Journal articles: 'Antigen tolerance'

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Oehen, S., L. Feng, Y. Xia, C. D. Surh, and S. M. Hedrick. "Antigen compartmentation and T helper cell tolerance induction." Journal of Experimental Medicine 183, no. 6 (June 1, 1996): 2617–26. http://dx.doi.org/10.1084/jem.183.6.2617.

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The process of antigen recognition depends in part on the amount of peptide antigen available and the affinity of the T cell receptor for a particular peptide-major histocompatibility complex (MHC) molecule complex. The availability of self antigen is limited by antigen processing, which is compartmentalized such that peptide antigens presented by MHC class I molecules originate in the cytoplasm, whereas peptide antigens presented by MHC class II molecules are acquired from the endocytic pathway. This segregation of the antigen-processing pathways may limit the diversity of antigens that influence the development and selection of, e.g., CD4-positive, MHC class II-specific T cells. Selection in this case might involve only a subset of self-encoded proteins, specifically those that are plasma membrane bound or secreted. To study these aspects of immune development, we engineered pigeon cytochrome for expression in transgenic mice in two forms: one in which it was expressed as a type II plasma membrane protein, and a second in which it was targeted to the mitochondria after cytoplasmic synthesis. Experiments with these mice clearly show that tolerance is induced in the thymus, irrespective of antigen compartmentation. Using radiation bone marrow chimeras, we further show that cytoplasmic/mitochondrial antigen gains access to the MHC class II pathway by direct presentation. As a result of studying the anatomy of the thymus, we show that the amount of antigen and the affinity of the TCR affect the location and time point of thymocytes under-going apoptosis.

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Carmona, Priscila, Yordanka Medina-Armenteros, Amanda Cabral, Sandra Maria Monteiro, Simone Gonçalves Fonseca, Ana Caetano Faria, Francine Lemos, et al. "Regulatory/inflammatory cellular response discrimination in operational tolerance." Nephrology Dialysis Transplantation 34, no. 12 (July 5, 2019): 2143–54. http://dx.doi.org/10.1093/ndt/gfz114.

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Abstract Background Antigen-specific cellular response is essential in immune tolerance. We tested whether antigen-specific cellular response is differentially modulated in operational tolerance (OT) in renal transplantation with respect to critical antigenic challenges in allotransplantation—donor antigens, pathogenic antigens and self-antigens. Methods We analysed the profile of immunoregulatory (REG) and pro-inflammatory (INFLAMMA) cytokines for the antigen-specific response directed to these three antigen groups, by Luminex. Results We showed that, in contrast to chronic rejection and healthy individuals, OT gives rise to an immunoregulatory deviation in the cellular response to donor human leucocyte antigen DR isotype peptides, while preserving the pro-inflammatory response to pathogenic peptides. Cellular autoreactivity to the N6 heat shock protein 60 (Hsp60) peptide also showed a REG profile in OT, increasing IL4, IL-5, IL-10 and IL-13. Conclusions The REG shift of donor indirect alloreactivity in OT, with inhibition of interleukin (IL)-1B, IL-8, IL-12, IL-17, granulocyte colony-stimulating factor, Interferon-γ and monocyte chemoattractant protein-1, indicates that this may be an important mechanism in OT. In addition, the differential REG profile of cellular response to the Hsp60 peptide in OT suggests that REG autoimmunity may also play a role in human transplantation tolerance. Despite cross-reactivity of antigen-specific T cell responses, a systemic functional antigen-specific discrimination takes place in OT.

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Taylor, Justin J., Ryan J. Martinez, Philip J. Titcombe, Laura O. Barsness, Stephanie R. Thomas, Na Zhang, Shoshana D. Katzman, Marc K. Jenkins, and Daniel L. Mueller. "Deletion and anergy of polyclonal B cells specific for ubiquitous membrane-bound self-antigen." Journal of Experimental Medicine 209, no. 11 (October 15, 2012): 2065–77. http://dx.doi.org/10.1084/jem.20112272.

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B cell tolerance to self-antigen is critical to preventing antibody-mediated autoimmunity. Previous work using B cell antigen receptor transgenic animals suggested that self-antigen–specific B cells are either deleted from the repertoire, enter a state of diminished function termed anergy, or are ignorant to the presence of self-antigen. These mechanisms have not been assessed in a normal polyclonal repertoire because of an inability to detect rare antigen-specific B cells. Using a novel detection and enrichment strategy to assess polyclonal self-antigen–specific B cells, we find no evidence of deletion or anergy of cells specific for antigen not bound to membrane, and tolerance to these types of antigens appears to be largely maintained by the absence of T cell help. In contrast, a combination of deleting cells expressing receptors with high affinity for antigen with anergy of the undeleted lower affinity cells maintains tolerance to ubiquitous membrane-bound self-antigens.

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Chung, Yeonseok, Jae-Hoon Chang, Mi-Na Kweon, Paul D. Rennert, and Chang-Yuil Kang. "CD8α–11b+ dendritic cells but not CD8α+ dendritic cells mediate cross-tolerance toward intestinal antigens." Blood 106, no. 1 (July 1, 2005): 201–6. http://dx.doi.org/10.1182/blood-2004-11-4240.

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Cross-presentation is a critical process by which antigen is displayed to CD8 T cells to induce tolerance. It is believed that CD8α+ dendritic cells (DCs) are responsible for cross-presentation, suggesting that the CD8α+ DC population is capable of inducing both cross-priming and cross-tolerance to antigen. We found that cross-tolerance against intestinal soluble antigen was abrogated in C57BL/6 mice lacking mesenteric lymph nodes (MLNs) and Peyer patches (PPs), whereas mice lacking PPs alone were capable of developing CD8 T-cell tolerance. CD8α–CD11b+ DCs but not CD8α+ DCs in the MLNs present intestinal antigens to relevant CD8 T cells, while CD8α+ DCs but not CD8α–CD11b+ DCs in the spleen exclusively cross-present intravenous soluble antigen. Thus, CD8α–CD11b+ DCs in the MLNs play a critical role for induction of cross-tolerance to dietary proteins.

