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Journal articles on the topic 'Immunosuppressive cells'

Author: Grafiati
Published: 4 June 2021
Last updated: 1 February 2022

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1

Salminen, Antero. "Increased immunosuppression impairs tissue homeostasis with aging and age-related diseases." Journal of Molecular Medicine 99, no. 1 (October 6, 2020): 1–20. http://dx.doi.org/10.1007/s00109-020-01988-7.

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Abstract Chronic low-grade inflammation is a common hallmark of the aging process and many age-related diseases. There is substantial evidence that persistent inflammation is associated with a compensatory anti-inflammatory response which prevents excessive tissue damage. Interestingly, the inflammatory state encountered with aging, called inflammaging, is associated with the anti-inflammaging process. The age-related activation of immunosuppressive network includes an increase in the numbers of myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and macrophages (Mreg/M2c). Immunosuppressive cells secrete several anti-inflammatory cytokines, e.g., TGF-β and IL-10, as well as reactive oxygen and nitrogen species (ROS/RNS). Moreover, immunosuppressive cells suppress the function of effector immune cells by catabolizing l-arginine and tryptophan through the activation of arginase 1 (ARG1) and indoleamine 2,3-dioxygenase (IDO), respectively. Unfortunately, the immunosuppressive armament also induces harmful bystander effects in neighboring cells by impairing host tissue homeostasis. For instance, TGF-β signaling can trigger many age-related degenerative changes, e.g., cellular senescence, fibrosis, osteoporosis, muscle atrophy, and the degeneration of the extracellular matrix. In addition, changes in the levels of ROS, RNS, and the metabolites of the kynurenine pathway can impair tissue homeostasis. This review will examine in detail the harmful effects of the immunosuppressive cells on host tissues. It seems that this age-related immunosuppression prevents inflammatory damage but promotes the tissue degeneration associated with aging and age-related diseases. Key messages • Low-grade inflammation is associated with the aging process and age-related diseases. • Persistent inflammation activates compensatory immunosuppression with aging. • The numbers of immunosuppressive cells increase with aging and age-related diseases. • Immunosuppressive mechanisms evoke harmful bystander effects in host tissues. • Immunosuppression promotes tissue degeneration with aging and age-related diseases.
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2

Himes, Benjamin T., Timothy E. Peterson, Tristan de Mooij, Luz M. Cumba Garcia, Mi-Yeon Jung, Sarah Uhm, David Yan, et al. "The role of extracellular vesicles and PD-L1 in glioblastoma-mediated immunosuppressive monocyte induction." Neuro-Oncology 22, no. 7 (February 21, 2020): 967–78. http://dx.doi.org/10.1093/neuonc/noaa029.

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Abstract Background Immunosuppression in glioblastoma (GBM) is an obstacle to effective immunotherapy. GBM-derived immunosuppressive monocytes are central to this. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule, expressed by GBM cells and GBM extracellular vesicles (EVs). We sought to determine the role of EV-associated PD-L1 in the formation of immunosuppressive monocytes. Methods Monocytes collected from healthy donors were conditioned with GBM-derived EVs to induce the formation of immunosuppressive monocytes, which were quantified via flow cytometry. Donor-matched T cells were subsequently co-cultured with EV-conditioned monocytes in order to assess effects on T-cell proliferation. PD-L1 constitutive overexpression or short hairpin RNA–mediated knockdown was used to determined the role of altered PD-L1 expression. Results GBM EVs interact with both T cells and monocytes but do not directly inhibit T-cell activation. However, GBM EVs induce immunosuppressive monocytes, including myeloid-derived suppressor cells (MDSCs) and nonclassical monocytes (NCMs). MDSCs and NCMs inhibit T-cell proliferation in vitro and are found within GBM in situ. EV PD-L1 expression induces NCMs but not MDSCs, and does not affect EV-conditioned monocytes T-cell inhibition. Conclusion These findings indicate that GBM EV-mediated immunosuppression occurs through induction of immunosuppressive monocytes rather than direct T-cell inhibition and that, while PD-L1 expression is important for the induction of specific immunosuppressive monocyte populations, immunosuppressive signaling mechanisms through EVs are complex and not limited to PD-L1.
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3

Himes, Benjamin, Timothy Peterson, Jasmine Tyson, Helen Lee, Tristan deMooij, Luz Cumba-Garcia, Mi-Yeon Jung, et al. "IMMU-36. THE ROLE OF PD-L1 IN GLIOBLASTOMA-DERIVED EXTRACELLULAR VESICLES IN THE INDUCTION OF IMMUNOSUPPRESSIVE MONOCYTES." Neuro-Oncology 21, Supplement_6 (November 2019): vi126—vi127. http://dx.doi.org/10.1093/neuonc/noz175.528.

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Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor, and novel therapeutic strategies that make a substantial impact on outcomes are sorely needed. Immunotherapies have shown great promise in the treatment of a number of cancers in recent year, and a concerted effort is being made to apply these treatment paradigms to GBM. However, many GBM patients exhibit profound immunosuppression, likely limiting the efficacy of such approaches. The mechanisms of this immunosuppression are poorly understood, but tumor-derived extracellular vesicles (EVs), may play a role. We demonstrate that GBM-derived EVs induce the development of myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). We further demonstrate that these EV-induced monocytic cells are immunosuppressive, resulting in impaired T cell proliferation upon co-culture. We found that the immunosuppressive effects of tumor-derived EVs appear to be driven by the induction of these immunosuppressive monocytes, as EV treatment of T cells did not significantly impact T cell proliferation. Further, we sought to characterize the important of programmed death ligand 1 (PD-L1) in the induction of these immunosuppressive monocyte populations. We found PD-L1 to be expressed in the EVs from GBM cell lines, and that modulation in PD-L1 expression via either constitutive overexpression or shRNA-mediated knockdown resulted in concordant changes in expression in tumor-derived EVs. We demonstrate that PD-L1 is important for the induction of NCM but not for MDSCs. Taken together, these findings point to a significant role for tumor-derived EVs in the induction of immunosuppressive monocytes in GBM, and that these cells may be a driving force of systemic immunosuppression. PD-L1 is one factor expressed in EVs that has immunomodulatory properties, but additional EV cargo likely plays a major role in the induction of immunosuppressive cells.
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4

Díaz-Tejedor, Andrea, Mauro Lorenzo-Mohamed, Noemí Puig, Ramón García-Sanz, María-Victoria Mateos, Mercedes Garayoa, and Teresa Paíno. "Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression." Cancers 13, no. 6 (March 17, 2021): 1353. http://dx.doi.org/10.3390/cancers13061353.

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Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments.
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5

Miyazaki, Tsubasa, Eiichi Ishikawa, Narushi Sugii, and Masahide Matsuda. "Therapeutic Strategies for Overcoming Immunotherapy Resistance Mediated by Immunosuppressive Factors of the Glioblastoma Microenvironment." Cancers 12, no. 7 (July 19, 2020): 1960. http://dx.doi.org/10.3390/cancers12071960.

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Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells—including M2-type macrophages and myeloid-derived suppressor cells—that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment.
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6

Wang, Xiaojie, Daniel L. Metzger, Mark Meloche, Jianqiang Hao, Ziliang Ao, and Garth L. Warnock. "Generation of Transplantable Beta Cells for Patient-Specific Cell Therapy." International Journal of Endocrinology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/414812.

