1)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 70.1. http://dx.doi.org/10.4049/jimmunol.188.supp.70.1.
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Abstract Background: Trypanosoma cruzi persistence has been associated with cardiac and gastrointestinal tissue damage in nearly 30% of the infected individuals; however, the pathogenic mechanisms are yet unknown. This study’s goal was to compare the activation status and proliferative capacity of T lymphocytes among chronic chagasic patients and uninfected controls. Methodology: Twenty-seven chronic chagasic patients, 20 healthy individuals and 28 non-chagasic cardiomyopathy donors were analyzed. Peripheral blood cells were stained with CD3, CD4, CD8, CD28, HLA-DR and CD38. PBMCs were labeled with CFSE and co-cultivated with PHA or T. cruzi lysate; at the fifth day post-stimulation cells were stained for CD3, CD4 and CD8. Results: Chagasic patients displayed higher frequencies of CD4+ (P=0.0001) and CD8+ (P=0.0002) T cells co-expressing HLA-DR and CD38 in comparison with healthy and non-chagasic cardiomyopathy donors. Also, the former group exhibited lower percentages of CD8+/CD28+ T lymphocytes (P=0.0005). After 5 days of stimulation, the proliferation index was lower in both CD4+ (P=0.01) and CD8+ (P=0.04) PHA-stimulated T cells from chagasic donors when compared with both control groups. Conclusions: Despite their increased activation status, the T lymphocytes from chagasic donors displayed reduced proliferative capacity after mitogenic stimulation, corroborating a dysfunctional cellular immune response in the chronic stages of the disease.
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Nakajima, Shihoko, Asako Chiba, Ayako Makiyama, Eri Hayashi, Goh Murayama, Ken Yamaji, Shigeto Kobayashi, Naoto Tamura, Yoshinari Takasaki, and Sachiko Miyake. "Association of mucosal-associated invariant T cells with different disease phases of polymyalgia rheumatica." Rheumatology 59, no. 10 (March 3, 2020): 2939–46. http://dx.doi.org/10.1093/rheumatology/keaa054.
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Abstract Objectives Although T cells are thought to be involved in the pathogenesis of PMR, whether innate-like T cells are involved in the process remains unknown. Methods The serum levels of 27 cytokines/chemokines in patients with PMR were measured by a multiplex immunoassay (Bio-Plex Assay). The cytokine-producing capacity of T and innate-like T cells was assessed by intracellular cytokine staining and flow cytometry. The frequency and activated status of T and innate-like T cells were investigated by flow cytometry and their associations with clinical parameters were assessed. Results The levels of inflammatory cytokines were associated with disease activity in PMR. The cytokine-producing capacity by CD8+ T and innate-like T cells was associated with disease activity. The frequency of HLA-DR+ CD38+ cells among CD8+ T cells was increased in patients with active disease. The frequencies of HLA-DR+ CD38+ cells among CD4+ T, mucosal-associated invariant T (MAIT) and γδ T cells were higher in patients with inactive disease. The frequency of HLA-DR+ CD38+ MAIT cells was associated with the PMR activity score and CRP levels in patients in remission. Conclusion The inflammatory cytokine-producing capacity and expression of activation markers of CD8+ T and innate-like T cells were associated with the disease activity of PMR. MAIT cell activation in patients in remission may contribute to the subclinical activity of the disease.
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Burns, Marie, Lennard Ostendorf, Robert Biesen, Andreas Grützkau, Falk Hiepe, Henrik E. Mei, and Tobias Alexander. "Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE." International Journal of Molecular Sciences 22, no. 5 (February 28, 2021): 2424. http://dx.doi.org/10.3390/ijms22052424.
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Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14++CD16+ monocytes, CD56+ CD16dim natural killer cells, marginal zone-like IgD+CD27+ B cells, and on CD4+ and CD8+ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies.
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Manna, Alak, Sonikpreet Aulakh, Taimur Sher, Sikander Ailawadhi, Asher Chanan-Khan, and Aneel Paulus. "CD38hi B-regulatory (B-reg) cells maintain pathological immune tolerance in chronic lymphocytic leukemia (CLL)/B cell diseases: Potential therapeutic considerations." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 71.13. http://dx.doi.org/10.4049/jimmunol.202.supp.71.13.
