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1
ADAMS, DAVID H., LIAN FU WANG, JAMES M. NEUBERGER, and ELWYN ELIAS. "INHIBITION OF LEUKOCYTE CHEMOTAXIS BY IMMUNOSUPPRESSIVE AGENTS." Transplantation 50, no. 5 (November 1990): 845–49. http://dx.doi.org/10.1097/00007890-199011000-00020.
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Smith, D. A., G. G. Schurig, S. A. Smith, and S. D. Holladay. "Inhibited Cytotoxic Leukocyte Activity in Tilapia (Oreochromis niloticus) Following Exposure to Immunotoxic Chemicals." International Journal of Toxicology 18, no. 3 (April 1999): 167–72. http://dx.doi.org/10.1080/109158199225459.
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The measure of the ability of cytotoxic immune cells to target and lyse foreign cells has been widely used as a predictor of im-munosuppression in chemical-exposed rodents. However, the efficacy of this function for predicting immunosuppressive chemical exposure in nonrodent species remains unknown. In the present report, tilapia ( Oreochromis niloticus) were exposed to 9 chemical agents known to inhibit rodent cytotoxic T lymphocyte (CTL) activity in mice, benzo[a]pyrene (B[a]P), 7, 12-dimethylbenzanthracene (DMBA), 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), dimethyl-nitrosamine (DMN), cadmium chloride (CdCl2), azathioprine (AZA), T2 mycotoxin (T2 toxin), hexachlorocyclohexane (lindane), and diethylstilbesterol(DES); and five chemical agents which do not inhibit this response, oxymethalone, acetonitrile, tert-butylhydro-quinone (TBHQ), toluene, and formaldehyde. Eight of the nine agents which inhibit rodent CTL responses also caused decreased cytolytic responses in fish. All five of the compounds with negative CTL effects in rodents were also negative in fish. Thus, 13 of the 14 chemical agents tested gave similar results in fish as reported in rodents, indicating a comparable pattern of inhibited immune cell cytolytic responses in chemical-exposed tilapia to that seen in the laboratory rodent models.
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Winston, Kevin, Hasan Maulahela, Lusiani Lusiani, Raditya Dewangga, and Lazuardi G. Ilhami. "Current Role of Anti-Integrin Therapy in Inflammatory Bowel Disease." Indonesian Journal of Gastroenterology, Hepatology, and Digestive Endoscopy 21, no. 2 (September 30, 2020): 137–45. http://dx.doi.org/10.24871/2122020137-145.
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Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder with multifactorial etiology. Management of IBD is divided into conventional treatment and new treatment with biologic agents. The first biologic agents used for IBD was tumor necrosis factor (TNF)-inhibitor. However, TNF-inhibitor as a biologic agent has several limitations such as low rate of clinical response and systemic immunosuppressive side effects. Anti-integrin is a recently developed biologic agent which selectively inhibits leukocyte trafficking towards site of inflammation. The inhibition is caused by blocking the actions of integrin, a cell adhesion molecules (CAMs) that is necessary for leukocyte trafficking and leukocytes express specific integrin receptors for specific organs. Therefore, use of gut-specific anti-integrin agents in IBD can selectively prevent influx of leukocytes into the intestine to reduce inflammation without reducing immune function in other locations. As a result, gut-specific anti-integrin is hypothesized to have lower risk of infections and lower risk of malignancy than TNF-inhibitor while maintaining high therapeutic benefits, making anti-integrin a promising therapy for IBD in the future.
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Pocheć, Ewa, Katarzyna Bocian, Marta Ząbczyńska, Grażyna Korczak-Kowalska, and Anna Lityńska. "Immunosuppressive Drugs Affect High-Mannose/Hybrid N-Glycans on Human Allostimulated Leukocytes." Analytical Cellular Pathology 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/324980.
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N-glycosylation plays an important role in the majority of physiological and pathological processes occurring in the immune system. Alteration of the type and abundance of glycans is an element of lymphocyte differentiation; it is also common in the development of immune-mediated inflammatory diseases. The N-glycosylation process is very sensitive to different environmental agents, among them the pharmacological environment of immunosuppressive drugs. Some results show that high-mannose oligosaccharides have the ability to suppress different stages of the immune response. We evaluated the effects of cyclosporin A (CsA) and rapamycin (Rapa) on high-mannose/hybrid-type glycosylation in human leukocytes activated in a two-way mixed leukocyte reaction (MLR). CsA significantly reduced the number of leukocytes covered by high-mannose/hybrid N-glycans, and the synergistic action of CsA and Rapa led to an increase of these structures on the remaining leukocytes. This is the first study indicating thatβ1 andβ3 integrins bearing high-mannose/hybrid structures are affected by Rapa and CsA. Rapa taken separately and together with CsA changed the expression ofβ1 andβ3 integrins and, by regulating the protein amount, increased the oligomannose/hybrid-type N-glycosylation on the leukocyte surface. We suggest that the changes in the glycosylation profile of leukocytes may promote the development of tolerance in transplantation.
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Cao, Jing-Yuan, Qing Guo, Ge-Fei Guan, Chen Zhu, Cun-Yi Zou, Lu-Yang Zhang, Wen Cheng, et al. "Elevated lymphocyte specific protein 1 expression is involved in the regulation of leukocyte migration and immunosuppressive microenvironment in glioblastoma." Aging 12, no. 2 (January 29, 2020): 1656–84. http://dx.doi.org/10.18632/aging.102706.
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Schnitzler, Johan G., Renate M. Hoogeveen, Lubna Ali, Koen H. M. Prange, Farahnaz Waissi, Michel van Weeghel, Julian C. Bachmann, et al. "Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation." Circulation Research 126, no. 10 (May 8, 2020): 1346–59. http://dx.doi.org/10.1161/circresaha.119.316206.
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Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state. Objective: We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism. Methods and Results: We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3–mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration. Conclusions: Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.
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Truong, Nga T. H., Tessa Gargett, Michael P. Brown, and Lisa M. Ebert. "Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies." Cancers 13, no. 9 (May 6, 2021): 2225. http://dx.doi.org/10.3390/cancers13092225.
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Adoptive T-cell therapy using autologous T cells genetically modified to express cancer-specific chimeric antigen receptors (CAR) has emerged as a novel approach for cancer treatment. CAR-T cell therapy has been approved in several major jurisdictions for treating refractory or relapsed cases of B-cell precursor acute lymphoblastic leukaemia and diffuse large B-cell lymphoma. However, in solid cancer patients, several clinical studies of CAR-T cell therapy have demonstrated minimal therapeutic effects, thus encouraging interest in better integrating CAR-T cells with other treatments such as conventional cytotoxic chemotherapy. Increasing evidence shows that not only do chemotherapy drugs have tumoricidal effects, but also significantly modulate the immune system. Here, we discuss immunomodulatory effects of chemotherapy drugs on circulating leukocyte populations, including their ability to enhance cytotoxic effects and preserve the frequency of CD8+ T cells and to deplete immunosuppressive populations including regulatory T cells and myeloid-derived suppressor cells. By modulating the abundance and phenotype of leukocytes in the blood (the ‘raw material’ for CAR-T cell manufacturing), we propose that prior chemotherapy could facilitate production of the most effective CAR-T cell products. Further research is required to directly test this concept and identify strategies for the optimal integration of CAR-T cell therapies with cytotoxic chemotherapy for solid cancers.
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Pavlath, G. K., T. A. Rando, and H. M. Blau. "Transient immunosuppressive treatment leads to long-term retention of allogeneic myoblasts in hybrid myofibers." Journal of Cell Biology 127, no. 6 (December 15, 1994): 1923–32. http://dx.doi.org/10.1083/jcb.127.6.1923.
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Normal and genetically engineered skeletal muscle cells (myoblasts) show promise as drug delivery vehicles and as therapeutic agents for treating muscle degeneration in muscular dystrophies. A limitation is the immune response of the host to the transplanted cells. Allogeneic myoblasts are rapidly rejected unless immunosuppressants are administered. However, continuous immunosuppression is associated with significant toxic side effects. Here we test whether immunosuppressive treatment, administered only transiently after allogeneic myoblast transplantation, allows the long-term survival of the transplanted cells in mice. Two immunosuppressive treatments with different modes of action were used: (a) cyclosporine A (CSA); and (b) monoclonal antibodies to intracellular adhesion molecule-1 and leukocyte function-associated molecule-1. The use of myoblasts genetically engineered to express beta-galactosidase allowed quantitation of the survival of allogeneic myoblasts at different times after cessation of the immunosuppressive treatments. Without host immunosuppression, allogeneic myoblasts were rejected from all host strains tested, although the relative time course differed as expected for low and high responder strains. The allogeneic myoblasts initially fused with host myofibers, but these hybrid cells were later destroyed by the massive immunological response of the host. However, transient immunosuppressive treatment prevented the hybrid myofiber destruction and led to their long-term retention. Even four months after the cessation of treatment, the hybrid myofibers persisted and no inflammatory infiltrate was present in the tissue. Such long-term survival indicates that transient immunosuppression may greatly increase the utility of myoblast transplantation as a therapeutic approach to the treatment of muscle and nonmuscle disease.
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Becker, Daniel J., Elizabeth M. Schultz, Jonathan W. Atwell, and Ellen D. Ketterson. "Urban residency and leukocyte profiles in a traditionally migratory songbird." Animal Migration 6, no. 1 (January 1, 2019): 49–59. http://dx.doi.org/10.1515/ami-2019-0002.
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Abstract Many animals are shifting migrations in response to human activities. In particular, human-induced changes to climate and habitat (e.g., urbanization) likely facilitate animals becoming year-round residents. Because migration can be energetically expensive, shifts to sedentary behavior could minimize energetic demands incurred and any immunosuppressive effects. Residency in urban habitats could also provide abundant resources and allow sedentary animals to invest more in immunity. However, urban habitats could also expose sedentary animals to novel stressors that counter such benefits. To examine how recent shifts to residency affects physiology in ways that may shape infectious disease dynamics, we analyzed leukocyte profiles of two dark-eyed junco (Junco hyemalis) populations from southern California: the Laguna Mountain population, in which birds breed in high-elevation forests and migrate altitudinally, and the urban University of California San Diego population, which was likely established by overwintering migrants in the 1980s and has since become non-migratory. Over a two-year study of each population’s breeding season, we found no difference in the ratios of heterophils to lymphocytes between populations. However, urban residents had more leukocytes than birds from the altitudinal migrant population. A multivariate analysis suggested urban residents had fewer monocytes, but effect sizes were small. These results suggest no differences in energy demands or stressors between urban resident and altitudinal migrant populations during their breeding season. However, urban residency may confer immunological benefits through anthropogenic resources, which could have important consequences for disease dynamics..