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Duong, Bao Hoa, Hua Tian, Takayuki Ota, Gladys Completo, Shoufa Han, José Luis Vela, Miyo Ota, et al. "Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo." Journal of Experimental Medicine 207, no. 1 (December 28, 2009): 173–87. http://dx.doi.org/10.1084/jem.20091873.

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Autoreactive B lymphocytes first encountering self-antigens in peripheral tissues are normally regulated by induction of anergy or apoptosis. According to the “two-signal” model, antigen recognition alone should render B cells tolerant unless T cell help or inflammatory signals such as lipopolysaccharide are provided. However, no such signals seem necessary for responses to T-independent type 2 (TI-2) antigens, which are multimeric antigens lacking T cell epitopes and Toll-like receptor ligands. How then do mature B cells avoid making a TI-2–like response to multimeric self-antigens? We present evidence that TI-2 antigens decorated with ligands of inhibitory sialic acid–binding Ig-like lectins (siglecs) are poorly immunogenic and can induce tolerance to subsequent challenge with immunogenic antigen. Two siglecs, CD22 and Siglec-G, contributed to tolerance induction, preventing plasma cell differentiation or survival. Although mutations in CD22 and its signaling machinery have been associated with dysregulated B cell development and autoantibody production, previous analyses failed to identify a tolerance defect in antigen-specific mutant B cells. Our results support a role for siglecs in B cell self-/nonself-discrimination, namely suppressing responses to self-associated antigens while permitting rapid “missing self”–responses to unsialylated multimeric antigens. The results suggest use of siglec ligand antigen constructs as an approach for inducing tolerance.

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Jung, Kyeong Cheon, Chung-Gyu Park, Yoon Kyung Jeon, Hyo Jin Park, Young Larn Ban, Hye Sook Min, Eun Ji Kim, et al. "In situ induction of dendritic cell–based T cell tolerance in humanized mice and nonhuman primates." Journal of Experimental Medicine 208, no. 12 (October 24, 2011): 2477–88. http://dx.doi.org/10.1084/jem.20111242.

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Induction of antigen-specific T cell tolerance would aid treatment of diverse immunological disorders and help prevent allograft rejection and graft versus host disease. In this study, we establish a method of inducing antigen-specific T cell tolerance in situ in diabetic humanized mice and Rhesus monkeys receiving porcine islet xenografts. Antigen-specific T cell tolerance is induced by administration of an antibody ligating a particular epitope on ICAM-1 (intercellular adhesion molecule 1). Antibody-mediated ligation of ICAM-1 on dendritic cells (DCs) led to the arrest of DCs in a semimature stage in vitro and in vivo. Ablation of DCs from mice completely abrogated anti–ICAM-1–induced antigen-specific T cell tolerance. T cell responses to unrelated antigens remained unaffected. In situ induction of DC-mediated T cell tolerance using this method may represent a potent therapeutic tool for preventing graft rejection.

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Feng, Xiangru, Jiaxue Liu, Weiguo Xu, Gao Li, and Jianxun Ding. "Tackling autoimmunity with nanomedicines." Nanomedicine 15, no. 16 (July 2020): 1585–97. http://dx.doi.org/10.2217/nnm-2020-0102.

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Tolerogenic immunotherapy aims to blunt pathogenic inflammation without affecting systemic immunity. However, the anti-inflammatory drugs and immunosuppressive biologics that are used in the clinic usually result in nonspecific immune cell suppression and off-target toxicity. For this reason, strategies have been developed to induce antigen-specific immune tolerance through the delivery of disease-relevant antigens by nanocarriers as a benefit of their preferential internalization by antigen-presenting cells. Herein, we discuss the recent advances in the nanotechnology-based antigen-specific tolerance approaches. Some of these designs are based on nanoparticles delivering antigens and immunoregulatory agents to modulate antigen-presenting pathways, while others directly target T cells via nanoparticle-based artificial antigen-presenting cells. These antigen-specific therapies are hoped to replace systemic immune suppression and provide long-term disease remission.

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Mapara, Markus Y., and Megan Sykes. "Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance." Journal of Clinical Oncology 22, no. 6 (March 15, 2004): 1136–51. http://dx.doi.org/10.1200/jco.2004.10.041.

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The development of malignant disease might be seen as a failure of immune surveillance. However, not all tumors are naturally immunogenic, and even among those that are immunogenic, the uncontrolled rapid growth of a tumor may sometimes out-run a robust immune response. Nevertheless, recent evidence suggests that mechanisms of tolerance that normally exist to prevent autoimmune disease may also preclude the development of an adequate antitumor response and that tumors themselves have the ability to thwart the development of effective immune responses against their antigens. A major challenge has been to develop approaches to breaking this tolerance in tumor-bearing hosts, and recent advances in our understanding of antigen presentation and tolerance have led to some promising strategies. An alternative approach is to use T cells from nontumor-bearing, allogeneic hosts in the form of lymphocyte infusions, with or without hematopoietic cell transplantation. Immunotherapy may occur in this setting via the response of nontolerant, tumor antigen-specific T cells from nontumor-bearing hosts or via the powerful destructive effect of an alloresponse directed against antigens shared by malignant cells in the recipient. Approaches to exploiting this beneficial effect without the deleterious consequence of graft-versus-host disease in allogeneic hematopoietic cell recipients are discussed.

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Horst, Andrea Kristina, Kingsley Gideon Kumashie, Katrin Neumann, Linda Diehl, and Gisa Tiegs. "Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease." Cellular & Molecular Immunology 18, no. 1 (October 27, 2020): 92–111. http://dx.doi.org/10.1038/s41423-020-00568-6.