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Abstract Chronic Lymphocytic Leukemia (CLL) is considered a disease of antigen-naive CD5+CD23+CD19+κ/λ+ B-lymphocytes, in which the tumor microenvironment is highly immunosuppressive. Among several human B cell subsets, B10 [CD24hiCD27+CD38hi]/B regulatory cells (Bregs) are functionally discernable in patients with aggressive CLL as they support and regulate immunological tolerance via production of IL-10 and transforming growth factor β (TGF-β). In an ex vivo setting, we noted CD38hi CLL Bregs to promote transformation and expansion of CD4+CD25+FoxP3+Tregs; an effect that was abrogated in the presence of IL10/TGF-β neutralizing antibodies. In patients with CLL, Bregs also prohibit the expansion of cytotoxic T cells (CD8+T cells; Tc), natural killer (NK) cells and other pro-inflammatory lymphocytes (CD4+ helper T cells; Th1 and Th17). We noted that patients with CLL had a significantly higher % of Tregs (11.8±2.0) compared to healthy donors (1.9±0.3) and similar to Bregs, a substantial proportion of CLL Tregs had high CD38 expression (MFI=616.8±36.2). We demonstrated that an anti-CD38 therapeutic antibody was able to eliminate CD38+ Bregs and Tregs from CLL patients by immune effector mechanisms (ADCC, CDC, ADCP) as well as direct mitochondrial/FcγR-mediated apoptosis. Furthermore, in a PDX model of CLL, mice treated with anti-CD38 therapy had decreased % Bregs and Tregs but increased Th17 and CD8+ T-cells (vs. vehicle; p<0.05). These observations carry implications beyond CLL for any Breg/Treg-dependent cancer or disease (i.e. Systemic Lupus Erythematosus, Rheumatoid arthritis, Sjögren’s syndrome), wherein CD38-targeted therapy could potentially rescue/improve an immune tolerant microenvironment by eradication of Bregs.
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Distler, Eva, Anna Jürchott, Abdo Konur, Astrid Schneider, Eva M. Wagner, Christoph Huber, Ralf G. Meyer, and Wolfgang Herr. "The CD38-Positive and CD38-Negative Subsets of CD34(high)-Positive Primary Acute Myeloid Leukemia Blasts Differ Considerably in the Expression of Immune Recognition Molecules." Blood 112, no. 11 (November 16, 2008): 2936. http://dx.doi.org/10.1182/blood.v112.11.2936.2936.
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Abstract Acute myeloid leukemia (AML) is thought to arise from a rare putative ‘leukemic stem cell’ that is capable of self-renewal and formation of leukemic blasts. Serial xenotransplantation studies in immunodeficient mice have shown that this leukemia-initiating cell resides at very low numbers within CD34(high)-positive CD38-negative AML cells. Thus, immunotherapeutic approaches successfully eradicating this cell compartment should result in cure from disease. The objective of our study was to characterize the immune phenotype of the CD38-negative and CD38-positive subsets of primary CD34(high)-positive AML blasts ex vivo. We obtained therapeutic leukapheresis products from 17 AML patients of FAB M0-M5 subtypes with white blood cell counts exceeding 10^11/L at primary diagnosis. These products were used to purify CD34-positive cells by immunomagnetic microbeads. CD34(high)-expressing cells were subsequently sorted by flow cytometry into CD38-negative and CD38-positive subsets, respectively. Both fractions were then phenotyped with fluorochrome-conjugated monoclonal antibodies for expression of surface markers previously described to differ between leukemic blasts and stem cells, i.e. CD71 (transferrin receptor), CD90 (Thy-1), CD117 (c-kit receptor), CD123 (IL3Ralpha), CD44, and CD11c. We also included markers relevant for recognition by natural killer cells and T cells, namely HLA class I, HLA-DR, CD40, CD54 (ICAM-1), CD58 (LFA-3), CD80 (B7.1), and CD86 (B7.2), as well as the lineage markers CD2, CD3, CD4, CD7, CD8, CD10, CD14, CD19, CD20, and CD56. Our results demonstrated that the CD38-positive and CD38-negative subsets of CD34(high)-positive AML blasts differed considerably in the expression of CD58, CD71, CD86, CD117, and HLA class I. Although these markers were detected on both subsets, the mean fluorescence intensity (MFI) values were lower in the CD38-negative compartment compared to the