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Islet cell transplantation offers a potential cure for type 1 diabetes, but it is challenged by insufficient donor tissue and side effects of current immunosuppressive drugs. Therefore, alternative sources of insulin-producing cells and isletfriendly immunosuppression are required to increase the efficiency and safety of this procedure. Beta cells can be transdifferentiated from precursors or another heterologous (non-beta-cell) source. Recent advances in beta cell regeneration from somatic cells such as fibroblasts could circumvent the usage of immunosuppressive drugs. Therefore, generation of patient-specific beta cells provides the potential of an evolutionary treatment for patients with diabetes.
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7

Kleist, Christian, Flavius Sandra-Petrescu, Lucian Jiga, Laura Dittmar, Elisabeth Mohr, Johann Greil, Walter Mier, et al. "Generation of suppressive blood cells for control of allograft rejection." Clinical Science 128, no. 9 (February 11, 2015): 593–607. http://dx.doi.org/10.1042/cs20140258.

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Immunosuppressants, used to prevent organ rejection, cause serious side effects. We induced specific immunosuppression towards the foreign transplant by administration of mitomycin C (MMC)-treated blood cells (MICs) from the organ donor, thus circumventing additional immunosuppressive medication.
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8

Morimoto-Ito, Hiroe, Masako Mizuno-Kamiya, Naoki Umemura, Yoshinori Inagaki, Eiji Takayama, Harumi Kawaki, Yasunori Muramatsu, Shinichiro Sumitomo, and Nobuo Kondoh. "Immunosuppressive Effect of Mesenchymal Stromal Cells is Enhanced by IL-1α from Oral Squamous Cell Carcinoma Cells." Open Dentistry Journal 13, no. 1 (June 30, 2019): 221–27. http://dx.doi.org/10.2174/1874210601913010221.

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Background: We have already reported that mouse Oral Squamous Carcinoma Cells (OSCCs) Sq-1979 specifically enhance the immunosuppressive activity of mesenchymal 10T1/2 cells via the functional soluble factor (s). Objective: In this report, we attempted to identify soluble factor(s) mediating the immunosuppression of Sq-1979 cells. Methods: L5-11 cells are a variant established from the metastatic lymph nodes of Sq-1979-implanted mice. Unlike parental Sq-1979 cells, however, L5-11 cells lack promotion of immunosuppressive activity in 10T1/2 cells. In order to identify cytokine mRNAs specifically expressed in Sq-1979 cells but not in L5-11 cells, cDNA microarray was performed. Conditioned medium from Sq-1979 cells (CM) was absorbed by several different neutralizing antibodies (abs) against the corresponding cytokines. The absorbed CM was then co-cultured with 10T1/2 cells and anti-CD3 antibody-stimulated mouse spleen cells. The Interferon (IFN) -γ producing capability of the stimulated spleen cells was evaluated using Enzyme-Linked Immunosorbent Assay (ELISA). By using a specific cytokine product instead of CM in this co-culture system the source of the immunosuppressive effect was identified. Results: The expression of Ccl2, Ccl7, Il1-α, IL1f6 and Il6 mRNAs was specifically elevated in Sq-1979 cells compared to L5-11 cells. The suppression of the IFN-γ producing capability of stimulated spleen cells in the co-culture system was specifically alleviated by absorbing the CM with anti-IL-1α ab. We further demonstrated that the immunosuppressive effect of CM in the co-culture system could be completely substituted by IL-1α protein (50 pmol/ ml). Conclusion: The immunosuppressive function of 10T1/2 cells is specifically promoted by IL-1α, secreted by Sq-1979 cells.
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9

Voll, Reinhard E., Martin Herrmann, Edith A. Roth, Christian Stach, Joachim R. Kalden, and Irute Girkontaite. "Immunosuppressive effects of apoptotic cells." Nature 390, no. 6658 (November 1997): 350–51. http://dx.doi.org/10.1038/37022.

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10

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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11

Mickler, Thomas A., and David E. Longnecker. "The Immunosuppressive Aspects of Blood Transfusion." Journal of Intensive Care Medicine 7, no. 4 (July 1992): 176–88. http://dx.doi.org/10.1177/088506669200700405.

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Blood transfusion is associated with immunosuppression, although the exact etiology of the immunosuppressive effect is not fully understood. The clinical significance of the immunosuppressive effect of blood transfusion has been examined in three situations: (1) studies of renal allograft survival after renal transplantation, (2) outcome studies in patients who have had surgical resection of solid cancer tumors, and (3) studies of infection rates in postoperative patients. In each scenario, the data support the conclusion that transfusion is associated with immunosuppression as manifested by increased renal allograft survival, increased recurrence and mortality rates in patients with cancer, and increased infection rates in postoperative patients who are transfused. Not all studies demonstrate an immunosuppressive effect of transfusion. There are several possible explanations for these discrepancies. First, prognostic variables other than transfusion itself account for the outcome results in these retrospective studies. Second, the extent of immunosuppression may be influenced by the type of blood product transfused, the amount transfused, and the timing of the transfusion; these factors have not been considered in all studies. For example, whole blood has been implicated as having a greater immunosuppressive effect than packed red blood cells, and many studies have shown that more than three units of packed red blood cells are necessary to affect outcome. Controlled animal studies have tested the hypothesis that transfusions increase solid tumor growth or the risk for infection. These studies have yielded conflicting results. Nevertheless, evidence that blood transfusion influences clinical outcome mitigates that a decision to transfuse must consider both risks and benefits of a transfusion; the possible consequences of immunosuppression must be included among the risks. Use of autologous blood, erythropoietin, and, in the future, synthetic hemoglobin may lead to improved outcome in patients with certain disease processes.
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12

Benten, W. P. M., F. Wunderlich, R. Herrmann, and W. N. Kühn-Velten. "Testrosterone-induced compared with oestradiol-induced immunosuppression against Plasmodium chabaudi malaria." Journal of Endocrinology 139, no. 3 (December 1993): 487–94. http://dx.doi.org/10.1677/joe.0.1390487.

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ABSTRACT Testosterone suppresses immunity against malaria caused by Plasmodium chabaudi in B10 mice. Since this effect is probably not mediated through the classical androgen-receptor response, we investigated whether testosterone might act, after aromatization to oestradiol (OE2), through the oestrogen receptor (ER). Indeed, OE2 was found to act immunosuppressively when used at only about 1% of the immunosuppressive dose of testosterone. This becomes evident as an OE2-induced suppression of self-healing of P. chabaudi infections in female and castrated male B10 mice. The immunosuppressive OE2 effect is associated with a 16-fold increase in the circulating level of OE2 and can be prevented by ER blockers such as tamoxifen and clomifene. In contrast, the immunosuppressive effect of testosterone, which is not associated with any changes in the level of OE2, cannot be abolished by ER blockers or by aromatase inhibitors, such as atamestane and drofazar hydrochloride. Moreover, OE2 and testosterone act differently on spleen cells; OE2 induces a decrease in CD4+-T-cells, whereas testosterone causes an increase in CD8+-T-cells and a decrease in total nucleated spleen cells. The immunosuppressive effect of testosterone, but not that of OE2, can be adoptively transferred to syngeneic mice by nucleated spleen cells, predominantly T-cells. Our data show that the immunosuppressive activity of testosterone, in contrast to OE2, is not mediated through the ER. The immunosuppressive action of testosterone is therefore thought to be primarily mediated through a non-genomic mechanism. Journal of Endocrinology (1993) 139, 487–494
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13

Lecourt, Séverine, Yves Lepelletier, Valérie Vanneaux, Rafika Jarray, Thomas Domet, Françoise Raynaud, Réda Hadj-Slimane, et al. "Human Muscle Progenitor Cells Displayed Immunosuppressive Effect through Galectin-1 and Semaphorin-3A." Stem Cells International 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/412610.