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AbstractThe liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.

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Parks, Christopher A., Kalli R. Henning, Kevin D. Pavelko, Michael J. Hansen, Virginia P. Van Keulen, Brendan K. Reed, Jennifer D. Stone, et al. "Breaking tolerance with engineered class I antigen-presenting molecules." Proceedings of the National Academy of Sciences 116, no. 8 (February 6, 2019): 3136–45. http://dx.doi.org/10.1073/pnas.1807465116.

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Successful efforts to activate T cells capable of recognizing weak cancer-associated self-antigens have employed altered peptide antigens to activate T cell responses capable of cross-reacting on native tumor-associated self. A limitation of this approach is the requirement for detailed knowledge about the altered self-peptide ligands used in these vaccines. In the current study we considered allorecognition as an approach for activating CTL capable of recognizing weak or self-antigens in the context of self-MHC. Nonself antigen-presenting molecules typically contain polymorphisms that influence interactions with the bound peptide and TCR interface. Recognition of these nonself structures results in peptide-dependent alloimmunity. Alloreactive T cells target their inducing alloantigens as well as third-party alloantigens but generally fail to target self-antigens. Certain residues located on the alpha-1/2 domains of class I antigen-presenting molecules primarily interface with TCR. These residues are more conserved within and across species than are residues that determine peptide antigen binding properties. Class I variants designed with amino acid substitutions at key positions within the conserved helical structures are shown to provide strong activating signals to alloreactive CD8 T cells while avoiding changes in naturally bound peptide ligands. Importantly, CTL activated in this manner can break self-tolerance by reacting to self-peptides presented by native MHC. The ability to activate self-tolerant T cells capable of cross-reacting on self-peptide-MHC in vivo represents an approach for inducing autoimmunity, with possible application in cancer vaccines.

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Worbs, Tim, Ulrike Bode, Sheng Yan, Matthias W. Hoffmann, Gabriele Hintzen, Günter Bernhardt, Reinhold Förster, and Oliver Pabst. "Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells." Journal of Experimental Medicine 203, no. 3 (March 13, 2006): 519–27. http://dx.doi.org/10.1084/jem.20052016.

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Oral tolerance induction is a key feature of intestinal immunity, generating systemic nonresponsiveness to ingested antigens. In this study, we report that orally applied soluble antigens are exclusively recognized in the intestinal immune system, particularly in the mesenteric lymph nodes. Consequently, the initiation of oral tolerance is impeded by mesenteric lymphadenectomy. Small bowel transplantation reveals that mesenteric lymph nodes require afferent lymph to accomplish the recognition of orally applied antigens. Finally, oral tolerance cannot be induced in CCR7-deficient mice that display impaired migration of dendritic cells from the intestine to the mesenteric lymph nodes, suggesting that immunologically relevant antigen is transported in a cell-bound fashion. These results demonstrate that antigen transport via afferent lymphatics into the draining mesenteric lymph nodes is obligatory for oral tolerance induction, inspiring new therapeutic strategies to exploit oral tolerance induction for the prevention and treatment of autoimmune diseases.

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HOYNE, GERARD F, KAREN TAN, MARTA CORSIN-JIMENEZ, KAREN WAHL, MAIRI STEWART, SARAH E M. HOWIE, and JONATHAN R LAMB. "Immunological Tolerance to Inhaled Antigen." American Journal of Respiratory and Critical Care Medicine 162, supplement_3 (October 2000): S169—S174. http://dx.doi.org/10.1164/ajrccm.162.supplement_3.15tac6.

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WEINER, HOWARD L., Z. JENNY ZHANG, SAMIA J. KHOURY, ARIEL MILLER, AHMAD AL-SABBAGH, STALEY A. BROD, OFER LIDER, et al. "Antigen-Driven Peripheral Immune Tolerance." Annals of the New York Academy of Sciences 636, no. 1 Antigen and C (December 1991): 227–32. http://dx.doi.org/10.1111/j.1749-6632.1991.tb33454.x.

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Kontos, Stephan, Alizée J. Grimm, and Jeffrey A. Hubbell. "Engineering antigen-specific immunological tolerance." Current Opinion in Immunology 35 (August 2015): 80–88. http://dx.doi.org/10.1016/j.coi.2015.05.005.

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Ferry, Helen, Margaret Jones, David J. Vaux, Ian S. D. Roberts, and Richard J. Cornall. "The Cellular Location of Self-antigen Determines the Positive and Negative Selection of Autoreactive B Cells." Journal of Experimental Medicine 198, no. 9 (November 3, 2003): 1415–25. http://dx.doi.org/10.1084/jem.20030279.

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Systemic autoimmune disease is frequently characterized by the production of autoantibodies against widely expressed intracellular self-antigens, whereas B cell tolerance to ubiquitous and highly expressed extracellular antigens is strictly enforced. To test for differences in the B cell response to intracellular and extracellular self-antigens, we sequestered a tolerogenic cell surface antigen intracellularly by addition of a two amino acid endoplasmic reticulum (ER) retention signal. In contrast to cell surface antigen, which causes the deletion of autoreactive B cells, the intracellularly sequestered self-antigen failed to induce B cell tolerance and was instead autoimmunogenic. The intracellular antigen positively selected antigen-binding B cells to differentiate into B1 cells and induced large numbers of IgM autoantibody-secreting plasma cells in a T-independent manner. By analyzing the impact of differences in subcellular distribution independently from other variables, such as B cell receptor affinity, antigen type, or tissue distribution, we have established that intracellular localization of autoantigen predisposes for autoantibody production. These findings help explain why intracellular antigens are targeted in systemic autoimmune diseases.