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Rossi, Elisa, Francisco Sanz-Rodriguez, Nelida Eleno, Annette Düwell, Francisco J. Blanco, Carmen Langa, Luisa M. Botella, Carlos Cabañas, José M. Lopez-Novoa, and Carmelo Bernabeu. "Endothelial endoglin is involved in inflammation: role in leukocyte adhesion and transmigration." Blood 121, no. 2 (January 10, 2013): 403–15. http://dx.doi.org/10.1182/blood-2012-06-435347.
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Abstract Human endoglin is an RGD-containing transmembrane glycoprotein identified in vascular endothelial cells. Although endoglin is essential for angiogenesis and its expression is up-regulated in inflammation and at sites of leukocyte extravasation, its role in leukocyte trafficking is unknown. This function was tested in endoglin heterozygous mice (Eng+/−) and their wild-type siblings Eng+/+ treated with carrageenan or LPS as inflammatory agents. Both stimuli showed that inflammation-induced leukocyte transendothelial migration to peritoneum or lungs was significantly lower in Eng+/− than in Eng+/+ mice. Leukocyte transmigration through cell monolayers of endoglin transfectants was clearly enhanced in the presence of endoglin. Coating transwells with the RGD-containing extracellular domain of endoglin, enhanced leukocyte transmigration, and this increased motility was inhibited by soluble endoglin. Leukocytes stimulated with CXCL12, a chemokine involved in inflammation, strongly adhered to endoglin-coated plates and to endoglin-expressing endothelial cells. This endoglin-dependent adhesion was abolished by soluble endoglin, RGD peptides, the anti-integrin α5β1 inhibitory antibody LIA1/2 and the chemokine receptor inhibitor AMD3100. These results demonstrate for the first time that endothelial endoglin interacts with leukocyte integrin α5β1 via its RGD motif, and this adhesion process is stimulated by the inflammatory chemokine CXCL12, suggesting a regulatory role for endoglin in transendothelial leukocyte trafficking.
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Wogensen, L., X. Huang, and N. Sarvetnick. "Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans." Journal of Experimental Medicine 178, no. 1 (July 1, 1993): 175–85. http://dx.doi.org/10.1084/jem.178.1.175.
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Transgenic expression of interleukin 10 (IL-10) in the islets of Langerhans leads to a pronounced pancreatic inflammation, without inflammation of the islets of Langerhans and without diabetes. A scattered infiltration of macrophages (M pi) precedes localized accumulations of CD4+ and CD8+ T lymphocytes, B lymphocytes, and M pi. This recruitment of inflammatory cells to the pancreas is somewhat surprising, since the biological activities of IL-10 in vitro indicate that IL-10 is a powerful immunosuppressive cytokine. Since endothelial cells play a major role in leukocyte extravasation, we examined if vascular changes and extralymphoid induction of peripheral and mucosal type vascular addressins contributed to IL-10-induced homing of mononuclear cells to the pancreas. The endothelium lining small vessels was highly activated in areas of inflammation, as the endothelial cells became cuboidal, and exhibited increased expression of major histocompatibility complex class II (Ia), intercellular adhesion molecule 1, and von Willebrand Factor. Furthermore, induction of vascular addressins simultaneously with accumulation of mononuclear cells around islets and vessels indicated that the endothelial cells take on the phenotype of differentiated endothelium specialized for leukocyte extravasation. In conclusion, pancreatic inflammation and vascular changes are prominent in IL-10 transgenic mice. We hypothesize that IL-10, in addition to its immuno-inhibitory properties, is a potent recruitment signal for leukocyte migration in vivo. These effects are relevant for in vivo therapeutic applications of IL-10.
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Roussos Torres, Evanthia T., Dimitrios N. Sidiropoulos, Emily Davis-Marcisak, Luciane Tsukamoto Kagohara, Roisin M. Connolly, Vered Stearns, Elizabeth M. Jaffee, and Elana J. Fertig. "Characterization of the immune tumor microenvironment of HER2-positive breast cancer following treatment with entinostat and immune checkpoint inhibition." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15061-e15061. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15061.
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e15061 Background: HER2+ breast cancers are known to be less-immunogenic and associated with low response rates to immune checkpoint inhibitors (ICIs). A combination of immunosuppressive signals that prevent cytotoxic T cells from infiltrating the tumor microenvironment (TME) and, low tumor antigen expression, contribute to immunotherapy resistance in this population. Epigenetic modulators can both reexpress tumor antigens and rewire the immunosuppressive environment. We previously used a histone deacetylase inhibitor, entinostat (ENT), in combination with ICIs to reverse the immunosuppressive TME and increase tumor antigen expression in a NeuN HER2+ mouse model of breast cancer. Our results showed that ENT in combination with anti-PD-1, anti-CTLA-4, provided a significant survival benefit compared to either treatment alone. Methods: This current study employs single cell RNA-sequencing on whole tumor samples from mice treated with ICIs and entinostat to investigate the role of epigenetic inhibitors in rewiring the expression of tumor antigens and the cellular landscape of the TME. We generate single cell data over 54,000 cells from 20 tumors treated with entinostat alone or in combination with anti-PD1 and anti-CTLA4 and their combination. Results: Analysis of cells in the TME identifies consistent proportion of monocytes, macrophages, T-cells, Myeloid Derived Suppressor Cells (MDSCs) and Cancer Associated Fibroblasts (CAFs) before and after treatment. Differential expression analysis within the cell types identifies distinct subpopulations and we explore those that are either proportionally higher or lower in each treatment group. Notably, pathway analysis on differentially expressed genes of each cell type identified that combination entinostat and checkpoint treatment increased T cell activation, leukocyte proliferation, myeloid leukocyte and neutrophil migration, and decreased Wnt signaling and histone modifications in tumor cells. These results are being corroborated in patient samples from a parallel clinical trial to provide translational relevance. Conclusions: Our current work provides insights into the transcriptional network within a breast tumor after treatment with ENT+ICIs. We predict our findings will bring us closer to identifying additional therapeutic targets and ultimately improve survival rates of patients with less-immunogenic tumors.
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Kim, Minsoo, Christopher V. Carman, Wei Yang, Azucena Salas, and Timothy A. Springer. "The primacy of affinity over clustering in regulation of adhesiveness of the integrin αLβ2." Journal of Cell Biology 167, no. 6 (December 20, 2004): 1241–53. http://dx.doi.org/10.1083/jcb.200404160.
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Dynamic regulation of integrin adhesiveness is required for immune cell–cell interactions and leukocyte migration. Here, we investigate the relationship between cell adhesion and integrin microclustering as measured by fluorescence resonance energy transfer, and macroclustering as measured by high resolution fluorescence microscopy. Stimuli that activate adhesion through leukocyte function–associated molecule-1 (LFA-1) failed to alter clustering of LFA-1 in the absence of ligand. Binding of monomeric intercellular adhesion molecule-1 (ICAM-1) induced profound changes in the conformation of LFA-1 but did not alter clustering, whereas binding of ICAM-1 oligomers induced significant microclustering. Increased diffusivity in the membrane by cytoskeleton-disrupting agents was sufficient to drive adhesion in the absence of affinity modulation and was associated with a greater accumulation of LFA-1 to the zone of adhesion, but redistribution did not precede cell adhesion. Disruption of conformational communication within the extracellular domain of LFA-1 blocked adhesion stimulated by affinity-modulating agents, but not adhesion stimulated by cytoskeleton-disrupting agents. Thus, LFA-1 clustering does not precede ligand binding, and instead functions in adhesion strengthening after binding to multivalent ligands.
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Nelson, R. D., N. Shibata, R. P. Podzorski, and M. J. Herron. "Candida mannan: chemistry, suppression of cell-mediated immunity, and possible mechanisms of action." Clinical Microbiology Reviews 4, no. 1 (January 1991): 1–19. http://dx.doi.org/10.1128/cmr.4.1.1.
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The ability of Candida albicans to establish an infection involves multiple components of this fungal pathogen, but its ability to persist in host tissue may involve primarily the immunosuppressive property of a major cell wall glycoprotein, mannan. Mannan and oligosaccharide fragments of mannan are potent inhibitors of cell-mediated immunity and appear to reproduce the immune deficit of patients with the mucocutaneous form of candidiasis. However, neither the exact structures of these inhibitory species nor their mechanisms of action have yet been clearly defined. Different investigators have proposed that mannan or mannan catabolites act upon monocytes or suppressor T lymphocytes, but research from unrelated areas has provided still other possibilities for consideration. These include interference with cytokine activities, lymphocyte-monocyte interactions, and leukocyte homing. To stimulate further research of the immunosuppressive property of C. albicans mannan, we have reviewed (i) the relationship of mannan to other antigens and virulence factors of the fungus; (ii) the chemistry of mannan, together with methods for preparation of mannan and mannan fragments; and (iii) the historical evidence for immunosuppression by Candida mannan and the mechanisms currently proposed for this property; and (iv) we have speculated upon still other mechanisms by which mannan might influence host defense functions. It is possible that understanding the immunosuppressive effects of mannan will provide clues to novel therapies for candidiasis that will enhance the efficacy of both available and future anti-Candida agents.
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Blázquez-Prunera, A., C. R. Almeida, and M. A. Barbosa. "Human Bone Marrow Mesenchymal Stem/Stromal Cells Preserve Their Immunomodulatory and Chemotactic Properties When Expanded in a Human Plasma Derived Xeno-Free Medium." Stem Cells International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/2185351.
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Due to their immunomodulatory and chemotactic properties, hMSC are being explored to treat immune-related diseases. For their use in human therapies, it is necessary to culture hMSC in xeno-free conditions. In this study, the impact that a xeno-free medium based on a human plasma derivate has on these properties was analysed. Bone marrow-derived hMSC preserved their immunosuppressive and immunostimulatory properties, as observed with in vitro assays with hMSC cocultured with mixed leukocyte reactions or with mitogen-stimulated leukocytes. Moreover, hMSC expanded in xeno-free medium were recruited by macrophages in both migration and invasion assays, which indicates that the cells maintained their chemotactic properties. These data suggest that xeno-free expanded hMSC preserved their immunomodulatory and chemotactic properties, indicating that the described xeno-free medium composition is a potential candidate to culture and expand hMSC for human cell therapies.