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In human skeletal muscle, myoblasts represent the main population of myogenic progenitors. We previously showed that, beside their myogenic differentiation capacities, myoblasts also differentiate towards osteogenic and chondrogenic lineages, some properties generally considered being hallmarks of mesenchymal stem cells (MSCs). MSCs are also characterized by their immunosuppressive potential, through cell-cell contacts and soluble factors, including prostaglandin E-2 (PGE-2), transforming growth factor-β1 (TGF-β1), interleukine-10, or indoleamine 2,3-dioxygenase. We and others also reported that Galectin-1 (Gal-1) and Semaphorin-3A (Sema-3A) were involved in MSCs-mediated immunosuppression. Here, we show that human myoblasts induce a significant and dose-dependant proliferation inhibition, independently of PGE-2 and TGF-β1. Our experiments revealed that myoblasts, in culture orin situin human muscles, expressed and secreted Gal-1 and Sema-3A. Furthermore, myoblasts immunosuppressive functions were reverted by using blocking antibodies against Gal-1 or Sema-3A. Together, these results demonstrate an unsuspected immunosuppressive effect of myoblasts that may open new therapeutic perspectives.
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Djouad, Farida, Pascale Plence, Claire Bony, Philippe Tropel, Florence Apparailly, Jacques Sany, Danièle Noël, and Christian Jorgensen. "Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals." Blood 102, no. 10 (November 15, 2003): 3837–44. http://dx.doi.org/10.1182/blood-2003-04-1193.

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Abstract Mesenchymal stem cells (MSCs) are largely studied for their potential clinical use. Recently, they have gained further interest after demonstration of an immunosuppressive role. In this study, we investigated whether in vivo injection of MSCs could display side effects related to systemic immunosuppression favoring tumor growth. We first showed in vitro that the murine C3H10T1/2 (C3) MSC line and primary MSCs exhibit immunosuppressive properties in mixed lymphocyte reaction. We demonstrated that this effect is mediated by soluble factors, secreted only on “activation” of MSCs in the presence of splenocytes. Moreover, the immunosuppression is mediated by CD8+ regulatory cells responsible for the inhibition of allogeneic lymphocyte proliferation. We then demonstrated that the C3 MSCs expressing the human bone morphogenetic protein 2 (hBMP-2) differentiation factor were not rejected when implanted in various allogeneic immunocompetent mice and were still able to differentiate into bone. Importantly, using a murine melanoma tumor model, we showed that the subcutaneous injection of B16 melanoma cells led to tumor growth in allogeneic recipients only when MSCs were coinjected. Although the potential side effects of immunosuppression induced by MSCs have to be considered in further clinical studies, the usefulness of MSCs for various therapeutic applications still remains of great interest. (Blood. 2003;102:3837-3844)
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Chen, Qun, Jinquan Cai, Bo Han, and Xiangqi Meng. "IMMU-28. IMMUNOGENOMIC ANALYSIS REVEALS LGALS1 CONTRIBUTES TO THE IMMUNE HETEROGENEITY AND IMMUNOSUPPRESSION IN GLIOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii365. http://dx.doi.org/10.1093/neuonc/noaa222.382.

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Abstract Mutualistic and dynamic communication between tumour cells and the surrounding microenvironment accelerates the initiation, progression, chemoresistance and immune evasion of glioblastoma (GBM). However, the immunosuppressive mechanisms of GBM has not been thoroughly elucidated to date. We enrolled six microenvironmental signatures to identify glioma microenvironmental genes. The functional enrichment analysis such as ssGSEA, ESTIMATE algorithm, Gene Ontology, Pathway analysis is conducted to discover the potential function of microenvironmental genes. In vivo and in vitro experiments are used to verify the immunologic function of LGALS1 in GBM. We screen eight glioma microenvironmental genes from glioma databases, and discover a key immunosuppressive gene (LGALS1 encoding Galectin-1) exhibiting obviously prognostic significance among glioma microenvironmental genes. Gliomas with different LGALS1 expression have specific genomic variation spectrums. Immunosuppression is a predominate characteristic in GBMs with high expression of LGALS1. Knockdown of LGALS1 remodels the GBM immunosuppressive microenvironment by down regulating M2 macrophages and myeloid-derived suppressor cells (MDSCs), and inhibiting immunosuppressive cytokines. Our results thus implied an important role of microenvironmental regulation in glioma malignancy and provided evidences of LGALS1 contributing to immunosuppressive environment in glioma and that targeting LGALS1 could remodel immunosuppressive microenvironment of glioma.
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McClure, Clara, Laura Brudecki, Donald A. Ferguson, Zhi Q. Yao, Jonathan P. Moorman, Charles E. McCall, and Mohamed El Gazzar. "MicroRNA 21 (miR-21) and miR-181b Couple with NFI-A To Generate Myeloid-Derived Suppressor Cells and Promote Immunosuppression in Late Sepsis." Infection and Immunity 82, no. 9 (June 30, 2014): 3816–25. http://dx.doi.org/10.1128/iai.01495-14.

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ABSTRACTThe sepsis initial hyperinflammatory reaction, if not treated early, shifts to a protracted state of immunosuppression that alters both innate and adaptive immunity and is associated with elevated mortality. Myeloid-derived suppressor cells (MDSCs) are myeloid progenitors and precursors that fail to differentiate into mature innate-immunity cells and are known for their potent immunosuppressive activities. We previously reported that murine MDSCs expand dramatically in the bone marrow during late sepsis, induced by cecal ligation and puncture, and demonstrated that they contribute to late-sepsis immunosuppression. However, the molecular mechanism responsible for generating these immature Gr1+CD11b+myeloid cells during sepsis remains unknown. We show here that sepsis generates a microRNA (miRNA) signature that expands MDSCs. We found that miRNA 21 (miR-21) and miR-181b expression is upregulated in early sepsis and sustained in late sepsis. Importantly, we found that simultaneousin vivoblockade of both miRNAs via antagomiR (a chemically modified miRNA inhibitor) injection after sepsis initiation decreased the bone marrow Gr1+CD11b+myeloid progenitors, improved bacterial clearance, and reduced late-sepsis mortality by 74%. Gr1+CD11b+cells isolated from mice injected with antagomiRs were able to differentiateex vivointo macrophages and dendritic cells and produced smaller amounts of the immunosuppressive interleukin 10 (IL-10) and transforming growth factor β (TGF-β) after stimulation with bacterial lipopolysaccharide, suggesting that immature myeloid cells regained their maturation potential and have lost their immunosuppressive activity. In addition, we found that the protein level of transcription factor NFI-A, which plays a role in myeloid cell differentiation, was increased during sepsis and that antagomiR injection reduced its expression. Moreover, knockdown of NFI-A in the Gr1+CD11b+cells isolated from late-septic mice increased their maturation potential and reduced their production of the immunosuppressive mediators, similar to antagomiR injection. These data support the hypothesis that sepsis reprograms myeloid cells and thus alters the innate immunity cell repertoire to promote immunosuppression, and they demonstrate that this process can be reversed by targeting miR-21 and miR-181b to improve late-sepsis survival.
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Zavazava, Nicholas. "iPS Cell-Derived Immunosuppressive Myeloid Cells." Transplantation 99, no. 11 (November 2015): 2245–46. http://dx.doi.org/10.1097/tp.0000000000000876.