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Avichezer, Dody, Rafael S. Grajewski, Chi-Chao Chan, Mary J. Mattapallil, Phyllis B. Silver, James A. Raber, Gregory I. Liou, et al. "An Immunologically Privileged Retinal Antigen Elicits Tolerance." Journal of Experimental Medicine 198, no. 11 (December 1, 2003): 1665–76. http://dx.doi.org/10.1084/jem.20030413.

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Immunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25+ T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role.

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Li, Xuemei, and Xiaoxia Li. "Progress of research on the immune tolerance of chronic HBV infection." Infection International 7, no. 3 (September 30, 2018): 88–93. http://dx.doi.org/10.2478/ii-2018-0026.

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Abstract Immune tolerance is a specific lack or negative response of T and B lymphocytes to antigen. According to different formation periods, immune tolerance can be divided into central and peripheral tolerances. The immune tolerance of the body to hepatitis B virus (HBV) after infection is the main cause of chronic HBV infection. In this paper, the functional defects of hepatitis B virus e antigen and dendritic cells, hyporesponsiveness of cytotoxic T lymphocyte, variation of helper T lymphocytes and cytokines, HBV genotype and genome, and the role of host gene polymorphism in the formation of immune tolerance in chronic HBV infection and its related research progress are introduced briefly.

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Maldonado, Roberto A., Robert A. LaMothe, Joseph D. Ferrari, Ai-Hong Zhang, Robert J. Rossi, Pallavi N. Kolte, Aaron P. Griset, et al. "Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance." Proceedings of the National Academy of Sciences 112, no. 2 (December 29, 2014): E156—E165. http://dx.doi.org/10.1073/pnas.1408686111.

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Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.

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Smith, Nicole H., Eldad A. Hod, Steven L. Spitalnik, James C. Zimring, and Jeanne E. Hendrickson. "Transfusion in the absence of inflammation induces antigen-specific tolerance to murine RBCs." Blood 119, no. 6 (February 9, 2012): 1566–69. http://dx.doi.org/10.1182/blood-2011-09-382655.

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Abstract Most human transfusion recipients fail to make detectable alloantibodies to foreign RBC antigens (“nonresponders”). Herein, we use a murine model to test the hypothesis that nonresponders may be immunologically tolerant. FVB mice transfused with RBCs expressing transgenic human glycophorin A (hGPA) antigen in the absence of inflammation produced undetectable levels of anti-hGPA immunoglobulins, unlike those transfused in the presence of polyinosinic:polycytidylic acid–induced inflammation. Mice in the nonresponder group failed to produce anti-hGPA after subsequent transfusions in the presence of polyinosinic:polycytidylic acid, whereas anti-hGPA levels increased in the responder group. This tolerance was antigen specific, because nonresponders to hGPA produced alloantibodies to RBCs that expressed a different transgenic antigen. This tolerance was not an idiosyncrasy of the hGPA antigen nor of the recipient strain, because B10.BR mice transfused with membrane-bound hen egg lysozyme antigen–transgenic RBCs also demonstrated induced nonresponsiveness. These data demonstrate that RBCs transfused in the absence of inflammation can induce tolerance.

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Robert, S., K. Van Huynegem, C. Gysemans, C. Mathieu, P. Rottiers, and L. Steidler. "Trimming of two major type 1 diabetes driving antigens, GAD65 and IA-2, allows for successful expression in Lactococcus lactis." Beneficial Microbes 6, no. 4 (August 2015): 591–601. http://dx.doi.org/10.3920/bm2014.0083.

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Type 1 diabetes (T1D) is a chronic autoimmune disease characterised by excessive immune reactions against auto-antigens of pancreatic β-cells. Restoring auto-antigen tolerance remains the superior therapeutic strategy. Oral auto-antigen administration uses the tolerogenic nature of the gut-associated immune system to induce antigen-specific tolerance. However, due to gastric degradation, proper mucosal product delivery often imposes a challenge. Recombinant Lactococcus lactis have proven to be effective and safe carriers for gastrointestinal delivery of therapeutic products: L. lactis secreting diabetes-associated auto-antigens in combination with interleukin (IL)-10 have demonstrated therapeutic efficacy in a well-defined mouse model for T1D. Here, we describe the construction of recombinant L. lactis secreting the 65 kDa isoform of glutamic acid decarboxylase (GAD65) and tyrosine phosphatase-like protein ICA512 (IA-2), two major T1D-related auto-antigens. Attempts to secrete full size human GAD65 and IA-2 protein by L. lactis were unsuccessful. Trimming of GAD65 and IA-2 was investigated to optimise antigen secretion while maintaining sufficient bacterial growth. GAD65370-575 and IA-2635-979 showed to be efficiently secreted by recombinant L. lactis. Antigen secretion was verified by immunoblotting. Plasmid-derived GAD65 and IA-2 expression was combined in single strains with human IL-10 expression, a desired combination to allow tolerance induction. This study reports the generation of recombinant L. lactis secreting two major diabetes-related auto-antigens: human GAD65 and IA-2, by themselves or combined with the anti-inflammatory cytokine human IL-10. Prohibitive sequence obstacles hampering antigen secretion were resolved by trimming the full size proteins.

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Shrestha, Umid Kumar. "Immunology of the gut and oral tolerance." Journal of Advances in Internal Medicine 4, no. 1 (December 18, 2015): 16–24. http://dx.doi.org/10.3126/jaim.v4i1.14176.