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Vita, Serena, Simona Gabrielli, Lucia Fontanelli Sulekova, Maurizio De Angelis, Francesco Alessandri, Francesco Pugliese, Franco Ruberto, et al. "Malaria in an asylum seeker paediatric liver transplant recipient: diagnostic challenges for migrant population." Journal of Infection in Developing Countries 15, no. 01 (January 31, 2021): 172–78. http://dx.doi.org/10.3855/jidc.12541.
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Transplanted patients are particularly exposed to a major risk of infectious diseases due to prolonged immunosuppressive treatment. Over the last decade, the growing migration flows and the transplant tourism have led to increasing infections caused by geographically restricted organisms. Malaria is an unusual event in organ transplant recipients than can be acquired primarily or reactivation following immunosuppression, by transfusion of blood products or through the transplanted organ. We report a rare case of Plasmodium falciparum infection in a liver transplanted two years-old African boy who presented to one Italian Asylum Seeker Center on May 2019. We outlined hereby diagnostic challenges, possible aetiologies of post-transplantation malaria and finally we summarized potential drug interactions between immunosuppressive agents and antimalarials. This report aims to increase the attention to newly arrived migrants, carefully evaluating patients coming from tropical areas and taking into consideration also rare tropical infections not endemic in final destination countries.
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van Kooyk, Y., M. E. Binnerts, C. P. Edwards, M. Champe, P. W. Berman, C. G. Figdor, and S. C. Bodary. "Critical amino acids in the lymphocyte function-associated antigen-1 I domain mediate intercellular adhesion molecule 3 binding and immune function." Journal of Experimental Medicine 183, no. 3 (March 1, 1996): 1247–52. http://dx.doi.org/10.1084/jem.183.3.1247.
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We have identified amino acid residues within the evolutionarily conserved I domain of the alpha-chain (CD11a) of the leukocyte integrin leukocyte function-associated antigen (LFA) 1 that are critical for intercellular adhesion molecule (ICAM) 3 (CD50) binding. ICAM-3, a ligand of LFA-1, is thought to mediate intercellular adhesion essential for the initiation of immune responses. Using a panel of human/murine I domain chimeras and point mutants, we observed that the Ile-Lys-Gly-Asn motif, located in the NH2-terminal part of the CD11a I domain, is required for ICAM-3 but not ICAM-1 binding. These findings demonstrate that the I domain of CD11a contains distinct functional subdomains for ligand specific binding. An aspartic acid located at position 137, which is essential to ICAM-1/LFA-1 interactions (Edwards, C.P., M. Champe, T. Gonzalez, M.E. Wessinger, S.A. Spencer, L.G. Presta, P.W. Berman, and S.C. Bodary. 1995. J. Biol. Chem. 270:12635-12640), was also critical for ICAM-3 binding, whereas Ser at position 139 did not effect ICAM-1 or ICAM-3 binding. A synthetic peptide containing the Ile-Lys-Gly-Asn motif inhibited ICAM-3-dependent adhesion and proliferation of T cells at micromolar concentrations, suggesting that this peptide interferes with immune recognition. These observations underscore the importance of ICAM-3 in leukocyte function, and may lead to development of a new category of immunosuppressive agents.
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Matsushima, Hironori, Hiroaki Tanaka, Norikatsu Mizumoto, and Akira Takashima. "Identification of crassin acetate as a new immunosuppressant triggering heme oxygenase-1 expression in dendritic cells." Blood 114, no. 1 (July 2, 2009): 64–73. http://dx.doi.org/10.1182/blood-2009-02-204297.
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Abstract By screening 720 natural compounds in a standard 2-way allogeneic mixed leukocyte reaction assay, we identified a potent immunosuppressive capacity of crassin acetate (CRA), a coral-derived cembrane diterpenoid. CRA efficiently inhibited allogeneic mixed leukocyte reaction as well as antigen-specific activation of CD4 T cells by bone marrow–derived dendritic cells (DCs). With regard to cellular targets, CRA suppressed not only mitogen-triggered T-cell activation, but also lipopolysaccharide-induced DC maturation, indicating dual functionality. Treatment with CRA at nontoxic doses induced heme oxygenase-1 (HO-1) mRNA/protein expression and HO-1 enzymatic activity in DCs, suggesting a unique mechanism of action. In fact, lipopolysaccharide-induced DC maturation was also inhibited by structurally unrelated compounds known to induce HO-1 expression or carbon monoxide (CO) release. Allergic contact hypersensitivity response to oxazolone and oxazolone-induced Langerhans cell migration from epidermis were both prevented almost completely by systemic administration of CRA. Not only do our results support the recent concept that HO-1/CO system negatively regulates immune responses, they also form both conceptual and technical frameworks for a more systematic, large-scale drug discovery effort to identify HO-1/CO-targeted immunosuppressants with dual target specificity.
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Senyuk, Vitalyi, Dolores Mahmud, Annie L. Oh, Pritesh R. Patel, and Damiano Rondelli. "C75 Fatty Acid Synthesis (FAS) Inhibitor Has Potent Immunosuppressive Activity." Blood 128, no. 22 (December 2, 2016): 2156. http://dx.doi.org/10.1182/blood.v128.22.2156.2156.
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Abstract Fatty acid synthesis (FAS) or oxidation (FAO) are important regulatory pathways in immune response. In fact, FAS plays a pivotal role in antigen presentation and T cells activation and FAO leads to fatty acid degradation which has been previously shown to regulate hematopoietic stem cell maintenance. Here we hypothesized that FAS can be a new target to suppress T cell alloimmune responses in solid organ or stem cell transplantations. Therefore, we tested if the FAS inhibitor C75 could suppress T cell alloreactivity without impairing normal hematopoiesis. The immuno-suppressive (IS) effect of moderate FAS inhibition was demonstrated in mixed leukocyte cultures (MLC) where C75 at 10 mkg/ml significantly reduced T cell proliferation and prevented the expansion of CD3+CD25+ and CD3+CD69+ T cells. In T cells stimulated by alloantigen, C75 also induced the downregulation of NF-kB gene expression and the upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) gene involved in ubiquitination and degradation of NF-kB protein. When compared to other standard IS agents, such as anti-thymocyte globulin (ATG), Cyclosporine A, Rapamycin or inhibitor of FAO Etomoxir, C75 showed similar anti-T cell activity. The same dose of C75 (10 mkg/ml) did not cause apoptotic death of human CD34+ cells in vitro, nor affected CD34+ cell clonogenicity in vitro. In fact, C75 increased the number of BFU-E and CFU-GM colonies (P < 0.05). We observed that the expression of de novo DNA methyltrasferases DNMT3A and DNMT3B, which are important regulators of stem cell renewal, was strongly reduced in CD34+ cells co-cultured for 3 days with allogeneic T cells. On the contrary, in the presence of C75 the expression of DNMT3A and DNMT3B was not different from baseline control. To test the in-vivo effect of C75 we utilized a xenograft model of stem cell rejection where 2 x 105 human CD34+ cells and HLA incompatible T lymphocytes were injected in immunodeficient nonobese diabetic/ltsz-scid/scid - IL2 receptor gamma chain knockout (NSG) mice at 1:1 ratio. Four weeks after transplantation, control NSG mice showed complete rejection of huCD45+CD34+ cells and the expansion of T cells in the marrow and spleen. NSG mice treated with intra-peritoneum injections of C75 every 3 days for 2 weeks, instead, showed 10-15% human CD45+ myeloid cells in the marrow and spleen at week 4 after transplant, suggesting at least a partial effect on preventing rejection of incompatible stem cells. We showed here that moderate FAS inhibition may represent a novel immunosuppressive strategy and our findings will prompt preclinical investigations exploiting the effect of FAS inhibitors alone or in combination with standard IS agents in models of allogeneic transplantation or bone marrow failure. Disclosures No relevant conflicts of interest to declare.
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Muraille, Eric, Fabienne Andris, Bernard Pajak, K. Martin Wissing, Thibaut De Smedt, Fabrice Desalle, Michel Goldman, et al. "Downregulation of Antigen-Presenting Cell Functions After Administration of Mitogenic Anti-CD3 Monoclonal Antibodies in Mice." Blood 94, no. 12 (December 15, 1999): 4347–57. http://dx.doi.org/10.1182/blood.v94.12.4347.
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Abstract Antibodies against CD3ɛ are widely used as immunosuppressive agents. Although it is generally assumed that these reagents exert their immunomodulatory properties by inducing T-cell deletion and/or inactivation, their precise mechanism of action remains to be elucidated. Using a murine model, we demonstrate in this report that administration of anti-CD3ɛ antibodies causes the migration and maturation of dendritic cells (DC) in vivo, as determined by immunohistochemical analysis. This maturation/migration process was followed by selective loss of splenic DC, which resulted in a selective inhibition of antigen-presenting cell (APC) functions in vitro. Spleen cells from anti-CD3ɛ–treated animals were unable to productively stimulate naive alloreactive T cells and Th1-like clones in response to antigen, while retaining the ability to present antigen to a T-cell hybridoma and Th2 clones. Anti-CD3ɛ treatment was found to induce a selective deficiency in the ability of spleen cells to produce bioactive interleukin-12 in response to CD40 stimulation. APC dysfunction was not observed when nonmitogenic forms of anti-CD3ɛ antibodies were used, suggesting that splenic DC loss was a consequence of in vivo T-cell activation. Nonmitogenic anti-CD3ɛ monoclonal antibodies were found to be less immunosuppressive in vivo, raising the possibility that APC dysfunction contributes to anti-CD3ɛ–induced immunomodulation. Collectively, these data suggest a novel mechanism by which mitogenic anti-CD3ɛ antibodies downregulate immune responses.
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Muraille, Eric, Fabienne Andris, Bernard Pajak, K. Martin Wissing, Thibaut De Smedt, Fabrice Desalle, Michel Goldman, et al. "Downregulation of Antigen-Presenting Cell Functions After Administration of Mitogenic Anti-CD3 Monoclonal Antibodies in Mice." Blood 94, no. 12 (December 15, 1999): 4347–57. http://dx.doi.org/10.1182/blood.v94.12.4347.424k31_4347_4357.