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Abumaree, Mohamed, Mohammed Al Jumah, Rishika A. Pace, and Bill Kalionis. "Immunosuppressive Properties of Mesenchymal Stem Cells." Stem Cell Reviews and Reports 8, no. 2 (September 3, 2011): 375–92. http://dx.doi.org/10.1007/s12015-011-9312-0.

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Brunel, Melanie, Florence Herr, and Antoine Durrbach. "Immunosuppressive Properties of Mesenchymal Stem Cells." Current Transplantation Reports 3, no. 4 (October 19, 2016): 348–57. http://dx.doi.org/10.1007/s40472-016-0120-y.

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Cai, Songjie, and Anil Chandraker. "Cell Therapy in Solid Organ Transplantation." Current Gene Therapy 19, no. 2 (August 20, 2019): 71–80. http://dx.doi.org/10.2174/1566523219666190603103840.

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Transplantation is the only cure for end-stage organ failure. Current immunosuppressive drugs have two major limitations: 1) non antigen specificity, which increases the risk of cancer and infection diseases, and 2) chronic toxicity. Cell therapy appears to be an innovative and promising strategy to minimize the use of immunosuppression in transplantation and to improve long-term graft survival. Preclinical studies have shown efficacy and safety of using various suppressor cells, such as regulatory T cells, regulatory B cells and tolerogenic dendritic cells. Recent clinical trials using cellbased therapies in solid organ transplantation also hold out the promise of improving efficacy. In this review, we will briefly go over the rejection process, current immunosuppressive drugs, and the potential therapeutic use of regulatory cells in transplantation.
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Himes, Benjamin, Cori Fain, Zachariah Tritz, Helen Li, Philipp Geiger, Timothy Peterson, and Ian Parney. "IMMU-15. HEPARIN INHIBITS THE EXTRACELLULAR VESICLE-MEDIATED INDUCTION OF IMMUNOSUPPRESSIVE MONOCYTES IN GLIOBLASTOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii107. http://dx.doi.org/10.1093/neuonc/noaa215.445.

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Abstract Glioblastoma (GBM) is the most common and fatal primary brain tumor in adults. The development of novel therapies is critical, as little has changed regarding the standard of care in nearly two decades. Immunotherapy holds much promise, as treatments including chimeric antigen receptor (CAR) T cells and immune checkpoint blockade inhibitors have transformed the treatment of a number of cancers in recent years. However, GBM patients exhibit profound immunosuppression, limiting the efficacy of these therapies. Understanding the mechanisms of GBM-mediated immunosuppression is critical to overcoming this barrier. GBM-derived extracellular vesicles (EVs) have been shown to mediate the induction of immunosuppressive monocytes, which may point to a mechanism of immunosuppression. EVs make initial contact with target cells through interactions between heparan sulfate proteoglycans, and soluble heparin has been shown to inhibit these interactions in some models. We demonstrate that soluble heparin inhibits the binding of GBM-derived EVs to monocytes in a dose-dependent manner, and that heparin treatment reduces the induction of immunosuppressive monocytes upon in vitro conditioning of monocytes with GBM-derived EVs (p< 0.01). Further, we demonstrate that heparin treated EV-conditioned monocytes are functionally less immunosuppressive than untreated EV-conditioned monocytes as measured by T cell proliferation in co-culture studies (p< 0.05). Taken together, these findings underscore the import of tumor-derived EVs in immunosuppression in GBM, and demonstrate the feasibility of targeting EV-monocyte interactions in treating GBM-mediated immunosuppression.
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Martin-Moreno, Paloma Leticia, Sudipta Tripathi, and Anil Chandraker. "Regulatory T Cells and Kidney Transplantation." Clinical Journal of the American Society of Nephrology 13, no. 11 (May 22, 2018): 1760–64. http://dx.doi.org/10.2215/cjn.01750218.

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The ability of the immune system to differentiate self from nonself is critical in determining the immune response to antigens expressed on transplanted tissue. Even with conventional immunosuppression, acceptance of the allograft is an active process often determined by the presence of regulatory T cells (Tregs). Tregs classically are CD4+ cells that constitutively express high levels of the IL-2 receptor α chain CD25, along with the transcription factor Foxp3. The use of Tregs in the field of solid organ transplantation is related specifically to the objective of achieving tolerance, with the goal of reducing or eliminating immunosuppressive drugs as well as maintaining tissue repair and managing acute rejection. A key issue in clinical use of Tregs is how to effectively expand the number of Tregs, either through increasing numbers of endogenous Tregs or by the direct infusion of exogenously expanded Tregs. In order to realize the benefits of Treg therapy in solid organ transplantation, a number of outstanding challenges need to be overcome, including assuring an effective expansion of Tregs, improving long-term Treg stability and reduction of risk-related to off-target, nonspecific, immunosuppressive effects related specially to cancer.
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Guo, Richard F., Frew H. Gebreab, Emily Hsiang-Ho Tang, Zhe Piao, Steve S. Lee, and Mario L. Perez. "Cutaneous Ulcer as Leading Symptom of Systemic Cytomegalovirus Infection." Case Reports in Infectious Diseases 2015 (2015): 1–4. http://dx.doi.org/10.1155/2015/723962.

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Cytomegalovirus (CMV) infection rarely manifests with skin ulcerations. We describe a case report of a 64-year-old woman with chronic immunosuppression for treatment of mixed connective tissue disease, presenting with new onset leg ulcerations after a recent change in immunosuppressive regimen. She subsequently developed fulminant hepatitis, encephalopathy, and pancytopenia and was found to have severe systemic CMV viremia. Skin ulcer biopsy was positive by immunohistochemical staining for CMV infected endothelial cells. Both systemic disease and skin ulcer rapidly improved after stopping immunosuppression and administering intravenous ganciclovir. New onset skin ulcers in an immunosuppressed individual, especially with recent changes in immunosuppressive regimen, should raise the suspicion of reactivation of CMV.
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Wang, Xiaojie, Jianqiang Hao, Gigi Leung, Trisia Breitkopf, Eddy Wang, Nicole Kwong, Noushin Akhoundsadegh, Garth L. Warnock, Jerry Shapiro, and Kevin J. McElwee. "Hair Follicle Dermal Sheath Derived Cells Improve Islet Allograft Survival without Systemic Immunosuppression." Journal of Immunology Research 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/607328.