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The pathogens and harmless antigens from the bacterial flora and food constantly expose the mucosal surface of the gastrointestinal tract. The mucosal epithelial cells act not only as a physical barrier, but also as a local immune system, which plays a vital role in defense and self-tolerance. The gut mucosal immune system comprises several compartments: Peyer’s patches and lymphoid follicles in the colonic mucosa, and lymphocytes in the lamina propria and intraepithelial lymphocytes. Peyer’s patches mediate antigen uptake via specialized epithelial cells (M cells) and are rich in B cells for class switching into IgA-secreting cells. IgA secretion is one of the primary defenses against pathogens at mucosal surfaces. The lamina propria contains a high proportion of activated and memory T cells that allows rapid immune response against pathogens. In the physiological situation, mucosally encountered antigens induce tolerance of lamina propria and intraepithelial lymphocytes by modified antigen presentation, antigen-induced anergy, or deletion of T cells, or regulation of effector T cells by regulatory or suppressor T cells. Costimulatory molecules mediate cellular interaction and induce regulatory cytokines. While the absence of gut immune privilege to food results in food allergy, the consequences of immune privilege collapse to commensal gut flora is Inflammatory Bowel Disease (IBD). Hence, the knowledge of the homeostatic regulation of the intestinal immune system paves the way for the development of the new immunomodulatory drugs in the therapy of IBD. Moreover, the generation of immune mediated cells through orally fed antigens could be the area of research in the treatment of certain autoimmune diseases.Journal of Advances in Internal Medicine 2015;04(01):16-24

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Belz, Gabrielle T., Georg M. N. Behrens, Chris M. Smith, Jacques F. A. P. Miller, Claerwen Jones, Kristina Lejon, C. Garrison Fathman, et al. "The CD8α+ Dendritic Cell Is Responsible for Inducing Peripheral Self-Tolerance to Tissue-associated Antigens." Journal of Experimental Medicine 196, no. 8 (October 14, 2002): 1099–104. http://dx.doi.org/10.1084/jem.20020861.

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We previously described a mechanism for the maintenance of peripheral self-tolerance. This involves the cross-presentation of tissue-associated antigens by a bone marrow–derived cell type that stimulates the proliferation and ultimate deletion of self-reactive CD8 T cells. This process has been referred to as cross-tolerance. Here, we characterize the elusive cell type responsible for inducing cross-tolerance as a CD8α+ dendritic cell (DC). To achieve this aim, transgenic mice were generated expressing yellow fluorescent protein (YFP) linked to CTL epitopes for ovalbumin and glycoprotein B (gB) of herpes simplex virus under the rat insulin promoter (RIP). Although tracking of YFP was inconclusive, the use of a highly sensitive gB-specific hybridoma that produced β-galactosidase on encounter with antigen, enabled detection of antigen presentation by cells isolated from the pancreatic lymph node. This showed that a CD11c+CD8α+ cell was responsible for cross-tolerance, the same DC subset as previously implicated in cross-priming. These data indicate that CD8α+ DCs play a critical role in both tolerance and immunity to cell-associated antigens, providing a potential mechanism by which cytotoxic T lymphocyte can be immunized to viral antigens while maintaining tolerance to self.

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Doyle, Hester A., Jing Zhou, Martin J. Wolff, Bohdan P. Harvey, Robert M. Roman, Renelle J. Gee, Raymond A. Koski, and Mark J. Mamula. "Isoaspartyl Post-translational Modification Triggers Anti-tumor T and B Lymphocyte Immunity." Journal of Biological Chemistry 281, no. 43 (September 1, 2006): 32676–83. http://dx.doi.org/10.1074/jbc.m604847200.

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A hallmark of the immune system is the ability to ignore self-antigens. In attempts to bypass normal immune tolerance, a post-translational protein modification was introduced into self-antigens to break T and B cell tolerance. We demonstrate that immune tolerance is bypassed by immunization with a post-translationally modified melanoma antigen. In particular, the conversion of an aspartic acid to an isoaspartic acid within the melanoma antigen tyrosinase-related protein (TRP)-2 peptide-(181-188) makes the otherwise immunologically ignored TRP-2 antigen immunogenic. Tetramer analysis of iso-Asp TRP-2 peptide-immunized mice demonstrated that CD8+ T cells not only recognized the isoaspartyl TRP-2 peptide but also the native TRP-2 peptide. These CD8+ T cells functioned as cytotoxic T lymphocytes, as they effectively lysed TRP-2 peptide-pulsed targets both in vitro and in vivo. Potentially, post-translational protein modification can be utilized to trigger strong immune responses to either tumor proteins or potentially weakly immunogenic pathogens.

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Eynon, E. E., and D. C. Parker. "Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens." Journal of Experimental Medicine 175, no. 1 (January 1, 1992): 131–38. http://dx.doi.org/10.1084/jem.175.1.131.

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We have investigated the ability of resting B cells, acting as antigen-presenting cells, to induce tolerance to soluble protein antigens in mice, using an antigen targeted specifically to B cells. We inject mice intravenously with ultracentrifuged Fab fragments of rabbit anti-mouse immunoglobulin D (IgD) (Fab anti-delta). Treatment with Fab anti-delta results in profound tolerance to challenge with 100 micrograms Fab nonimmune rabbit Ig (Fab NRG), precipitated in alum, as measured by antibody production. Tolerance to rabbit Fab is antigen specific, since the treated mice make normal antibody responses to a control antigen, chicken Ig. Tolerance is dependent on antigen presentation by B cells, since intravenous injection of soluble Fab NRG, which is not targeted to B cells, results in a much lower frequency and degree of tolerance, especially at lower doses. T cell help in this system is affected, since T cells from Fab anti-delta-treated mice fail to provide help for an adoptive primary antibody response to Fab NRG when transferred together with normal B cells into severe combined immunodeficient (SCID) mice. The antigen-specific B cell compartment is also affected during tolerance induction, since B cells from treated animals make less antibody than normal B cells when transferred into SCID mice with normal T cells. Although the mechanism of nonresponsiveness in the helper T cell compartment remains to be determined, we think it is likely that the precursors of helper T cells are inactivated or deleted by encountering antigen presented by small, resting B cells, which lack accessory signals necessary to induce helper T cell proliferation and differentiation to effector function.(ABSTRACT TRUNCATED AT 250 WORDS)

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Fukaya, Tomohiro, Hideaki Takagi, Yumiko Sato, Kaori Sato, Kawori Eizumi, Honami Taya, Tahiro Shin, et al. "Crucial roles of B7-H1 and B7-DC expressed on mesenteric lymph node dendritic cells in the generation of antigen-specific CD4+Foxp3+ regulatory T cells in the establishment of oral tolerance." Blood 116, no. 13 (September 30, 2010): 2266–76. http://dx.doi.org/10.1182/blood-2009-10-250472.