Full textAbstract:
Antibodies against CD3ɛ are widely used as immunosuppressive agents. Although it is generally assumed that these reagents exert their immunomodulatory properties by inducing T-cell deletion and/or inactivation, their precise mechanism of action remains to be elucidated. Using a murine model, we demonstrate in this report that administration of anti-CD3ɛ antibodies causes the migration and maturation of dendritic cells (DC) in vivo, as determined by immunohistochemical analysis. This maturation/migration process was followed by selective loss of splenic DC, which resulted in a selective inhibition of antigen-presenting cell (APC) functions in vitro. Spleen cells from anti-CD3ɛ–treated animals were unable to productively stimulate naive alloreactive T cells and Th1-like clones in response to antigen, while retaining the ability to present antigen to a T-cell hybridoma and Th2 clones. Anti-CD3ɛ treatment was found to induce a selective deficiency in the ability of spleen cells to produce bioactive interleukin-12 in response to CD40 stimulation. APC dysfunction was not observed when nonmitogenic forms of anti-CD3ɛ antibodies were used, suggesting that splenic DC loss was a consequence of in vivo T-cell activation. Nonmitogenic anti-CD3ɛ monoclonal antibodies were found to be less immunosuppressive in vivo, raising the possibility that APC dysfunction contributes to anti-CD3ɛ–induced immunomodulation. Collectively, these data suggest a novel mechanism by which mitogenic anti-CD3ɛ antibodies downregulate immune responses.
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Saito, Mikio, Manabu Abe, Tomoyasu Furukawa, Motohiro Yagi, Yoshihiro Koike, Yutaka Wakasugi, Norihiko Tabuchi, and Katsuji Uno. "Study on Patients Who Underwent Suspected Diagnosis of Allergy to Amide-Type Local Anesthetic Agents by the Leukocyte Migration Test." Allergology International 63, no. 2 (2014): 267–77. http://dx.doi.org/10.2332/allergolint.13-oa-0653.
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Al Amin, Md, Ishtiaque A. Chowdhury, KMM Mahbub, Mafruhi Sattar, Masum Shahriar, Md Ruhul Kuddus, and Mohammad A. Rashid. "Anti-inflammatory and Analgesic Activities of Asteracantha longifolia Nees." Bangladesh Pharmaceutical Journal 15, no. 2 (November 13, 2012): 171–76. http://dx.doi.org/10.3329/bpj.v15i2.12586.
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The present study was designed to evaluate the analgesic and anti-inflammatory activities of the ethanol extract of whole plant of Asteracantha longifolia Nees (family Acanthaceae) in mice. The analgesic activity was determined for its central and peripheral pharmacological actions using hotplate, formalin induced pain and acetic acid-induced writhing test in mice. Anti inflammatory effects were determined by ear swelling induced by croton oil, xyleneinduced ear edema, leukocyte migration induced by carrageenan, cotton pellet-induced granuloma formation. Tramadol (10 mg/kg) and Ibuprofen (100 mg/kg) were used as reference analgesic agents. The crude ethanol extract showed a significant inhibition of ear swelling caused by croton oil and xylene in mice. The crude extract decreased leukocyte migration induced by carrageenan, also moderately inhibited the weight of granuloma induced by a cotton pellet, as well as the formalin-induced pain. The extract given by p.o. route, produced significant inhibition of abdominal constrictions caused by acetic acid. Moreover, the extract also showed moderate analgesic activity on the hot plate pain threshold in mice. These data demonstrated that the plant may contain bioactive compounds possessing anti-inflammatory and analgesic activities. DOI: http://dx.doi.org/10.3329/bpj.v15i2.12586 Bangladesh Pharmaceutical Journal 15(2): 171-176, 2012
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Tan, Fang, Flaubert Mbeunkui, Crystal Harris, and Solomon F. Ofori-Acquah. "Mechanisms for Transcriptional Activation of the Human Activated Leukocyte Cell Adhesion Molecule Gene and Its Silencing by Immunosuppressive Toxins." Blood 108, no. 11 (November 16, 2006): 1637. http://dx.doi.org/10.1182/blood.v108.11.1637.1637.
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Abstract Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a member of the immunoglobulin super-family. It is expressed on the surfaces of activated monocytes, dendritic cells and macrophages. These immune cells use ALCAM through homotypic and heterotypic adhesions to control multiple stages in the inflammatory response. Indeed, anti-ALCAM antibodies and recombinant soluble ALCAM significantly inhibit monocyte transendothelial migration, stabilization of the immunological synapse and dendritic cell-mediated T-lymphocyte proliferation. Despite this significance, there is currently no understanding of how the human ALCAM gene is regulated. In this study, we identified the mechanisms for transcription, basal transcriptional activation and immunosuppressive silencing of the ALCAM gene. A common site for transcription of the ALCAM gene was identified 350 base pairs (bp) upstream from the translational start site. Multiple truncated fragments of the ALCAM promoter was cloned from genomic DNA and sub-cloned upstream of a promoterless luciferase vector. A proximal 650-bp promoter sequence conferred tissue-independent activation in hematopoietic, epithelial and endothelial cells. A canonical Sp1 binding sequence at −550 upstream of the translational start site was mapped within this proximal positive regulatory promoter region. Site-directed mutagenesis revealed this sequence was essential for optimum ALCAM promoter activity. Importantly, Sp1 occupied the cognate sequence in vivo as determined by chromatin immunoprecipitation assays. Over-expression of Sp1 significantly increased ALCAM promoter activity whereas a control expression vector had no impact. DNA sequences in the interval −600 to −800 negatively influenced promoter activity in a tissue-specific manner. This region contained a putative binding sequence for the aryl hydrocarbon receptor (Ahr), which highlighted ALCAM as a potential target of the immunosuppressing ligand dioxin. This hypothesis was tested by examination of whether ALCAM activation is blocked by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in monocytes differentiating into macrophages and dendritic cells. Expression of ALCAM was increased 3–5-fold in HL-60 and THP-1 monocytes treated with the differentiating agent phorbol 12-myristate 13-acetate. TCDD dose dependently blocked this activation, indeed, the highest concentration of TCDD (25 nM) used in this study completely blocked ALCAM activation in both monocytic cells. In conclusion, we have unveiled for the first time, the molecular basis for transcription and basal trans-activation of the human ALCAM gene, and identified the Ahr-pathway as a powerful silencer of ALCAM gene activation. Further studies of the ALCAM promoter, may clarify how this gene is up-regulated as part of the inflammatory response, and how it is silenced by immunotoxins. Heterologous expression of ALCAM may be a potential strategy to mitigate the immunosuppressive effects of dioxins and polycyclic aromatic hydrocarbons.
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Blaich, Birgit, Rachida Siham BelAiba, Sabine Merl, Agnes Görlach, Adnan Kastrati, Albert Schömig, and Rainer Wessely. "Comparative characterization of cellular and molecular anti-restenotic profiles of paclitaxel and sirolimus." Thrombosis and Haemostasis 97, no. 06 (2007): 1003–12. http://dx.doi.org/10.1160/th06-10-0586.
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SummaryPleiotropic anti-restenotic properties of drugs that are eluted from coated stents are critical for efficacy and safety. Little is known about comparative drug properties in appropriate human coronary target cell lines for the two compounds that are utilized on FDA-approved drug-eluting stent (DES) platforms, paclitaxel (PTX) and sirolimus (SRL). Target cell lines that play a pivotal role for the pathogenesis of restenosis and vascular healing include human coronary artery smooth muscle (CASMC) and endothelial cells (CAEC). PTX and SRL inhibited CASMC and CAEC proliferation and migration efficiently. However, there was a differential effect on proliferation and migration in CAEC with a more profound inhibition of both parameters by PTX, even at low dosages. Induction of cytotoxicity and apoptosis was pronounced in PTX- and very modest in SRL-treated CASMC and CAEC. PTX increased eNOS activity and nitric oxide (NO) release from CAEC. Neutrophilic leukocyte activation and transmigration, which should be avoided since it may precipitate adverse coronary events such as restenosis and stent thrombosis, was suppressed by SRL, whereas PTX tended to increase neutrophilic leucocyte activity. Therefore, although the primary drug target, inhibition of mitogen-mediated CASMC proliferation, is effectively accomplished by both drugs, auxiliary pharmacological properties that are crucial for the anti-restenotic drug effect and vascular healing are considerably different between PTX and SRL. In comparison with PTX, SRL shows minor interference with endothelial cell proliferation and migration, lower levels of cytotoxicity and apoptosis, a broader therapeutic range and distinctive immunosuppressive properties.
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Kosoff, David, Leigh Ellis, David J. Beebe, and Joshua Michael Lang. "Targeting tumor-associated macrophage (TAM) mediated inhibition of T-cell migration in prostate cancer using epigenetic modifying agents." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 166. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.166.
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166 Background: Cytotoxic T lymphocytes (CTLs) perform vital anti-tumor functions and are critical to the efficacy of many anticancer therapies. In prostate cancer, the characteristic paucity of activated CTLs within the tumor microenvironment (TME) may be a key factor in disease progression and likely underlies the limited role for immune checkpoint inhibitors (ICIs) in prostate cancer treatment. In this study, we utilized novel microfluidic technologies to evaluate whether TAMs may be driving the exclusion of T cells from the prostate TME and whether the immunosuppressive functions of TAMs could be modified by epigenetic modifying agents. Methods: Primary macrophages and autologous T cells were derived from peripheral blood samples of prostate cancer patients at the University of Wisconsin. Mono-, co-, and tri-culture systems of macrophages, T cells, and 22RV1 cells (androgen-dependent prostate cancer cell line) were cultured in 2D and 3D in microfluidic cell culture platforms. Culture systems were treated with the EZH2 inhibitors (EZH2i) DZNep or EPZ-6438 or left untreated. Macrophages were also treated with M1 (IFN-g) and M2 (IL-4) polarizing cytokines. Systems were analyzed for T cell migration as well as mRNA and protein expression in each cell population. Results: Autologous macrophages inhibited activated T cell migration towards tumor cells in a multi-cellular microscale TME. T cell migration was restored through treatment with EZH2i. Gene expression analysis identified that EZH2i altered macrophage gene expression in the unpolarized and M1/M2 polarized states. In particular, there was increased expression of genes involved in T cell recruitment/chemotaxis, including CXCL10, CXCL11, CXCL12, following EZH2i treatment. Conclusions: We used novel microfluidic technologies to model and analyze multicellular TMEs using primary, patient-derived cells. We demonstrate that TAM-mediated suppression of T cell migration is mediated, in part, through epigenetic pathways, which can be targeted with EZH2i. Treatment with EZH2i, alone or in combination other therapies such as ICIs, may enhance cytotoxic T cell migration and activity in primary prostate cancer.