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Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1) or fibroblasts (FB, group 2) under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days,P<0.001) without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation.
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Fillatreau, S. "SP0065 Immunosuppressive Activities of B Cells and Plasma Cells." Annals of the Rheumatic Diseases 75, Suppl 2 (June 2016): 17.2–17. http://dx.doi.org/10.1136/annrheumdis-2016-eular.6355.

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Kraut, E. H., J. C. Neff, B. A. Bouroncle, D. Gochnour, and M. R. Grever. "Immunosuppressive effects of pentostatin." Journal of Clinical Oncology 8, no. 5 (May 1990): 848–55. http://dx.doi.org/10.1200/jco.1990.8.5.848.

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The immune function of patients with hairy cell leukemia (HCL) and solid tumors was evaluated before and after treatment with the investigational drug 2'-deoxycoformycin (pentostatin; dCF). Thirteen HCL patients received doses of dCF of 2 to 4 mg/m2 intravenously at 2- to 6-week intervals for up to 15 courses. After completion of treatment, 12 of 13 patients had resolution of severe monocytopenia and five of nine had normal monocyte antibody dependent cellular cytotoxicity. There was statistically significant depression of total lymphocytes, T cells, and B cells. Evaluation of T subsets showed a decrease in CD4+ cells. Immunoglobulin G (IgG) in sera were decreased from baseline, while IgM and IgA were unaffected. There was no significant effect on skin-test reactivity or large granular lymphocyte numbers. Lymphoblastic transformation was variably affected. Natural-killer (NK) cell function was improved or unchanged after dCF treatment. Reevaluation of seven patients at 21 to 119 weeks after receiving dCF demonstrated that recovery to normal T- and B-cell numbers and subsets does occur. Five solid tumor patients were given dCF at 4 mg/m2 intravenously at 1- to 2-week intervals for up to five courses. There was significant reduction in T cells, B cells, CD4+, and CD8+ cells with no statistically significant effect on the other immune parameters. We conclude that low doses of dCF can cause persistent immunosuppression though recovery may occur after the drug is stopped. In patients followed after completion of dCF, there was no associated increase in second malignancies or unusual infections.
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Crane, M., L. M. Foulds, J. A. Muir, and M. P. Hedger. "136. SPECIFICITY STUDIES ON THE IMMUNOSUPPRESSIVE AND CYTOTOXIC ACTIVITIES OF LYSOPHOSPHATIDYLCHOLINES (LPCs) OF GONADAL ORIGIN." Reproduction, Fertility and Development 21, no. 9 (2009): 55. http://dx.doi.org/10.1071/srb09abs136.

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The immunosuppressive activity of ovarian follicular fluid and testicular interstitial fluid is due to the presence of several LPCs, but the specificity of this inhibition is a potential source of controversy, as these molecules also possess lytic activity. In the following study, we compared the immunosuppressive and cytotoxic activities of the two most abundant gonadal LPCs, 1-palmitoyl-sn-glycero-3-phosphocholine (16:0aLPC) and 1-oleoyl-sn-glycero-3-phosphocholine (18:1aLPC), together with a number of related lysophospholipids (LPs), using a T-cell activation inhibition assay and an ovarian granulosa cell viability assay. Both the immunosuppressive and cytotoxic activities of the LPCs were blocked by serum (>5%) and serum albumin (>5mg/ml) in vitro. In the absence of serum proteins, the most immunosuppressive LPCs were 16:0aLPC, 18:0aLPC, 18:1aLPC and platelet activating factor (PAF; 1-O-palmitoyl-2-O-acetyl-sn-glycero-3-phosphocholine) with IC50 values of 1.2-4.3 μM. Curiously, PAF was the LPC most cytotoxic to granulosa cells (IC50 10 μM). The other immunosuppressive LPCs exhibited cytotoxicity within the range of 40-50 μM, i.e. at doses 10–50-fold higher than their immunosuppressive concentrations. Comparison of LPs of different structures indicated that optimal immunosuppression is related to a phosphocholine, but not serine, ethanolamine or phosphate group, at sn-3, and an ester- or ether-linked fatty acid of chain length C16-C18 at sn-1. Acetylation of sn-2, as in PAF, had only minor effects on immunosuppressive activity, but greatly increased cytotoxicity. These data establish that inhibition of activated T-cells is not a direct consequence of the cytotoxicity of these molecules, although some structural features that contribute to lytic activity, such as fatty acid chain length, overlap with the ability to confer immunosuppression. On the basis of these data, we propose that the effects of LPCs on T-cell proliferation may not be mediated by a specific lock-and-key receptor, but rather by a direct interaction with the cell membrane at concentrations significantly below their lytic concentrations.
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Terme, Magali, Orianne Colussi, Elie Marcheteau, Corinne Tanchot, Eric Tartour, and Julien Taieb. "Modulation of Immunity by Antiangiogenic Molecules in Cancer." Clinical and Developmental Immunology 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/492920.

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In the last decades a new class of therapeutic drugs have been developed that block tumor angiogenesis. These antiangiogenic molecules, which target VEGF or VEGFR, PDGFR, and c-kit, can act not only on endothelial cells but also on immune cells. Some antiangiogenic molecules inhibit the development of immunosuppressive mechanisms developed by the tumors to escape the immune system (such as regulatory T cells, myeloid-derived suppressor cells, and immunosuppressive cytokines). These immunomodulatory effects must be characterized in detail to enable a better prescription of these treatments. In this paper we will focus on the impact of anti-angiogenic drugs on immunosuppression and their potential combination with immunotherapeutic strategies. Interestingly, immune parameters or their modulation during treatment could serve as potential biomarkers of response or resistance to anti-angiogenic therapies.
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Gerasimova, O. A., V. V. Borovik, N. V. Marchenko, and I. I. Tileubergenov. "Tolerance and minimization of immunosuppressive therapy after liver transplantation." Russian Journal of Transplantology and Artificial Organs 23, no. 3 (September 16, 2021): 162–70. http://dx.doi.org/10.15825/1995-1191-2021-3-162-170.

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In this review of current publications, we look at the molecular mechanisms of tolerance of the liver and its allografts in terms of minimization and possibilities of withdrawing immunosuppressive therapy, mainly in the long-term period after liver transplantation. Information about clinical trials with regulatory T cells (Tregs) for the purpose of tolerance induction is presented. Data from a new consensus study on individualization of immunosuppressive therapy regimens are presented. Options for possible withdrawal of immunosuppression both in the early and in the long term after liver transplantation (LT) are considered. We suggest a way to study the lymphoproliferative potential of a liver transplant recipient to be investigated, since not only rejection determines life expectancy, but also the degree of immunosuppression effect on bone marrow depending on patient age.
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Abe, Masanori, and Angus W. Thomson. "Influence of immunosuppressive drugs on dendritic cells." Transplant Immunology 11, no. 3-4 (July 2003): 357–65. http://dx.doi.org/10.1016/s0966-3274(03)00050-9.

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Kermarrec, Laetitia, Tony Durand, Michel Neunlist, Philippe Naveilhan, and Isabelle Neveu. "Enteric glial cells have specific immunosuppressive properties." Journal of Neuroimmunology 295-296 (June 2016): 79–83. http://dx.doi.org/10.1016/j.jneuroim.2016.04.011.