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Abstract Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to fed antigens. However, the molecular mechanism mediating oral tolerance remains unclear. In this study, we examined the role of the B7 family members of costimulatory molecules in the establishment of oral tolerance. Deficiencies of B7-H1 and B7-DC abrogated the oral tolerance, accompanied by enhanced antigen-specific CD4+ T-cell response and IgG1 production. Mesenteric lymph node (MLN) dendritic cells (DCs) displayed higher levels of B7-H1 and B7-DC than systemic DCs, whereas they showed similar levels of CD80, CD86, and B7-H2. MLN DCs enhanced the antigen-specific generation of CD4+Foxp3+ inducible regulatory T cells (iTregs) from CD4+Foxp3− T cells rather than CD4+ effector T cells (Teff) relative to systemic DCs, owing to the dominant expression of B7-H1 and B7-DC. Furthermore, the antigen-specific conversion of CD4+Foxp3− T cells into CD4+Foxp3+ iTregs occurred in MLNs greater than in peripheral organs during oral tolerance under steady-state conditions, and such conversion required B7-H1 and B7-DC more than other B7 family members, whereas it was severely impaired under inflammatory conditions. In conclusion, our findings suggest that B7-H1 and B7-DC expressed on MLN DCs are essential for establishing oral tolerance through the de novo generation of antigen-specific CD4+Foxp3+ iTregs.

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Adler, Adam J., David W. Marsh, Gregory S. Yochum, James L. Guzzo, Ankesh Nigam, William G. Nelson, and Drew M. Pardoll. "CD4+ T Cell Tolerance to Parenchymal Self-Antigens Requires Presentation by Bone Marrow–derived Antigen-presenting Cells." Journal of Experimental Medicine 187, no. 10 (May 18, 1998): 1555–64. http://dx.doi.org/10.1084/jem.187.10.1555.

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T cell tolerance to parenchymal self-antigens is thought to be induced by encounter of the T cell with its cognate peptide–major histocompatibility complex (MHC) ligand expressed on the parenchymal cell, which lacks appropriate costimulatory function. We have used a model system in which naive T cell receptor (TCR) transgenic hemagglutinin (HA)-specific CD4+ T cells are adoptively transferred into mice expressing HA as a self-antigen on parenchymal cells. After transfer, HA-specific T cells develop a phenotype indicative of TCR engagement and are rendered functionally tolerant. However, T cell tolerance is not induced by peptide–MHC complexes expressed on parenchymal cells. Rather, tolerance induction requires that HA is presented by bone marrow (BM)–derived cells. These results indicate that tolerance induction to parenchymal self-antigens requires transfer to a BM-derived antigen-presenting cell that presents it to T cells in a tolerogenic fashion.

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Von Bubnoff, D., H. De La Salle, J. Weßendorf, S. Koch, D. Hanau, and T. Bieber. "Antigen-presenting cells and tolerance induction." Allergy 57, no. 1 (January 2002): 2–8. http://dx.doi.org/10.1046/j.0105-4538.2001.00001.x-i4.

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28

Parker, David C., and Elizabeth E. Eynon. "Antigen presentation in acquired immunological tolerance." FASEB Journal 5, no. 13 (October 1991): 2777–84. http://dx.doi.org/10.1096/fasebj.5.13.1916102.

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von Bubnoff, D., H. de la Salle, J. Wessendorf, S. Koch, D. Hanau, and T. Bieber. "Antigen-presenting cells and tolerance induction." Allergy 57, no. 1 (January 2002): 2–8. http://dx.doi.org/10.1034/j.1398-9995.2002.01150.x.

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30

&NA;. "DELETIONAL TOLERANCE TO A MODEL ANTIGEN." Transplantation 82, Suppl 2 (July 2006): 893. http://dx.doi.org/10.1097/00007890-200607152-02500.

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31

MORRIS, PETER J., KATHRYN J. WOOD, and MARGARET J. DALLMAN. "Antigen-Induced Tolerance to Organ Allografts." Annals of the New York Academy of Sciences 636, no. 1 Antigen and C (December 1991): 295–305. http://dx.doi.org/10.1111/j.1749-6632.1991.tb33460.x.

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32

Öhlén, Claes, Michael Kalos, Laurence E. Cheng, Aaron C. Shur, Doley J. Hong, Bryan D. Carson, Niels C. T. Kokot, et al. "CD8+ T Cell Tolerance to a Tumor-associated Antigen Is Maintained at the Level of Expansion Rather than Effector Function." Journal of Experimental Medicine 195, no. 11 (May 28, 2002): 1407–18. http://dx.doi.org/10.1084/jem.20011063.

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CD8+ T cell tolerance to self-proteins prevents autoimmunity but represents an obstacle to generating T cell responses to tumor-associated antigens. We have made a T cell receptor (TCR) transgenic mouse specific for a tumor antigen and crossed TCR-TG mice to transgenic mice expressing the tumor antigen in hepatocytes (gag-TG). TCRxgag mice showed no signs of autoimmunity despite persistence of high avidity transgenic CD8+ T cells in the periphery. Peripheral CD8+ T cells expressed phenotypic markers consistent with antigen encounter in vivo and had upregulated the antiapoptotic molecule Bcl-2. TCRxgag cells failed to proliferate in response to antigen but demonstrated cytolytic activity and the ability to produce interferon γ. This split tolerance was accompanied by inhibition of Ca2+ flux, ERK1/2, and Jun kinasephosphorylation, and a block in both interleukin 2 production and response to exogenous interleukin 2. The data suggest that proliferation and expression of specific effector functions characteristic of reactive cells are not necessarily linked in CD8+ T cell tolerance.