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Adhikary, Sabina, Virginia P. Kocieda, Jui-Hung Yen, Ronald F. Tuma, and Doina Ganea. "Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression." Blood 120, no. 18 (November 1, 2012): 3741–49. http://dx.doi.org/10.1182/blood-2012-06-435362.
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Abstract Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators. Previous studies reported that CB2R signaling also reduces leukocyte migration. Migration of dendritic cells (DCs) to various sites is required for their activation and for the initiation of adaptive immune responses. Here, we report for the first time that CB2R signaling affects DC migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase 9 (MMP-9) expression. Reduced MMP-9 production by DCs results in decreased migration to draining lymph nodes in vivo and in vitro in the matrigel migration assay. The effect on Mmp-9 expression is mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to Mmp-9 promoter activator protein 1 sites. We postulate that, by dampening production of MMP-9 and subsequent MMP-9–dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs.
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Saeed, Rubina W., Santosh Varma, Tina Peng-Nemeroff, Barbara Sherry, David Balakhaneh, Jared Huston, Kevin J. Tracey, Yousef Al-Abed, and Christine N. Metz. "Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation." Journal of Experimental Medicine 201, no. 7 (April 4, 2005): 1113–23. http://dx.doi.org/10.1084/jem.20040463.
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Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the α7 nicotinic acetylcholine receptor (α7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the α7 nAChR, we examined the effect of cholinergic stimulation on endothelial cell activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial cell adhesion molecule expression. Using endothelial cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial cell activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor–κB nuclear entry in an inhibitor κB (IκB)α- and IκBε-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.
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Henriques, Bárbara O., Olívia Corrêa, Elaine Patrícia C. Azevedo, Rodrigo M. Pádua, Vívian Louise S. de Oliveira, Thiago Henrique C. Oliveira, Daiane Boff, et al. "In VitroTNF-αInhibitory Activity of Brazilian Plants and Anti-Inflammatory Effect ofStryphnodendron adstringensin an Acute Arthritis Model." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/9872598.
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Stryphnodendronspecies, popularly named “barbatimão,” are traditionally used in Brazil as anti-inflammatory agents. This study aimed to investigate the effect of barbatimão and 11 other species on the production of tumor necrosis factor-alpha (TNF-α) in lipopolysaccharide- (LPS-) stimulated THP-1 cells, as well as their anti-arthritis activity. The extracts ofStryphnodendron adstringens,Stryphnodendron obovatum,Campomanesia lineatifolia, andTerminalia glabrescenspromoted a concentration-dependent inhibition of TNF-α. Mice injected with LPS in the knee joint were treatedper oswith fractions from the selected extracts. Both the organic (SAO) and the aqueous (SAA) fractions ofS. adstringenspromoted a dose-dependent reduction of leukocyte migration and neutrophil accumulation into the joint, but none of them reduced CXCL1 concentration in the periarticular tissue. In contrast, treatment withC. lineatifoliaandT. glabrescensfractions did not ameliorate the inflammatory parameters. Analyses of SAO by Ultra Performance Liquid Chromatography (UPLC) coupled to electrospray ionization mass spectrometry (ESI-MS) led to the identification of gallic acid along with 11 prodelphinidins, characterized as monomers and dimers of the B-type. Our findings contribute to some extent to corroborating the traditional use ofS. adstringensas an anti-inflammatory agent. This activity is probably related to a decrease of leukocyte migration into the inflammatory site. Polyphenols like gallic acid and prodelphinidins, identified in the active fraction, may contribute to the observed activity.
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Bergan, John J., Geert W. Schmid-Schönbein, and Shinya Takase. "Therapeutic Approach to Chronic Venous Insufficiency and its Complications: Place of Daflon® 500 mg." Angiology 52, no. 1_suppl (August 2001): S43—S47. http://dx.doi.org/10.1177/0003319701052001s06.
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Early manifestations of chronic venous insufficiency (CVI) are edema, hyperpigmentation, and lipodermatosclerosis. Late complications are cutaneous ulceration and delayed healing. The specific hallmarks of this inflammation include CD68-positive infiltration into the dermal tissue, monocytes, and lymphocytes and enhanced endothelial permeability. This may lead to "fibrin cuff" formation. In addition, membrane adhesion molecules are present and cytokine expression is seen. In one experimental model of mesenteric venous hypertension, the inflammatory process was detected in its earliest stages. This was evident in the form of neutrophilic leukocyte adhesion to venular endothelium as well as migration of cells across the endothelium and basement membrane into the interstitial space. Simultaneously, parenchymal cell death was detected. This suggests that the mechanism that triggers the inflammatory reaction is venous hypertension. This may cause venous distension and a shift in fluid shear stress. Our obser vations suggest that patients with venous insufficiency demonstrate circulatory humoral stim ulators for leukocyte activation. Otherwise, there is evidence that the inflammatory reaction is limited to the region of the venous ulceration or at least to the skin areas with severe microangiopathy. It may be that activated leukocytes traverse perivascular cuffs and release active transforming growth factor-β1 (TGF-β1) which has been found to be elevated exclu sively in areas of clinically active CVI. Surgical intervention markedly decreases the number of dysfunctional vein segments and allows pharmacologic agents to protect normal structures from continuing damage. Daflon® 500 mg, the purified micronized flavonoid fraction containing 90% diosmin and 10% hesperidin, acts favorably in venous ulcer treatment by inhibiting the synthesis of prostaglandins and free radicals. It decreases bradykinin-induced microvascular leakage and may act favorably to inhibit leukocyte activation, trapping, and migration. Clinically, edema is reduced, ulcer healing is accelerated, and leukocyte trapping diminished. The action of micronized purified flavonoid fraction is beginning to be better understood, and as further knowledge is gained, better pharmacologic control of CVI is a tantalizing promise.
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Thivierge, Maryse, Christian Le Gouill, Michel J. Tremblay, Jana Stanková, and Marek Rola-Pleszczynski. "Prostaglandin E2 Induces Resistance to Human Immunodeficiency Virus-1 Infection in Monocyte-Derived Macrophages: Downregulation of CCR5 Expression by Cyclic Adenosine Monophosphate." Blood 92, no. 1 (July 1, 1998): 40–45. http://dx.doi.org/10.1182/blood.v92.1.40.413k43_40_45.
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The chemokine receptor CCR5 can function as a coreceptor for human immunodeficiency virus-1 (HIV-1) entry into CD4+ T cells and macrophages, especially during the early stages of HIV-1 infection. The regulation of CCR5 expression may affect not only leukocyte migration, but also infectivity by HIV-1 and, therefore, acquired immunodeficiency syndrome (AIDS) pathogenesis. We report here that agents which increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) rapidly downregulate CCR5 gene expression, with consequent loss of CCR5 expression and function in monocytes/macrophages. Chemotaxis and intracellular Ca2+mobilization in monocytes pretreated with prostaglandin E2or dibutyryl-cAMP for 24 hours were significantly reduced in response to the CCR5 ligand, MIP-1β. Moreover, HIV-1 entry into monocyte-derived macrophages pretreated with dibutyryl-cAMP or prostaglandin E2 was markedly decreased. Our findings suggest that resistance to HIV-1 can be induced by agents which increase cellular levels of cAMP and that this may suggest additional therapeutic strategies to limit infection by HIV-1.
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Cooper, David K. C., H. Iwase, L. Wang, T. Yamamoto, Qi Li, J. Li, H. Zhou, and H. Hara. "Bringing Home The Bacon: Update on The State of Kidney Xenotransplantation." Blood Purification 45, no. 1-3 (2018): 254–59. http://dx.doi.org/10.1159/000485163.
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Background: There is a continuing critical shortage of organs from deceased human donors for transplantation, particularly for patients awaiting kidney transplantation. Efforts are being made to resolve the donor kidney shortage by the transplantation of kidneys from genetically-engineered pigs. Summary: This review outlines the pathobiological barriers to pig organ xenotransplantation in primates, which include (i) antibody-dependent complement-mediated rejection, (ii) a T cell-mediated elicited antibody and cellular response, (iii) coagulation dysregulation between pigs and primates, and (iv) a persistent inflammatory response. As a result of increasing genetic manipulation of the pig and the introduction of novel immunosuppressive agents, pig kidney graft survival has increased from minutes to months, and even to >1 year in some cases. Aspects of the selection of the patients for a first clinical trial are discussed. Although there would appear to be some cross-reactivity between anti-human leukocyte antigen (HLA) antibodies and swine leukocyte antigens expressed in pigs, some HLA-sensitized patients will be at no disadvantage if they receive a pig kidney. Furthermore, the current limited evidence is that, even if the patient becomes sensitized to pig antigens (after a pig organ transplant), this would not be detrimental to a subsequent allotransplant. The potential risk of infection with a pig microorganism, and the function of a pig kidney in a primate are also discussed. Key Message: The recent encouraging results of pig kidney transplantation in nonhuman primates suggest the likelihood of a successful (and safe) initial clinical trial, with graft survival for months or possibly years.
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Fabbri, Monica, Silvia Di Meglio, Maria Cristina Gagliani, Elisa Consonni, Raffaella Molteni, Jeffrey R. Bender, Carlo Tacchetti, and Ruggero Pardi. "Dynamic Partitioning into Lipid Rafts Controls the Endo-Exocytic Cycle of the αL/β2Integrin, LFA-1, during Leukocyte Chemotaxis." Molecular Biology of the Cell 16, no. 12 (December 2005): 5793–803. http://dx.doi.org/10.1091/mbc.e05-05-0413.