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32

Torres Andón, Fernando, and María José Alonso. "Nanomedicine and cancer immunotherapy – targeting immunosuppressive cells." Journal of Drug Targeting 23, no. 7-8 (September 14, 2015): 656–71. http://dx.doi.org/10.3109/1061186x.2015.1073295.

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Alizadeh, Darya, and Nicolas Larmonier. "Chemotherapeutic Targeting of Cancer-Induced Immunosuppressive Cells." Cancer Research 74, no. 10 (April 28, 2014): 2663–68. http://dx.doi.org/10.1158/0008-5472.can-14-0301.

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34

Mondragón, Laura, Guido Kroemer, and Lorenzo Galluzzi. "Immunosuppressive γδ T cells foster pancreatic carcinogenesis." OncoImmunology 5, no. 11 (September 27, 2016): e1237328. http://dx.doi.org/10.1080/2162402x.2016.1237328.

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35

Siegel, Georg, Richard Schäfer, and Francesco Dazzi. "The Immunosuppressive Properties of Mesenchymal Stem Cells." Transplantation 87, Supplement (May 2009): S45—S49. http://dx.doi.org/10.1097/tp.0b013e3181a285b0.

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36

Muraki, Junro, Joel Fischer, Joseph C. Addonizio, George R. Nagamatsu, and J. W. Chiao. "Immunosuppressive factor derived from renal cancer cells." Urology 34, no. 4 (October 1989): 205–9. http://dx.doi.org/10.1016/0090-4295(89)90373-7.

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37

Ahlenstiel-Grunow, Thurid, Xiaofei Liu, Raphael Schild, Jun Oh, Christina Taylan, Lutz T. Weber, Hagen Staude, et al. "Steering Transplant Immunosuppression by Measuring Virus-Specific T Cell Levels: The Randomized, Controlled IVIST Trial." Journal of the American Society of Nephrology 32, no. 2 (December 15, 2020): 502–16. http://dx.doi.org/10.1681/asn.2020050645.

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BackgroundPharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants.MethodsIn a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation.ResultsIn the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events.ConclusionsSteering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs.Clinical Trial registry name and registration number:IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912
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Zhang, Chao, Shuo Wang, Cheng Yang, and Ruiming Rong. "The Crosstalk between Myeloid Derived Suppressor Cells and Immune Cells: To Establish Immune Tolerance in Transplantation." Journal of Immunology Research 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/4986797.

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Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of myeloid precursor and progenitor cells and endowed with a robust immunosuppressive activity in multiple pathophysiological conditions. Recent studies have uncovered the crosstalk between MDSCs and immune cells (i.e., natural killer cells, dendritic cells, macrophages, natural killer T cells, and regulatory T cells) and its role in the establishment and maintenance of immune tolerant microenvironment in transplantation. Considering their strong immunosuppressive capability, MDSCs could become a prospective clinical regimen during transplantation tolerance induction, resulting in long-term graft survival with decreased or without immunosuppressive drugs. The review summarized recent research advances in this field and looked ahead at the research directions in the future.
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Bodeau, Sandra, Chloé Sauzay, Olivier Pluquet, Gabriel Choukroun, and Antoine Galmiche. "A potential role of the unfolded protein response in post-transplant cancer." Clinical Science 131, no. 13 (June 23, 2017): 1429–36. http://dx.doi.org/10.1042/cs20170152.

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Cancer is one of the major causes of mortality in organ transplant patients receiving immunosuppressive regimen based on Cyclosporin A (CsA). Organ transplantation and chronic immunosuppression are typically associated with skin cancers (both squamous cell carcinoma and melanoma) and renal cell carcinoma (RCC). Recent studies have shown that in addition to its immunosuppressive effects, accounted for by the inhibition of calcineurin and the modulation of the transcriptional programme of lymphocytes, CsA also directly stimulates the growth and aggressive behaviour of various cancer cells. Using renal carcinogenesis as an example, we discuss the current evidence for a role of cellular proteostasis, i.e. the regulation of the production, maturation and turnover of proteins in eukaryotic cells, in tumorigenesis arising under conditions of chronic immunosuppression. We present the recent studies showing that CsA induces the unfolded protein response (UPR) in normal and transformed kidney cells. We examine how the UPR might be important, considering in particular the genomic analyses showing the existence of a correlation between the levels of expression of the actors of the UPR, the chaperones of the endoplasmic reticulum (ER) and the aggressiveness of renal carcinoma. The UPR may offer a possible explanation for how immunosuppressive regimens based on CsA promote renal carcinogenesis. We discuss the opportunities offered by this biological knowledge in terms of screening, diagnosis and treatment of post-transplant cancers, and propose possible future translational studies examining the role of tumour proteostasis and the UPR in this context.
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Scholl, Juliete Nathali, Camila Kehl Dias, Laurent Muller, Ana Maria Oliveira Battastini, and Fabrício Figueiró. "Extracellular vesicles in cancer progression: are they part of the problem or part of the solution?" Nanomedicine 15, no. 26 (November 2020): 2625–41. http://dx.doi.org/10.2217/nnm-2020-0256.

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Extracellular vesicles (EVs) are released especially by cancer cells. They modulate the tumor microenvironment by interacting with immune cells while carrying immunosuppressive or immunostimulatory molecules. In this review, we will explore some conflicting reports regarding the immunological outcomes of EVs in cancer progression, in which they might initiate an antitumor immune response or an immunosuppressive response. Concerning immunosuppression, the role of tumor-derived EVs’ in the adenosinergic system is underexplored. The enhancement of adenosine (ADO) levels in the tumor microenvironment impairs T-cell function and cytokine release. However, some tumor-derived EVs may deliver immunostimulatory factors, promoting immunogenic activity, even with ADO production. The modulatory role of ADO over the tumor progression represents a piece in an intricate microenvironment with anti and pro tumoral seesaw-like mechanisms.
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Klinker, Matthew W., Ross A. Marklein, Jessica L. Lo Surdo, Cheng-Hong Wei, and Steven R. Bauer. "Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity." Proceedings of the National Academy of Sciences 114, no. 13 (March 10, 2017): E2598—E2607. http://dx.doi.org/10.1073/pnas.1617933114.

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Human mesenchymal stromal cell (MSC) lines can vary significantly in their functional characteristics, and the effectiveness of MSC-based therapeutics may be realized by finding predictive features associated with MSC function. To identify features associated with immunosuppressive capacity in MSCs, we developed a robust in vitro assay that uses principal-component analysis to integrate multidimensional flow cytometry data into a single measurement of MSC-mediated inhibition of T-cell activation. We used this assay to correlate single-cell morphological data with overall immunosuppressive capacity in a cohort of MSC lines derived from different donors and manufacturing conditions. MSC morphology after IFN-γ stimulation significantly correlated with immunosuppressive capacity and accurately predicted the immunosuppressive capacity of MSC lines in a validation cohort. IFN-γ enhanced the immunosuppressive capacity of all MSC lines, and morphology predicted the magnitude of IFN-γ–enhanced immunosuppressive activity. Together, these data identify MSC morphology as a predictive feature of MSC immunosuppressive function.
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Ruers, T. J., W. A. Buurman, C. J. van Boxtel, C. J. van der Linden, and G. Kootstra. "Immunohistological observations in rat kidney allografts after local steroid administration." Journal of Experimental Medicine 166, no. 5 (November 1, 1987): 1205–20. http://dx.doi.org/10.1084/jem.166.5.1205.