CD38-positive counterpart (medians: CD58, 1335 versus 1933; CD71, 657 versus 811; CD86, 746 versus 753; CD117, 490 versus 758; HLA class I, 4431 versus 6000). We compared the MFI values of both cell subsets with the Wilcoxon signed-rank test. P-values below 5% were detected for CD58 (p=0.005), CD71 (p=0.003), CD86 (p=0.041), CD117 (p=0.009), and HLA class I (p=0.011), respectively. The CD38-positive and CD38-negative subsets showed comparable intense staining for CD11c, CD44, CD54, CD123, and HLA-DR. In contrast, CD90, CD80, CD40, and the lineage markers were negative in both fractions. We concluded from these results that primary CD34(high)-positive CD38-negative AML blasts containing small numbers of leukemia-initiating cells expressed overall lower levels of the immune recognition molecules CD58 (LFA-3), CD86 (B7.2), and HLA class I compared to their CD38-positive counterparts. However, all CD34(high)-positive CD38-negative AML cells showed detectable HLA class I expression on the cell surface, making them accessible to T-cell based immunotherapies. In line with previous data, CD71 (transferrin receptor) and CD117 (c-kit receptor) were observed at reduced levels on CD34(high)-positive CD38-negative AML cells. Ongoing functional studies explore if the CD38-negative and CD38-positive subsets of CD34(high)-positive AML blasts differ in the immunogenicity for leukemia-reactive CD4 and CD8 T cells, both in vitro as well as in immunodeficient mice in vivo.
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de Carvalho, Paulo Germano, Raphael de Oliveira Rodrigues, Silvia Fernandes Ribeiro da Silva, Ilana Farias Ribeiro, Herene Barros de Miranda Lucena, Lilian Roberta Costa Martins, Silvia Helena Rabenhorst, Érico Antônio Gomes de Arruda, and Aparecida Tiemi Nagao-Dias. "CD38+CD8+ and CD38+CD4+ T Cells and IFN Gamma (+874) Polymorphism Are Associated with a Poor Virological Outcome." Immunological Investigations 45, no. 4 (April 21, 2016): 312–27. http://dx.doi.org/10.3109/08820139.2016.1157603.
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Eller, Michael A., Nilu Goonetilleke, Boonrat Tassaneetrithep, Leigh Anne Eller, Margaret C. Costanzo, Susan Johnson, Michael R. Betts, et al. "Expansion of Inefficient HIV-Specific CD8 T Cells during Acute Infection." Journal of Virology 90, no. 8 (February 3, 2016): 4005–16. http://dx.doi.org/10.1128/jvi.02785-15.
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ABSTRACTAttrition within the CD4+T cell compartment, high viremia, and a cytokine storm characterize the early days after HIV infection. When the first emerging HIV-specific CD8+T cell responses gain control over viral replication it is incomplete, and clearance of HIV infection is not achieved even in the rare cases of individuals who spontaneously control viral replication to nearly immeasurably low levels. Thus, despite their partial ability to control viremia, HIV-specific CD8+T cell responses are insufficient to clear HIV infection. Studying individuals in the first few days of acute HIV infection, we detected the emergence of a unique population of CD38+CD27−CD8+T cells characterized by the low expression of the CD8 receptor (CD8dim). Interestingly, while high frequencies of HIV-specific CD8+T cell responses occur within the CD38+CD27−CD8dimT cell population, the minority populations of CD8brightT cells are significantly more effective in inhibiting HIV replication. Furthermore, the frequency of CD8dimT cells directly correlates with viral load and clinical predictors of more rapid disease progression. We found that a canonical burst of proliferative cytokines coincides with the emergence of CD8dimT cells, and the size of this population inversely correlates with the acute loss of CD4+T cells. These data indicate, for the first time, that early CD4+T cell loss coincides with the expansion of a functionally impaired HIV-specific CD8dimT cell population less efficient in controlling HIV viremia.IMPORTANCEA distinct population of activated CD8+T cells appears during acute HIV infection with diminished capacity to inhibit HIV replication and is predictive of viral set point, offering the first immunologic evidence of CD8+T cell dysfunction during acute infection.