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Krishnan, Lakshmi, Lise Deschatelets, Felicity C. Stark, Komal Gurnani, and G. Dennis Sprott. "Archaeosome Adjuvant Overcomes Tolerance to Tumor-Associated Melanoma Antigens Inducing Protective CD8+T Cell Responses." Clinical and Developmental Immunology 2010 (2010): 1–13. http://dx.doi.org/10.1155/2010/578432.

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Vesicles comprised of the ether glycerolipids of the archaeonMethanobrevibacter smithii(archaeosomes) are potent adjuvants for evoking CD8+T cell responses. We therefore explored the ability of archaeosomes to overcome immunologic tolerance to self-antigens. Priming and boosting of mice with archaeosome-antigen evoked comparable CD8+T cell response and tumor protection to an alternate boosting strategy utilizing live bacterial vectors for antigen delivery. Vaccination with melanoma antigenic peptides TRP181-189and Gp10025-33delivered in archaeosomes resulted in IFN-γproducing antigen-specific CD8+T cells with strong cytolytic capability and protection against subcutaneous B16 melanoma. Targeting responses against multiple antigens afforded prolonged median survival against melanoma challenge. Entrapment of multiple peptides within the same vesicle or admixed formulations were both effective at evoking CD8+T cells against each antigen. Melanoma-antigen archaeosome formulations also afforded therapeutic protection against established B16 tumors when combined with depletion of T-regulatory cells. Overall, we demonstrate that archaeosome adjuvants constitute an effective choice for formulating cancer vaccines.

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34

Ogawa, Haruko, Deng-Ping Yin, Jikun Shen, and Uri Galili. "Tolerance induction to a mammalian blood group–like carbohydrate antigen by syngeneic lymphocytes expressing the antigen." Blood 101, no. 6 (March 15, 2003): 2318–20. http://dx.doi.org/10.1182/blood-2002-07-2151.

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Tolerance induction to transplantation-associated carbohydrate antigens, such as blood group A or B and the α-gal epitope (Galα1-3Galβ1-4GlcNAc-R), is of clinical significance. This study demonstrates tolerance induction to the α-gal epitope in the experimental animal model of α1,3galactosyltransferanse knockout mice (KO mice) lacking α-gal epitopes by administering syngeneic lymphocytes expressing α-gal epitopes. Repeated immunization of control KO mice with pig kidney membranes (PKM) expressing many α-gal epitopes induces an extensive anti-Gal antibody response against this epitope. In contrast, KO mice that received as few as 2 × 106 wild-type (WT) lymphocytes were tolerized and failed to produce anti-Gal following PKM immunizations. Accordingly, control mice producing anti-Gal rapidly rejected transplanted WT hearts, whereas tolerized mice did not reject WT hearts. These findings suggest that autologous blood lymphocytes processed to express a carbohydrate antigen may induce a similar tolerance to such an antigen upon administration into humans.

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35

Wang, Hongwei, Fengdong Cheng, Alex Cuenca, Pedro Horna, Zheng Zheng, Kapil Bhalla, and Eduardo M. Sotomayor. "Imatinib mesylate (STI-571) enhances antigen-presenting cell function and overcomes tumor-induced CD4+ T-cell tolerance." Blood 105, no. 3 (February 1, 2005): 1135–43. http://dx.doi.org/10.1182/blood-2004-01-0027.

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Abstract Tumor antigen–specific T-cell tolerance imposes a significant barrier to the development of effective therapeutic cancer vaccines. Bone marrow–derived antigen-presenting cells (APCs) are critical in the induction of this unresponsive state. Here we show that in vitro treatment of APCs with the tyrosine kinase inhibitor, imatinib mesylate (STI-571), enhances the activation of naive antigen-specific T cells and restores the responsiveness of tolerant T cells from tumor-bearing hosts. Furthermore, in vivo treatment with STI-571 not only prevented the induction of tolerance in tumor-specific CD4+ T cells, preserving their responsiveness to a subsequent immunization, but also resulted in enhanced vaccine efficacy. These findings demonstrate that tolerance to tumor antigens is not an insurmountable obstacle and points to modulation of APC function as a promising strategy in the immunotherapy of cancer.

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36

Chung, Chun Yuen J., Dirk Ysebaert, Zwi N. Berneman, and Nathalie Cools. "Dendritic Cells: Cellular Mediators for Immunological Tolerance." Clinical and Developmental Immunology 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/972865.

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In general, immunological tolerance is acquired upon treatment with non-specific immunosuppressive drugs. This indiscriminate immunosuppression of the patient often causes serious side-effects, such as opportunistic infectious diseases. Therefore, the need for antigen-specific modulation of pathogenic immune responses is of crucial importance in the treatment of inflammatory diseases. In this perspective, dendritic cells (DCs) can have an important immune-regulatory function, besides their notorious antigen-presenting capacity. DCs appear to be essential for both central and peripheral tolerance. In the thymus, DCs are involved in clonal deletion of autoreactive immature T cells by presenting self-antigens. Additionally, tolerance is achieved by their interactions with T cells in the periphery and subsequent induction of T cell anergy, T cell deletion, and induction of regulatory T cells (Treg). Various studies have described, modulation of DC characteristics with the purpose to induce antigen-specific tolerance in autoimmune diseases, graft-versus-host-disease (GVHD), and transplantations. Promising results in animal models have prompted researchers to initiate first-in-men clinical trials. The purpose of current review is to provide an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of dendritic cell-based therapeutic opportunities in autoimmune diseases.