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In this report we investigated local regulatory mechanisms in graft rejection and their response to local immunosuppressive therapy. For this purpose local immunosuppression was induced in rat kidney allografts by intrarenal infusion of prednisolone. Intrarenal drug delivery resulted in high drug levels within the graft and low systemic drug levels. Systemic drug levels were by themselves not sufficiently immunosuppressive to induce graft survival, and local prednisolone levels within the graft proved to be responsible for prolongation of graft survival. During intrarenal drug delivery, systemic responsiveness to the renal allograft proved normal, since intrarenally treated grafts were infiltrated by MHC class II-positive host cells and, except for a somewhat lower percentage of macrophages, cellular infiltration in intrarenal treated grafts was comparable to untreated grafts. However, T cells and macrophages present in intrarenally treated grafts were not able to destroy the grafted tissue. Local immunosuppressive therapy resulted in inhibition of IL-2-R expression, absence of IFN-gamma, and prevention of MHC class II induction on grafted tissue. These observations strongly indicate the presence of local regulatory mechanisms in graft rejection. The experimental model described can be used for further analysis of these intragraft events. Moreover, the results demonstrate that local immunosuppressive therapy can contribute to effective inhibition of cellular immune response in graft rejection.
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Li, Zhaoting, Lianghan Zhu, Honghao Sun, Yuexin Shen, Dandan Hu, Wenhao Wu, Yixin Wang, Chenggen Qian, and Minjie Sun. "Fluorine assembly nanocluster breaks the shackles of immunosuppression to turn the cold tumor hot." Proceedings of the National Academy of Sciences 117, no. 52 (December 14, 2020): 32962–69. http://dx.doi.org/10.1073/pnas.2011297117.

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Clinical investigations have shown that a nonimmunogenic “cold” tumor is usually accompanied by few immunopositive cells and more immunosuppressive cells in the tumor microenvironment (TME), which is still the bottleneck of immune activation. Here, a fluorine assembly nanocluster was explored to break the shackles of immunosuppression, reawaken the immune system, and turn the cold tumor “hot.” Once under laser irradiation, FS@PMPt produces sufficient reactive oxygen species (ROS) to fracture the ROS-sensitive linker, thus releasing the cisplatin conjugated PMPt to penetrate into the tumors and kill the regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Meanwhile, ROS will induce potent immunogenic cell death (ICD) and further promote the accumulation of dendritic cells (DCs) and T cells, therefore not only increasing the infiltration of immunopositive cells from the outside but also reducing the immunosuppressive cells from the inside to break through the bottleneck of immune activation. The FS@PMPt nanocluster regulates the immune process in TME from negative to positive, from shallow to deep, to turn the cold tumor into a hot tumor and provoke a robust antitumor immune response.
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Molina, Maria L., David García-Bernal, Salvador Martinez, and Rut Valdor. "Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma." Cancers 12, no. 1 (December 31, 2019): 102. http://dx.doi.org/10.3390/cancers12010102.

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Glioblastoma (GB) has been shown to up-regulate autophagy with anti- or pro-oncogenic effects. Recently, our group has shown how GB cells aberrantly up-regulate chaperone-mediated autophagy (CMA) in pericytes of peritumoral areas to modulate their immune function through cell-cell interaction and in the tumor’s own benefit. Thus, to understand GB progression, the effect that GB cells could have on autophagy of immune cells that surround the tumor needs to be deeply explored. In this review, we summarize all the latest evidence of several molecular and cellular immunosuppressive mechanisms in the perivascular tumor microenvironment. This immunosuppression has been reported to facilitate GB progression and may be differently modulated by several types of autophagy as a critical point to be considered for therapeutic interventions.
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Egan, Hannah, Oliver Treacy, Kevin Lynch, Niamh Leonard, Amir Nader, Margaret Sheehan, Sean Hynes, et al. "865 Sugar high: Does the sialic acid profile of cancer-associated fibroblasts induce a more tumour-permissive microenvironment?" Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A918. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0865.

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BackgroundImmunosuppressive tumour microenvironments (TME) inhibit the effectiveness of cancer immunotherapies. Sialic acids, which exist as terminal sugars of glyco-conjugates, are highly expressed on cancer cells and are involved in various pathological processes including increased immune evasion, tumour invasiveness and tumour cell metastasis.1 Siglecs (Sialic acid-binding immunoglobulin-type lectins) are expressed on immune cell surfaces and bind sialic acid. Siglec binding to hypersialylated tumour glycans blocks immune cell activation to promote immunosuppression.1 2Intestinal stromal cells (iSCs), precursors to cancer-associated fibroblasts (CAFs), are a key component of the TME and play a vital role in tumour progression by enhancing a tumour-promoting microenvironment. The aim of this study was therefore to investigate if iSC/CAF sialylation contributes to enhanced immunosuppression in the TME.Methods iSCs were isolated from colorectal cancer patient biopsies and cultured ex vivo. Informed consent was obtained from all patients prior to sampling. Tumour-derived iSCs were termed CAFs while control iSCs, isolated from tumour-adjacent non-cancerous tissue, were termed normal-associated fibroblasts (NAFs). NAFs/CAFs were then co-cultured with healthy allogeneic PBMCs and their immunosuppressive properties were assessed by flow cytometry.ResultsCAFs significantly supressed the proliferation of CD8+ and CD4+ T-cells and induced a more exhausted T-cell phenotype as evidenced by increased expression of the exhaustion markers TIM-3, LAG-3 and PD-1 when compared to co-culture with control NAFs, thereby demonstrating their potent immunosuppressive properties. Strikingly, CAFs also induced significantly higher expression of both Siglec-7 and Siglec-9 receptors on CD8+ T-cells specifically.To elucidate the role of sialylation on CAF-mediated immunosuppression, NAFs/CAFs were treated with the sialyltransferase inhibitor (SI) P-3FAX-Neu5Ac prior to co-culture. Reduction of sialic acid expression on NAFs/CAFs was confirmed by flow cytometry and the SI-treated NAFs/CAFs were then co-cultured with allogeneic T-cells to assess the functional consequences of reduced NAF/CAF sialylation. SI-treated CAFs induced significantly less CD4+TIM-3+ and both CD4+LAG-3+ and CD8+LAG-3+ T-cells compared to their untreated counterparts. Interestingly, SI-treated CAFs also induced significantly less Siglec-7 and -9 receptor-expressing CD8+ T-cells.ConclusionsThese results demonstrate that non-haematopoietic stromal cells in the tumour-microenvironment can suppress activated T-cells and that this immunosuppressive effect can be significantly reversed through the modulation of sialylation on the stromal cell surface. These results support the hypothesis that stromal cell sialylation plays a role in their immunosuppressive properties. Understanding how sialylation of stromal cells is regulated and functions to enhance immunosuppression in the TME could uncover novel immune checkpoints to reactivate anti-tumour immunity, allowing for tumour cell clearance.Ethics ApprovalThis study was approved by Galway University Hospitals’ Clinical Research Ethics Committee, approval number C.A 2074.ConsentN/AReferencesWang L, Liu Y, Wu L, Sun XL. Sialyltransferase inhibition and recent advances. Biochim Biophys Acta 2016 Jan; 1864(1):143-53.Munkley J, Scott E. Targeting aberrant sialylation to treat cancer. Medicines (Basel) 2019 Oct 13;6(4):102.
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Harrell, Carl R., Marina Gazdic, Crissy Fellabaum, Nemanja Jovicic, Valentin Djonov, Nebojsa Arsenijevic, and Vladislav Volarevic. "Therapeutic Potential of Amniotic Fluid Derived Mesenchymal Stem Cells Based on their Differentiation Capacity and Immunomodulatory Properties." Current Stem Cell Research & Therapy 14, no. 4 (May 23, 2019): 327–36. http://dx.doi.org/10.2174/1574888x14666190222201749.