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Cell migration entails the dynamic redistribution of adhesion receptors from the cell rear toward the cell front, where they form new protrusions and adhesions. This process may involve regulated endo-exocytosis of integrins. Here we show that in primary neutrophils unengaged αL/β2integrin (LFA-1) is internalized and rapidly recycled upon chemoattractant stimulation via a clathrin-independent, cholesterol-sensitive pathway involving dynamic partitioning into detergent-resistant membranes (DRM). Persistent DRM association is required for recycling of the internalized receptor because 1) >90% of endocytosed LFA-1 is associated with DRM, and a large fraction of the internalized receptor colocalizes intracellularly with markers of DRM and the recycling endocytic compartment; 2) a recycling-defective mutant (αL/β2Y735A) dissociates rapidly from DRM upon being endocytosed and is subsequently diverted into a late endosomal pathway; and 3) a dominant negative Rab11 mutant (Rab11S25N) induces intracellular accumulation of endocytosed αL/β2and prevents its enrichment in chemoattractant-induced lamellipodia. Notably, chemokine-induced migration of neutrophils over immobilized ICAM-1 is abrogated by cholesterol-sequestering agents. We propose that DRM-associated endocytosis allows efficient retrieval of integrins, as they detach from their ligands, followed by polarized recycling to areas of the plasma membrane, such as lamellipodia, where they establish new adhesive interactions and promote outside-in signaling events.
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Wolfram, Dolores, Evi M. Morandi, Nadine Eberhart, Theresa Hautz, Hubert Hackl, Bettina Zelger, Gregor Riede, et al. "Differentiation between Acute Skin Rejection in Allotransplantation and T-Cell Mediated Skin Inflammation Based on Gene Expression Analysis." BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/259160.
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Advances in microsurgical techniques and immunosuppressive medication have rendered transplantation of vascularized composite allografts possible, when autologous tissue is neither available nor sufficient for reconstruction. However, skin rejection and side effects of long-term immunosuppression still remain a major hurdle for wide adoption of this excellent reconstructive technique. Histopathologic changes during acute skin rejection in vascular composite allotransplantation often mimic inflammatory skin disorders and are hard to distinguish. Hence, the identification of diagnostic and therapeutic markers specific for skin rejection is of particular clinical need. Here we present novel markers allowing for early differentiation between rejection in hind limb allotransplantation and contact hypersensitivity. Assessment of Ccl7, Il18, and Il1b expression is most indicative of distinguishing skin rejection from skin inflammatory disorders. Gene expression levels varied significantly across skin types and regions, indicating localization specific mechanism of leukocyte migration and infiltration. Expression of Il12b, Il17a, and Il1b gene expression levels differed significantly between rejection and inflammation, independent of the skin type. In synopsis of the RNA expression profile and previously assessed protein expression, the Il1 family appears as a promising option for accurate skin rejection diagnosis and, as a following step, for development of novel rejection treatments.
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Dharma, Sanam Sahjram, Tara Barone, Sheila Figel, Meaghan Birkemeier, Yali Zhang, Robert Fenstermaker, and Michael Ciesielski. "OTME-21. The role of Glioblastoma associated mesenchymal stem cells in immune suppression." Neuro-Oncology Advances 3, Supplement_2 (July 1, 2021): ii18. http://dx.doi.org/10.1093/noajnl/vdab070.072.
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Abstract Glioblastoma (GBM) is an aggressive brain cancer, with an overall survival of 14.6 months. The tumor microenvironment in GBM plays major roles in immunosuppression and modulation of the response to therapies. GBM patients with higher levels of mesenchymal stem like cells (G-MSC) show poor overall survival as compared to patients with no/lower G-MSC levels. Our lab found that levels of G-MSC corelate with CD4+ T cells in humans and murine models of GBM, and with immunosuppressive molecules like PTGS2, the gene for cyclooxygenase 2. To investigate the mechanism by which G-MSCs promote immunosuppression, we isolated G-MSCs from an orthotopic mouse model of GBM and subjected them to RNASeq analysis to obtain an unbiased picture of transcriptomic changes occurring upon activation. We identified changes in multiple immune modulating pathways involving antigen presentation, leukocyte migration and activation, and immune checkpoints. Our findings indicate that G-MSCs represent a key immune modulating faction in the microenvironment. Further dissection of the role of these cells in immune modulation will aid us in understanding the biology of the brain tumor microenvironment and identifying potential combination therapies.
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Furie, MB, MC Tancinco, and CW Smith. "Monoclonal antibodies to leukocyte integrins CD11a/CD18 and CD11b/CD18 or intercellular adhesion molecule-1 inhibit chemoattractant-stimulated neutrophil transendothelial migration in vitro." Blood 78, no. 8 (October 15, 1991): 2089–97. http://dx.doi.org/10.1182/blood.v78.8.2089.2089.
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Abstract Intercellular adhesion molecule-1 (ICAM-1) is present on the endothelium and binds to one or more members of the CD11/CD18 family of leukocyte surface integrins. To assess the role of these molecules in mediating chemotaxis of neutrophils across the endothelium, an in vitro model consisting of monolayers of human umbilical vein endothelial cells (HUVEC) grown on amniotic connective tissue was used. Neutrophils placed on the apical sides of these cultures migrated across the endothelium in response to chemoattractants added basally. Monoclonal antibodies (MoAbs) to CD11a, CD11b, and CD18 on the neutrophils inhibited this migration by 52% +/- 11%, 29% +/- 19%, and 90% +/- 7%, respectively. An MoAb to ICAM-1 inhibited transendothelial chemotaxis of the leukocytes by 55% +/- 16%. Inhibition was mediated by binding of the MoAb to ICAM-1 on the HUVEC, rather than by any direct effect of the antibody on the neutrophils. When used in combination, MoAbs to CD11a and to CD11b inhibited migration in a nearly additive fashion. A similar additive effect was observed when MoAbs to CD11b and to ICAM-1 were used together. In contrast, MoAbs to CD11a and to ICAM-1 produced no more inhibition when used in combination than when added singly. These results show that ICAM-1, CD11a/CD18, and CD11b/CD18 all participate in controlling migration of neutrophils across endothelial monolayers in response to chemotactic agents.
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Furie, MB, MC Tancinco, and CW Smith. "Monoclonal antibodies to leukocyte integrins CD11a/CD18 and CD11b/CD18 or intercellular adhesion molecule-1 inhibit chemoattractant-stimulated neutrophil transendothelial migration in vitro." Blood 78, no. 8 (October 15, 1991): 2089–97. http://dx.doi.org/10.1182/blood.v78.8.2089.bloodjournal7882089.
Full textAbstract:
Intercellular adhesion molecule-1 (ICAM-1) is present on the endothelium and binds to one or more members of the CD11/CD18 family of leukocyte surface integrins. To assess the role of these molecules in mediating chemotaxis of neutrophils across the endothelium, an in vitro model consisting of monolayers of human umbilical vein endothelial cells (HUVEC) grown on amniotic connective tissue was used. Neutrophils placed on the apical sides of these cultures migrated across the endothelium in response to chemoattractants added basally. Monoclonal antibodies (MoAbs) to CD11a, CD11b, and CD18 on the neutrophils inhibited this migration by 52% +/- 11%, 29% +/- 19%, and 90% +/- 7%, respectively. An MoAb to ICAM-1 inhibited transendothelial chemotaxis of the leukocytes by 55% +/- 16%. Inhibition was mediated by binding of the MoAb to ICAM-1 on the HUVEC, rather than by any direct effect of the antibody on the neutrophils. When used in combination, MoAbs to CD11a and to CD11b inhibited migration in a nearly additive fashion. A similar additive effect was observed when MoAbs to CD11b and to ICAM-1 were used together. In contrast, MoAbs to CD11a and to ICAM-1 produced no more inhibition when used in combination than when added singly. These results show that ICAM-1, CD11a/CD18, and CD11b/CD18 all participate in controlling migration of neutrophils across endothelial monolayers in response to chemotactic agents.
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Bordin, JO, NM Heddle, and MA Blajchman. "Biologic effects of leukocytes present in transfused cellular blood products." Blood 84, no. 6 (September 15, 1994): 1703–21. http://dx.doi.org/10.1182/blood.v84.6.1703.1703.
Full textAbstract:
Abstract A considerable literature has accumulated over the past decade indicating that leukocytes present in allogeneic cellular blood components, intended for transfusion, are associated with adverse effects to the recipient. These include the development of febrile transfusion reactions, graft-versus-host disease, alloimmunization to leukocyte antigens, and the immunomodulatory effects that might influence the prognosis of patients with a malignancy. Moreover, it has become evident that such leukocytes may be the vector of infectious agents such as CMV, HTLV-I/II, and EBV as well as other viruses. An interesting development that has occurred coincidentally in transfusion medicine is that agencies responsible for the provision of blood products are being designated manufacturers of biologicals. The trend among manufacturers of biologicals is to try to produce pure products to provide for the specific therapeutic need of patients. Thus, with the realization that allogeneic leukocytes and their products may have adverse biologic activities, there is increasing pressure from various sources for the reduction of the leukocyte content in allogeneic blood components to minimize the occurrence of their adverse effects. Although the threshold leukocyte number below which these effects might no longer occur is still to be determined, a 2 to 3 log10 leukocyte reduction, provided by the currently available commercial leukocyte filters, has been shown to reduce the frequency of many of such reactions. On the other hand, the immunosuppressive effects produced by the infusion of allogeneic leukocytes might be beneficial for some patients, ie, for the maintenance of kidney allografts, in possibly reducing the relapse rate in patients with inflammatory bowel diseases, and in ameliorating recurrent spontaneous abortion. Moreover, therapeutic granulocyte transfusions may be of benefit in certain well- defined categories of patients infected with bacteria, yeast, and/or fungi. These include neonates with bacterial sepsis associated with bone marrow failure as well as severely neutropenic leukemic patients with an infection unresponsive to appropriate and specific antibiotic therapy. Many of the results obtained with the use of leukocyte depletion filters are tantalizing, but the actual clinical benefit of leukodepletion has not been established in most instances, because much of the available data are retrospective or from uncontrolled clinical trials. Moreover, issues of cost-effectiveness and quality control have not been considered adequately. Properly designed prospective clinical trials are essential to provide data with which to answer such questions and also to help define the optimal conditions required for the preparation of blood components ultimately destined for clinical use. Only with the availability of such data can sound decisions be made about the clinical value of leukodepletion.
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Bordin, JO, NM Heddle, and MA Blajchman. "Biologic effects of leukocytes present in transfused cellular blood products." Blood 84, no. 6 (September 15, 1994): 1703–21. http://dx.doi.org/10.1182/blood.v84.6.1703.bloodjournal8461703.