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Collins, Sabrina, Adarsh Joshi, Lei Shen, Subhasree Das, Kaveri Suryanarayan, Dean Bottino, Cheryl Li, et al. "357 TAK-573, an anti-CD38–attenuated interferon alpha (IFNα) fusion protein (Attenukine™), has demonstrated IFNα receptor (IFNAR) pathway modulation in patients with relapsed/refractory multiple myeloma." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A382. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0357.
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BackgroundTAK-573, a humanized, anti-CD38, IgG4, monoclonal antibody genetically fused to two attenuated IFNα2b molecules, was designed for targeted delivery of attenuated IFNα2b to CD38 expressing (CD38+) cells, utilizing a unique epitope of CD38 that does not compete with current anti-CD38 therapies. Preclinical evaluation of TAK-573 confirmed activation of type I IFN signaling in CD38+ cells inducing direct anti-proliferative effects on multiple myeloma (MM) cells and direct and indirect immune cell activation. Here we provide the preliminary analyses of the pharmacodynamic data currently available from the ongoing Ph I/II TAK-573-1501 clinical study in patients with relapsed/refractory MM (NCT03215030).MethodsPeripheral blood (PB) and bone marrow (BM) aspirates were collected from patients at pre- and post-dose time points for exploratory biomarker analyses. CD38 receptor occupancy (RO) and receptor density (RD) were determined using a 9-color flow cytometry assay. Whole transcriptome sequencing of bulk RNA was performed and analyzed to assess the type I IFN gene signature. Serum samples were analyzed using Olink’s Proximity Extension Assay Immuno-Oncology panel to measure changes in cytokine levels. Mass cytometry-based immunophenotyping was utilized to characterize changes in immune cell prevalence and activation status of cryopreserved cells.ResultsAdministration of TAK-573 resulted in a dose dependent increase in CD38 RO of PB-derived immune cells with saturation detected 4 hours after the end of infusion (EOI) at doses ≥ 0.2 mg/kg. The duration of saturation was dose dependent with doses ≥ 0.75 mg/kg saturating CD38 RO through 24 hours. All dose levels tested resulted in increases in the type I IFN gene signature at 24 hours. Consistent with CD38 being an IFN stimulated gene, TAK-573 treatment resulted in CD38 RD increases most notably on NK cells, but also on other CD38+ cells including MM cells. Circulating levels of IFN-associated cytokines were also elevated, with maximal induction 4 hours after the EOI. CD8+ T-cells in BM showed increased CD69 expression in 7 of 9 patients analyzed, 3 of whom also showed increases in both IFNγ and granzyme B positivity suggesting TAK-573 treatment results in increased BM cytolytic CD8+ T-cells, in a subset of patients.Abstract 357 Figure 1Proposed Mechanism of Action of TAK-573ConclusionsThese preliminary biomarker data indicate that TAK-573 is a pharmacologically active molecule that mediates its effect through IFNAR pathway modulation. Additional data are being collected to further refine the mechanism of action (Image 1), which will inform the recommended phase 2 dose and optimal schedule of administration for the development of TAK-573.Trial RegistrationClinicalTrials. gov: NCT03215030Ethics ApprovalThe TAK-573-1501 study is approved by WIRB-Copernicus Group, University of Nebraska Medical Center, Dana Farber Cancer Institute and Advarra IRBs.
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Demosthenes, John Paul, Gnanadurai John Fletcher, Uday George Zachariah, George Mannil Varghese, Susanne Alexander Pulimood, Priya Abraham, and Rajesh Kannangai. "Chronic Immune Activation Among Treatment Naïve HIV/ HBV Coinfected Individuals From Southern India." Current HIV Research 19, no. 4 (August 30, 2021): 332–41. http://dx.doi.org/10.2174/1570162x19666210506160642.