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Background: Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. Objective: In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. Methods: An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: “amniotic fluid derived mesenchymal stem cells”, “cell-therapy”, “degenerative diseases”, “inflammatory diseases”, “regeneration”, “immunosuppression”. Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. Results: AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. Conclusion: Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.
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Dharma, Sanam, Sheila Figel, Tara Barone, Michael Ciesielski, and Robert Fenstermaker. "TAMI-63. GLIOBLASTOMA ASSOCIATED MESENCHYMAL STEM LIKE CELLS (G-MSC) WHICH INFILTRATE TUMORS IN HUMAN AND MOUSE ARE STRONGLY ASSOCIATED WITH IMMUNOSUPPRESSION." Neuro-Oncology 22, Supplement_2 (November 2020): ii227. http://dx.doi.org/10.1093/neuonc/noaa215.950.

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Abstract Glioblastoma (GBM) is the most aggressive form of brain cancer with an overall survival (OS) less than 16 months. Glioblastoma associated mesenchymal stem like cells (G-MSC) were identified in human patient samples, and higher presence of these cells in patient samples co-relates with lower overall survival. Our lab and others have also identified these cells in orthotopic GL261 glioblastoma murine models. We hypothesize that infiltration of G-MSC plays a key role in creating the highly immunosuppressive environment seen in GBMs. In order to investigate this, we utilized data from the TCGA database to stratify patients into two groups, showing higher or lower expression of the G-MSC markers (CD73, CD90, CD105). Patients expressing higher levels of G-MSC markers showed higher expression of CD4+ cells, as compared to patients with lower G-MSC marker expression. Further, patients with higher G-MSC markers showed high levels of PTGS2, the gene encoding cyclooxygenase 2 (COX2), a known tumor growth promoting and immunosuppressive molecule. We further investigated CD4+ T cell infiltration using GL261 orthotopic implants and observed that CD4+ T cells positively corelated with levels of G-MSC in these tumors. Our studies indicate that levels of G-MSC co-relate with immune cell infiltration and the expression of immunosuppressive factors such as COX2, underlining the importance of these cells in immunosuppression-driven resistance to therapy. These studies will be later utilized to develop rationale combination therapies to improve the overall survival in GBM.
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Lee, Kyo Won. "Mechanisms and clinical applications of immunosuppressive medications." Journal of the Korean Medical Association 63, no. 5 (May 10, 2020): 251–58. http://dx.doi.org/10.5124/jkma.2020.63.5.251.

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Immunosuppressive medications and regimens have evolved with significant advancements in the understanding of the immunologic process after solid organ transplantation. Medications can block the communication between antigen-presenting cells and T-cells, the activation and proliferation of T-cells, antibody production by plasma cells, and the activation of the complement system by antibodies. T-cell depleting antibodies and interleukin-2 receptor blockers are commonly used during induction therapy. Calcineurin inhibitors, antimetabolites, antiproliferative agents, and corticosteroids are commonly used in maintenance therapy regimens. These medications decrease the rates of rejection episodes and markedly increase the survival rates of short-term grafts. However, in terms of the survival rate of long-term grafts, there is still room for improvement. Opportunistic infections, development of cancer, metabolic diseases, and calcineurin inhibitor toxicity are hurdles in the improvement in survival rates of long-term grafts. Therefore, many efforts are being taken to overcome these hurdles, such as the development of new drugs, individualization of immunosuppression, and induction of immune tolerance.
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49

Moyano, Jairo, and Luisa Aguirre. "Opioids in the immune system: from experimental studies to clinical practice." Revista da Associação Médica Brasileira 65, no. 2 (February 2019): 262–69. http://dx.doi.org/10.1590/1806-9282.65.2.262.

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SUMMARY INTRODUCTION: Opioids interact with both innate and adaptive immune systems and have direct effects on opioid receptors located on immune cells. Research on this topic has provided evidence of the opioid influence on the immune response associated with surgical stress. The immunological effects of opioids are currently being investigated, particularly whether they influence the outcome of surgery or the underlying disease regarding important aspects like infection or cancer progression. This review addresses background research related to the influence of the opioid receptor on the immune system, the immunosuppressive effect associated with major opioids during the perioperative period, and their clinical relevance. The objective of the study was to review the effects of opioids on the immune system. Methods: A search strategy was conducted in PubMed, Embase, and the Cochrane databases using the terms “immunosuppression,” “immune system,” “surgical procedures,” “analgesics,” “opioids” and “perioperative care.” Results: The immunosuppressive effect of opioids was identified over 30 years ago. They include signaling and acting directly through immune cells, including B and T lymphocytes, NK cells, monocytes, and macrophages, as well as activating the downstream pathways of the hypothalamic-pituitary-adrenal (HPA) axis leading to the production of immunosuppressive glucocorticoids in the peripheral and sympathetic nervous system.
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50

Jensen, Kent P., David A. Hongo, XuHuai Ji, PingPing Zheng, Rahul D. Pawar, Thomas Hsin-Hsu Wu, Stephan Busque, et al. "Development of immunosuppressive myeloid cells to induce tolerance in solid organ and hematopoietic cell transplant recipients." Blood Advances 5, no. 17 (August 25, 2021): 3290–302. http://dx.doi.org/10.1182/bloodadvances.2020003669.

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Abstract Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs has long been the goal of organ transplantation. We studied changes in the balance of T cells and myeloid cells in the blood of HLA-matched and -mismatched patients given living donor kidney transplants followed by total lymphoid irradiation, anti-thymocyte globulin conditioning, and donor hematopoietic cell transplant to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In preclinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive polymorphonuclear (pmn) myeloid-derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of pmn MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes, including profound depletion of T cells and a marked increase in MDSCs in blood posttransplant. Posttransplant pmn MDSCs transiently increased expression of lectin-type oxidized LDL receptor-1, a marker of immunosuppression, and production of the T-cell inhibitor arginase-1. These posttransplant pmn MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous T-cell receptor microbead-stimulated pretransplant T cells when cocultured in vitro. In conclusion, we elucidated changes in receptors and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to those of MDSCs required for tolerance in mice. These trials were registered at www.clinicaltrials.gov as #NCT00319657 and #NCT01165762.
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