Full textAbstract:
A considerable literature has accumulated over the past decade indicating that leukocytes present in allogeneic cellular blood components, intended for transfusion, are associated with adverse effects to the recipient. These include the development of febrile transfusion reactions, graft-versus-host disease, alloimmunization to leukocyte antigens, and the immunomodulatory effects that might influence the prognosis of patients with a malignancy. Moreover, it has become evident that such leukocytes may be the vector of infectious agents such as CMV, HTLV-I/II, and EBV as well as other viruses. An interesting development that has occurred coincidentally in transfusion medicine is that agencies responsible for the provision of blood products are being designated manufacturers of biologicals. The trend among manufacturers of biologicals is to try to produce pure products to provide for the specific therapeutic need of patients. Thus, with the realization that allogeneic leukocytes and their products may have adverse biologic activities, there is increasing pressure from various sources for the reduction of the leukocyte content in allogeneic blood components to minimize the occurrence of their adverse effects. Although the threshold leukocyte number below which these effects might no longer occur is still to be determined, a 2 to 3 log10 leukocyte reduction, provided by the currently available commercial leukocyte filters, has been shown to reduce the frequency of many of such reactions. On the other hand, the immunosuppressive effects produced by the infusion of allogeneic leukocytes might be beneficial for some patients, ie, for the maintenance of kidney allografts, in possibly reducing the relapse rate in patients with inflammatory bowel diseases, and in ameliorating recurrent spontaneous abortion. Moreover, therapeutic granulocyte transfusions may be of benefit in certain well- defined categories of patients infected with bacteria, yeast, and/or fungi. These include neonates with bacterial sepsis associated with bone marrow failure as well as severely neutropenic leukemic patients with an infection unresponsive to appropriate and specific antibiotic therapy. Many of the results obtained with the use of leukocyte depletion filters are tantalizing, but the actual clinical benefit of leukodepletion has not been established in most instances, because much of the available data are retrospective or from uncontrolled clinical trials. Moreover, issues of cost-effectiveness and quality control have not been considered adequately. Properly designed prospective clinical trials are essential to provide data with which to answer such questions and also to help define the optimal conditions required for the preparation of blood components ultimately destined for clinical use. Only with the availability of such data can sound decisions be made about the clinical value of leukodepletion.
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Storb, Rainer, Cong Yu, Todd Barnett, John L. Wagner, H. Joachim Deeg, Richard A. Nash, Hans-Peter Kiem, et al. "Stable Mixed Hematopoietic Chimerism in Dog Leukocyte Antigen–Identical Littermate Dogs Given Lymph Node Irradiation Before and Pharmacologic Immunosuppression After Marrow Transplantation." Blood 94, no. 3 (August 1, 1999): 1131–36. http://dx.doi.org/10.1182/blood.v94.3.1131.415k21_1131_1136.
Full textAbstract:
Stable mixed donor/host hematopoietic chimerism can be accomplished in dog leukocyte antigen (DLA)-identical littermate dogs given sublethal (200 cGy) total-body irradiation (TBI) before and immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) after transplant (Blood 89:3048, 1997). Studies were based on the hypothesis that drugs that prevent graft-versus-host disease (GVHD) after transplant also suppress host-versus-graft (HVG) reactions and thereby enhance engraftment. Here, we asked whether pretransplant TBI provided marrow space for the graft to home or caused host immunosuppression. To address the questions, recipients were given pretransplant irradiation to cervical, thoracic, and abdominal lymph nodes (except pelvis), DLA-identical littermate marrow grafts, and MMF/CSP posttransplant. Six dogs that received 450 cGy irradiation showed initial engraftment. Two rejected their grafts after 8 and 18 weeks, 1 died with GVHD and engraftment, and 3 are alive as mixed chimeras after 57 to 97 weeks. Four dogs given 200 cGy irradiation also showed initial engraftment, but rejected their grafts after 10 to 18 weeks. Mixed chimerism was present in nonirradiated marrow and lymph node spaces and involved granulocytes, T cells, and monocytes. While other explanations are possible, results seem consistent with the hypothesis that pretransplant radiation provides host immunosuppression, and grafts can create their own marrow space. These data set the stage for the development of novel transplant regimens that substitute immunosuppressive for cytotoxic agents.
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Garcia, Joe G. N., Alexander D. Verin, Maria Herenyiova, and Denis English. "Adherent neutrophils activate endothelial myosin light chain kinase: role in transendothelial migration." Journal of Applied Physiology 84, no. 5 (May 1, 1998): 1817–21. http://dx.doi.org/10.1152/jappl.1998.84.5.1817.
Full textAbstract:
Increased vascular endothelial cell (EC) permeability and neutrophilic leukocyte (PMN) diapedesis through paracellular gaps are cardinal features of acute inflammation. Activation of the EC contractile apparatus is necessary and sufficient to increase vascular permeability in specific models of EC barrier dysfunction. However, it is unknown whether EC contraction with subsequent paracellular gap formation is required for PMN transendothelial migration in response to chemotactic factors. To test this possibility, we assessed migration of human PMNs across confluent bovine pulmonary arterial EC monolayers. Transendothelial PMN migration in the absence of a chemotactic gradient was minimal, whereas abluminal addition of leukotriene B4(LTB4; 5 μM) resulted in significantly increased PMN migration. Reductions in EC myosin light chain kinase (MLCK) activity by EC monolayer pretreatment with specific MLCK inhibitors (KT-5926 or ML-7) or by increases in cAMP-protein kinase A activity (cholera toxin) significantly reduced PMN transmigration (30–70% inhibition). In contrast, pretreatment with the myosin-associated phosphatase inhibitor calyculin resulted in the accumulation of phosphorylated myosin light chains, EC contraction, and significantly enhanced PMN migration. Finally, the interaction of PMNs with 32P-labeled EC monolayers was shown to directly increase EC myosin phosphorylation in a time-dependent fashion. Taken together, these results are consistent with the hypothesis that the phosphorylation status of EC myosin regulates PMN migration and further indicate that EC MLCK is activated by chemoattractant-stimulated PMNs. Neutrophil-dependent activation of the EC contractile apparatus with subsequent paracellular gap formation may be a key determinant of transendothelial PMN migration responses to chemotactic agents.
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Carbone, Maria Luigia, Pedro Miguel Lacal, Serena Messinese, Laura De Giglio, Carlo Pozzilli, Severino Persechino, Cinzia Mazzanti, Cristina Maria Failla, and Gianluca Pagnanelli. "Multiple Sclerosis Treatment and Melanoma Development." International Journal of Molecular Sciences 21, no. 8 (April 22, 2020): 2950. http://dx.doi.org/10.3390/ijms21082950.
Full textAbstract:
Therapy of multiple sclerosis (MS) with disease-modifying agents such as natalizumab or fingolimod has been associated with the development of cutaneous melanoma. Here we briefly revise literature data and report of a case of a 48-year old woman who developed a melanoma and several atypical naevi after sub sequential treatment with natalizumab (1 year) and fingolimod (7 years). By immunohistochemistry we observed the presence of T cells and leukocyte infiltration as well as of vascular endothelial growth factor (VEGF)-A expression in the patient melanoma biopsy. Then, we analyzed proliferation, migration and VEGF-A expression in three melanoma cell lines and found out that both natalizumab and fingolimod inhibited tumor cell proliferation but promoted or blocked cell migration depending on the cell line examined. VEGF-A secretion was augmented in one melanoma cell line only after fingolimod treatment. In conclusion, our in vitro data do not support the hypothesis of a direct action of natalizumab or fingolimod on melanoma progression but acting on the tumor microenvironment these treatments could indirectly favor melanoma evolution.
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Kubes, Paul. "Polymorphonuclear leukocyte – endothelium interactions: a role for pro-inflammatory and anti-inflammatory molecules." Canadian Journal of Physiology and Pharmacology 71, no. 1 (January 1, 1993): 88–97. http://dx.doi.org/10.1139/y93-013.
Full textAbstract:
The movement of polymorphonuclear leukocytes (PMNs) from the mainstream of blood to the extravascular space is a characteristic feature of the inflammatory response. This process requires that the PMN initially contacts the endothelium, then adheres firmly to the vessel wall, and finely migrates out of the microvasculature. Each of these events requires signals or pro-inflammatory molecules that direct the PMN to the potential site of inflammation. These molecules include histamine, which appears to be of importance in the initial recruitment of PMNs, leukotriene B4, which promotes PMN adhesion, and platelet-activating factor, which may contribute to both the adhesion process as well as the migration through the endothelial barrier. Although many other pro-inflammatory molecules have been identified, including the cytokines and complement, the three aforementioned molecules are used in this review as paradigms of the varying functions that pro-inflammatory molecules have in the inflammatory process. There is a growing body of evidence that in addition to the many pro-inflammatory agents found in the body there are a number of important anti-inflammatory molecules, including nitric oxide, prostacyclin, and adenosine. Each of these molecules possess important properties that serve to interrupt or protect against the ongoing inflammatory process. The anti-inflammatory potential of these endogenous molecules is discussed.Key words: nitric oxide, histamine, platelet-activating factor, prostacyclin, leukotriene B4, adenosine.
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Imamura, Ryoichi, Yoshiko Matsuda, Koichi Tsutahara, Norio Nonomura, and Shiro Takahara. "Impact of Immunoglobulin M-Type Donor-Specific Human Leukocyte Antigen–Antibody Levels in Supernatants from Cultured Peripheral Blood Mononuclear Cells as Predictors of Antibody-Mediated Rejection." Pathogens 9, no. 9 (September 5, 2020): 733. http://dx.doi.org/10.3390/pathogens9090733.
Full textAbstract:
Background: Antibody-mediated rejection (AMR) is a crucial barrier in the long-term prognosis of transplant recipients. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from kidney allograft recipients (N = 41) and cultured in vitro for 1 week. Furthermore, the supernatants of the cultured PBMCs were analyzed by Luminex single-antigen beads. Results: Analyses using Luminex single-antigen beads revealed the presence of immunoglobulin (Ig) G donor-specific anti-HLA antibodies (DSAs) was detected in the supernatants of cultured PBMCs collected more frequently than IgM in de novo DSA-sensitized patients with AMR, and IgM were detectable in patients with stable graft function mainly and several IgM DSAs were detectable in the supernatants of the cultured PBMCs before detecting the IgG levels in sera. We also found that the DSA-specific IgM-secreting memory B cells (mBCs) were more sensitive to the chronic use of immunosuppressive agents than to the IgG-secreting mBCs. Conclusions: In the transplant recipients, the assessment of supernatants of cultured PBMCs provide more details of immune reactions than the commonly used method that directly measures IgG DSA levels in patient sera and some IgM DSA detection may be a better predictor of IgG DSAs production, which may cause AMR and enable early intervention, in initial stages of AMR development.