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Background : Chronic immune activation is one of the most widely recognized hallmarks of HIV infection. T-cells that express CD38+ and HLA-DR+ show poor proliferative potential, signal transduction, and increased apoptotic potential. This affects HIV pathogenesis and its outcome and further complicates with a coinfection like HBV. Method: Study Design: Cross-sectional. Blood samples were collected and analyzed for virological markers using ELISA for HBeAg and RT-PCR for HIV&HBV Viral load. Chronic immune activation markers of CD8+ and CD4+ T cells were measured by Flow cytometry for both HIV and HBV Results: There was a significant increase in HBV replication shown by higher HBV DNA (p=0.002), a higher proportion of HBeAg (p=0.0049), and lower CD4 counts (p=0.04) among HIV/HBV coinfected individuals, compared to the monoinfected groups. The frequencies of CD4+ CD38+ HLA-DR+ and CD8+ CD38+ HLA-DR+ in the HIV/HBV coinfection were significantly higher than HBV monoinfected group (P<0.0001) and in the HIV monoinfected group (P< 0.0001). The Liver fibrosis score APRI and FIB-4, were higher in the coinfected group compared with HBV monoinfected group (0.67 vs. 0.25, p = 0.0085; 3.48 vs. 0.98, p = 0.0026) respectively. The cytokine levels of IL-17, Fas-L,TNF -α, IL-10, IL-2 and Granzyme B were also measured and compared among the study groups. Conclusion: Our data suggest that HIV probably influences immune activation of CD4+ and CD8+ T cells and this may play a significant role in accelerating the disease outcome among HIV/HBV coinfected individuals.
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Beran, Ondrej, Petr Kodym, Marek Maly, Alzbeta Davidova, Gabriela Reinvartova, David Jilich, Michal Holub, and Hanus Rozsypal. "The Effect of LatentToxoplasma gondiiInfection on the Immune Response in HIV-Infected Patients." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/271842.
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A relationship between latent toxoplasmosis and the immune system during HIV disease is poorly understood. Therefore, the aim of this follow-up study was to characterize immunological parameters in HIV-infected patients with latent toxoplasmosis and noninfected individuals. A total of 101 HIV-infected patients were enrolled in the study. The patients were classified into two groups based on anti-Toxoplasma gondiiantibodies: a group of 55 toxoplasma-positive persons (TP) and a group of 46 toxoplasma-negative persons (TN). Absolute counts of several lymphocyte subsets decreased in the TP group, namely, T cells (p=0.007), B cells (p=0.002), NK cells (p=0.009), CD4 T cells (p=0.028), and CD8 T cells (p=0.004). On the other hand, the percentage of CD8 T cells expressing CD38 and HLA-DR significantly increased during the follow-up in the TP group (p=0.003,p=0.042, resp.) as well as the intensity of CD38 and HLA-DR expression (MFI) on CD8 T cells (p=0.001,p=0.057, resp.). In the TN group, analysis of the kinetics of immunological parameters revealed no significant changes over time. In conclusion, the results suggest that latentT. gondiiinfection modulates the immune response during HIV infection.
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Sun, Changbo, Koji Nagaoka, Yukari Kobayashi, Hidewaki Nakagawa, Kazuhiro Kakimi, and Jun Nakajima. "Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1." Cancers 13, no. 21 (November 2, 2021): 5508. http://dx.doi.org/10.3390/cancers13215508.
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An important factor associated with primary resistance to immune-checkpoint therapies (ICT) is a “cold” tumor microenvironment (TME), characterized by the absence of T cell infiltration and a non-inflammatory milieu. Whole-exome and RNA sequencing to predict neoantigen expression was performed on the LLC1 cell line which forms “cold” tumors in mice. Dendritic cell (DC)-based vaccination strategies were developed using candidate neoantigen long peptides (LPs). A total of 2536 missense mutations were identified in LLC1 and of 132 candidate neoantigen short peptides, 25 were found to induce CD8+ T cell responses. However, they failed to inhibit LLC1 growth when incorporated into a cancer vaccine. In contrast, DCs pulsed with LPs induced CD4+ and CD8+ T cell responses and one of them, designated L82, delayed LLC1 growth in vivo. By RNA-Seq, CD38 was highly expressed by LLC1 tumor cells and, therefore, anti-CD38 antibody treatment was combined with L82-pulsed DC vaccination. This combination effectively suppressed tumor growth via a mechanism relying on decreased regulatory T cells in the tumor. This study demonstrated that an appropriate vaccination strategy combining neoantigen peptide-pulsed DC with anti-CD38 antibody can render an ICT-resistant “cold” tumor susceptible to immune rejection via a mechanism involving neutralization of regulatory T cells.
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Omede, P., M. Boccadoro, G. Gallone, R. Frieri, S. Battaglio, V. Redoglia, and A. Pileri. "Multiple myeloma: increased circulating lymphocytes carrying plasma cell-associated antigens as an indicator of poor survival." Blood 76, no. 7 (October 1, 1990): 1375–79. http://dx.doi.org/10.1182/blood.v76.7.1375.1375.
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Abstract In multiple myeloma (MM) an increase in circulating lymphocytes expressing plasma cell-associated antigens (PCAA) has been described. Its prognostic significance was evaluated in this study. The immunologic phenotype of peripheral blood lymphocytes was analyzed with a panel of monoclonal antibodies specific for B, T, natural killer lymphocytes, and PCAA (CD38, PCA1) in 52 MM patients at diagnosis, remission, and during relapse, 18 monoclonal gammopathy of undetermined significance (MGUS), and 25 normal controls. No significant phenotypic alteration was observed in MGUS. In MM, the number of B lymphocytes was in the normal range at diagnosis and during the subsequent phases. A CD4/CD8 ratio decrease, during relapse, was due to both a CD4+ reduction and to an expansion of a subset of CD8+ activated suppressor lymphocytes. CD38+ and PCA1+ lymphocytes at diagnosis were significantly higher than in MGUS, and a further increase was observed during relapse, suggesting a correlation between PCAA expression and disease activity. The prognostic significance of increased PCAA was confirmed by a survival analysis of 32 patients evaluated at diagnosis using a CD38 cutoff of 0.45 x 10(9)/L positive lymphocytes. Median survival for patients with high values was only 14 months, whereas it was not reached at 32 months by those with low values (P less than .0007).
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Omede, P., M. Boccadoro, G. Gallone, R. Frieri, S. Battaglio, V. Redoglia, and A. Pileri. "Multiple myeloma: increased circulating lymphocytes carrying plasma cell-associated antigens as an indicator of poor survival." Blood 76, no. 7 (October 1, 1990): 1375–79. http://dx.doi.org/10.1182/blood.v76.7.1375.bloodjournal7671375.
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In multiple myeloma (MM) an increase in circulating lymphocytes expressing plasma cell-associated antigens (PCAA) has been described. Its prognostic significance was evaluated in this study. The immunologic phenotype of peripheral blood lymphocytes was analyzed with a panel of monoclonal antibodies specific for B, T, natural killer lymphocytes, and PCAA (CD38, PCA1) in 52 MM patients at diagnosis, remission, and during relapse, 18 monoclonal gammopathy of undetermined significance (MGUS), and 25 normal controls. No significant phenotypic alteration was observed in MGUS. In MM, the number of B lymphocytes was in the normal range at diagnosis and during the subsequent phases. A CD4/CD8 ratio decrease, during relapse, was due to both a CD4+ reduction and to an expansion of a subset of CD8+ activated suppressor lymphocytes. CD38+ and PCA1+ lymphocytes at diagnosis were significantly higher than in MGUS, and a further increase was observed during relapse, suggesting a correlation between PCAA expression and disease activity. The prognostic significance of increased PCAA was confirmed by a survival analysis of 32 patients evaluated at diagnosis using a CD38 cutoff of 0.45 x 10(9)/L positive lymphocytes. Median survival for patients with high values was only 14 months, whereas it was not reached at 32 months by those with low values (P less than .0007).