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Goralski, Kerry B., Ashley E. Jackson, Brendan T. McKeown, and Christopher J. Sinal. "More Than an Adipokine: The Complex Roles of Chemerin Signaling in Cancer." International Journal of Molecular Sciences 20, no. 19 (September 26, 2019): 4778. http://dx.doi.org/10.3390/ijms20194778.
Full textAbstract:
Chemerin is widely recognized as an adipokine, with diverse biological roles in cellular differentiation and metabolism, as well as a leukocyte chemoattractant. Research investigating the role of chemerin in the obesity–cancer relationship has provided evidence both for pro- and anti-cancer effects. The tumor-promoting effects of chemerin primarily involve direct effects on migration, invasion, and metastasis as well as growth and proliferation of cancer cells. Chemerin can also promote tumor growth via the recruitment of tumor-supporting mesenchymal stromal cells and stimulation of angiogenesis pathways in endothelial cells. In contrast, the majority of evidence supports that the tumor-suppressing effects of chemerin are immune-mediated and result in a shift from immunosuppressive to immunogenic cell populations within the tumor microenvironment. Systemic chemerin and chemerin produced within the tumor microenvironment may contribute to these effects via signaling through CMKLR1 (chemerin1), GPR1 (chemerin2), and CCLR2 on target cells. As such, inhibition or activation of chemerin signaling could be beneficial as a therapeutic approach depending on the type of cancer. Additional studies are required to determine if obesity influences cancer initiation or progression through increased adipose tissue production of chemerin and/or altered chemerin processing that leads to changes in chemerin signaling in the tumor microenvironment.
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Fiocchi, Claudio. "New Concepts of Pathogenesis in Inflammatory Bowel Disease." Canadian Journal of Gastroenterology 9, no. 5 (1995): 261–70. http://dx.doi.org/10.1155/1995/847312.
Full textAbstract:
The precise etiology and mechanisms of inflammatory bowel disease (IBD) are still unclear. Nevertheless, several concepts are gaining acceptance and constitute the basis for a better understanding of its pathogenesis and for improved therapy. The association of Crohn’s disease (CD) and ulcerative colitis (UC) with ‘western’ lifestyle is well recognized, and is considered a reason for the increasing frequency of CD and UC in countries with previously low incidence. Proposed linkages of CD and UC with particular human leukocyte antigen haplotypes suggest a genetic predisposition, but no uniform or consistent patterns have emerged. Similarly, the study of susceptibility or disease markers has not offered reproducible results. The search for specific infectious agents is being pursued, and the measles virus is presently considered a possible culprit. A true explosion has occurred in the area of animal models, and a large number of chemically or genetically induced experimental colitides are at hand. Immunological factors continue to dominate the bulk of basic research in IBD. This area is vast and complex, and autoantibodies, immune, epithelial and mesenchymal cells, lipid mediators, cytokines, neuropeptides and oxygen metabolites are under investigation. Finally, other factors whose role in IBD is uncertain, including smoking and possible abnormalities of intestinal permeability or mucus composition, continue to receive attention. These extensive and varied efforts are yielding some profits, and new forms of therapy are being devised. Based mostly on studies of soluble mediators, a number of novel immunosuppressive and highly specific blocking agents are being developed and undergoing clinical trials.
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Lu, L., W. A. Rudert, S. Qian, D. McCaslin, F. Fu, A. S. Rao, M. Trucco, J. J. Fung, T. E. Starzl, and A. W. Thomson. "Growth of donor-derived dendritic cells from the bone marrow of murine liver allograft recipients in response to granulocyte/macrophage colony-stimulating factor." Journal of Experimental Medicine 182, no. 2 (August 1, 1995): 379–87. http://dx.doi.org/10.1084/jem.182.2.379.
Full textAbstract:
Allografts of the liver, which has a comparatively heavy leukocyte content compared with other vascularized organs, are accepted permanently across major histocompatibility complex barriers in many murine strain combinations without immunosuppressive therapy. It has been postulated that this inherent tolerogenicity of the liver may be a consequence of the migration and perpetuation within host lymphoid tissues of potentially tolerogenic donor-derived ("chimeric") leukocytes, in particular, the precursors of chimeric dendritic cells (DC). In this study, we have used granulocyte/macrophage colony-stimulating factor to induce the propagation of progenitors that give rise to DC (CD45+, CD11c+, 33D1+, nonlymphoid dendritic cell 145+, major histocompatibility complex class II+, B7-1+) in liquid cultures of murine bone marrow cells. Using this technique, together with immunocytochemical and molecular methods, we show that, in addition to cells expressing female host (C3H) phenotype (H-2Kk+; I-E+; Y chromosome-), a minor population of male donor (B10)-derived cells (H-2Kb+; I-A+; Y chromosome+) can also be grown in 10-d DC cultures from the bone marrow of liver allograft recipients 14 d after transplant. Highly purified nonlymphoid dendritic cell 145+ DC sorted from these bone marrow-derived cell cultures were shown to comprise approximately 1-10% cells of donor origin (Y chromosome+) by polymerase chain reaction analysis. In addition, sorted DC stimulated naive, recipient strain T lymphocytes in primary mixed leukocyte cultures. Evidence was also obtained for the growth of donor-derived cells from the spleen but not the thymus. In contrast, donor cells could not be propagated from the bone marrow or other lymphoid tissues of nonimmunosuppressed C3H mice rejecting cardiac allografts from the same donor strain (B10). These findings provide a basis for the establishment and perpetuation of cell chimerism after organ transplantation.
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Requião-Moura, Lúcio R., Elizabeth De Francesco Daher, Cassio R. Moreira Albino, Savio de Oliveira Brilhante, Geraldo Bezerra da Silva Junior, Silvana Daher Costa, and Tainá Veras de Sandes-Freitas. "Tropical Infections in the Context of Kidney Transplantation in Latin America." American Journal of Tropical Medicine and Hygiene 105, no. 3 (September 15, 2021): 564–72. http://dx.doi.org/10.4269/ajtmh.19-0926.
Full textAbstract:
ABSTRACT. Reports on tropical infections among kidney transplant (KT) recipients have increased in recent years, mainly because of the growing number of KT programs located in tropical and subtropical areas, and greater mobility or migration between different areas of the world. Endemic in emerging and developing regions, like most countries in Latin America, tropical infections are an important cause of morbidity and mortality in this population. Tropical infections in KT recipients may exhibit different pathways for acquisition compared with those in nonrecipients, such as transmission through a graft and reactivation of a latent infection triggered by immunosuppression. Clinical presentation may differ compared with that in immunocompetent patients, and there are also particularities in diagnostic aspects, treatment, and prognosis. KT patients must be screened for latent infections and immunized properly. Last, drug–drug interactions between immunosuppressive agents and drugs used to treat tropical infections are an additional challenge in KT patients. In this review, we summarize the management of tropical infections in KT patients.
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Issekutz, Andrew C., Nancy Lopes, and Thomas B. Issekutz. "Role of interleukin-1 and tumour necrosis factor in leukocyte recruitment to acute dermal inflammation." Mediators of Inflammation 1, no. 5 (1992): 347–53. http://dx.doi.org/10.1155/s0962935192000528.
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The cytokines IL-1 and TNF-α are involved in inflammation and their production is stimulated by various agents, especially endotoxin (LPS). Here, using the human IL-1 receptor antagonist (IL-1RA) and a new monoclonal antibody (mAb 7F11) to rabbit TNF, the role of endogenous IL-l and TNF production in acute (3h) leukocyte (PMNL) recruitment to dermal inflammation in rabbits has been studied. IL-1RA inhibited by 27% the PMNL accumulation in reactions induced by killed Escherichia coli (p < 0.05) but not by LPS. The monoclonal antibody to TNF inhibited by 27% and 38% (p < 0.002) the PMNL accumulation in LPS and E. coli reactions respectively, but a combination of the mAb with IL-1RA was not more effective. Treatment of human umbilical vein endothelium with LPS for 3 h activated endothelium to induce PMNL transendothelial migration in vitro, which was not inhibited by IL-1RA, antibody to TNF-α, IL-1 or to IL-8. In conclusion, TNF and IL-1 may partially mediate acute PMNL infiltration in vivo to LPS and Gram negative bacteria, but there is a major IL-1/TNF independent mechanism, at least in dermal inflammation, which may be due to direct LPS activation of the microvasculature or perhaps the generation of cytokines other than IL-1 and TNF.
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Stashenko, P., R. Teles, and R. D'Souza. "Periapical Inflammatory Responses and Their Modulation." Critical Reviews in Oral Biology & Medicine 9, no. 4 (October 1998): 498–521. http://dx.doi.org/10.1177/10454411980090040701.
Full textAbstract:
Periapical inflammatory responses occur as a consequence of bacterial infection of the dental pulp, as a result of caries, trauma, or iatrogenic insult. Periapical inflammation stimulates the formation of granulomas and cysts, with the destruction of bone. These inflammatory responses are complex and consist of diverse elements. Immediate-type responses-including vasodilatation, increased vascular permeability, and leukocyte extravasation-are mediated by endogenous mediators, including prostanoids, kinins, and neuropeptides. Non-specific immune responses-including polymorphonuclear leukocyte and monocyte migration and activation, and cytokine production-are elicited in response to bacteria and their products. Interleukin-1 and prostaglandins in particular have been implicated as central mediators of periapical bone resorption. Chronic periapical inflammation further involves specific T- and B-cell-mediated anti-bacterial responses, and activates a network of regulatory cytokines which are produced by Th 1- and Th2-type T-lymphocytes. Various naturally occurring and genetically engineered models of immunodeficiency are beginning to help elucidate those components of the immune system which protect the pulpal/periapical complex. Both specific and non-specific responses interface with and are regulated by the neural system. The modulation of these responses by immune response modifiers, cytokine antagonists, and other novel therapeutic agents is discussed. As an experimental model, periapical inflammation has many advantages which permit it to be used in studies of microbial ecology and pathogenesis, host response, neuroimmunology, and bone resorption and regeneration.