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Perdicchio, Maurizio, Juan M. Ilarregui, Marleen I. Verstege, Lenneke A. M. Cornelissen, Sjoerd T. T. Schetters, Steef Engels, Martino Ambrosini, et al. "Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells." Proceedings of the National Academy of Sciences 113, no. 12 (March 3, 2016): 3329–34. http://dx.doi.org/10.1073/pnas.1507706113.

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Sialic acids are negatively charged nine-carbon carboxylated monosaccharides that often cap glycans on glycosylated proteins and lipids. Because of their strategic location at the cell surface, sialic acids contribute to interactions that are critical for immune homeostasis via interactions with sialic acid-binding Ig-type lectins (siglecs). In particular, these interactions may be of importance in cases where sialic acids may be overexpressed, such as on certain pathogens and tumors. We now demonstrate that modification of antigens with sialic acids (Sia-antigens) regulates the generation of antigen-specific regulatory T (Treg) cells via dendritic cells (DCs). Additionally, DCs that take up Sia-antigen prevent formation of effector CD4+ and CD8+ T cells. Importantly, the regulatory properties endowed on DCs upon Sia-antigen uptake are antigen-specific: only T cells responsive to the sialylated antigen become tolerized. In vivo, injection of Sia-antigen–loaded DCs increased de novo Treg-cell numbers and dampened effector T-cell expansion and IFN-γ production. The dual tolerogenic features that Sia-antigen imposed on DCs are Siglec-E–mediated and maintained under inflammatory conditions. Moreover, loading DCs with Sia-antigens not only inhibited the function of in vitro–established Th1 and Th17 effector T cells but also significantly dampened ex vivo myelin-reactive T cells, present in the circulation of mice with experimental autoimmune encephalomyelitis. These data indicate that sialic acid-modified antigens instruct DCs in an antigen-specific tolerogenic programming, enhancing Treg cells and reducing the generation and propagation of inflammatory T cells. Our data suggest that sialylation of antigens provides an attractive way to induce antigen-specific immune tolerance.

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Sotomayor, Eduardo M., Ivan Borrello, Frédérique-Marie Rattis, Alex G. Cuenca, Jacob Abrams, Kevin Staveley-O'Carroll, and Hyam I. Levitsky. "Cross-presentation of tumor antigens by bone marrow–derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression." Blood 98, no. 4 (August 15, 2001): 1070–77. http://dx.doi.org/10.1182/blood.v98.4.1070.

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Tumor antigen-specific T-cell tolerance may limit the efficacy of therapeutic cancer vaccines. Direct presentation of antigens by tumor cells incapable of providing adequate costimulation to tumor-specific T cells has been suggested as the basis for this unresponsiveness. Using parent-into-F1 bone marrow (BM) chimeras, this study unambiguously demonstrates that the induction of this tolerant state requires T-cell recognition of tumor antigen presented by BM-derived antigen-presenting cells (APCs), not tumor cells themselves. In the absence of host APC presentation, tumor-specific T cells remained functional, even in the setting of antigen expressed by B-cell lymphomas residing in secondary lymphoid tissues. The intrinsic APC capacity of tumor cells has therefore little influence over T-cell priming versus tolerance, a decision that is regulated at the level of host APCs.

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39

Peschl, Patrick, Markus Reindl, Kathrin Schanda, Mireia Sospedra, Roland Martin, and Andreas Lutterotti. "Antibody responses following induction of antigen-specific tolerance with antigen-coupled cells." Multiple Sclerosis Journal 21, no. 5 (September 8, 2014): 651–55. http://dx.doi.org/10.1177/1352458514549405.

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We have recently demonstrated the safety and tolerability of a novel therapeutic regimen employing autologous blood cells chemically coupled with seven myelin peptides to induce antigen-specific tolerance in MS (ETIMS study). The aim of the current study was an extended safety analysis to assess the effect of the ETIMS approach on antibodies to common autoantigens, the myelin peptides used and common recall antigens. None of the patients showed induction of autoantibody responses. One patient had a measurable myelin peptide-specific response at baseline, which was reduced after treatment. Total immunoglobulins and recall antibody responses showed no significant change.

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40

Bam, Marpe, and Tamishraha Bagchi. "MART-1 transcript is absent in PBMCs from Vitiligo patients." Open Life Sciences 4, no. 4 (December 1, 2009): 528–35. http://dx.doi.org/10.2478/s11535-009-0057-6.

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AbstractMechanisms occurring in the thymus and periphery are responsible for the generation and maintenance of tolerance in the immune system. Various reports have shown that the existence of an antigen in the peripheral circulation results in tolerance induction towards that protein. These observations imply that the lack of a self antigen can lead to induction of autoimmunity. Previously we have reported that Tyrosinase related protein-2 (TRP-2) transcripts from peripheral blood mononuclear cells (PBMCs) are absent in vitiligo patients but present in healthy individuals. Here, we show that MART1 (Melanoma antigen recognized by T cells) transcripts are not detected in the PBMCs of vitiligo patients but is detected in healthy controls. Our result suggests that as MART1 is not expressed in the PBMCs, MART1 is also not available for induction and maintenance of peripheral tolerance in vitiligo patients. We therefore conclude that nonexpression of MART1 in PBMCs of vitiligo patients may be somehow responsible for the tolerance breakdown finally resulting in the induction of autoimmunity seen against these self antigens in vitiligo.

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41

Wilcox, Ryan A., Koji Tamada, Dallas B. Flies, Gefeng Zhu, Andrei I. Chapoval, Bruce R. Blazar, W. Martin Kast, and Lieping Chen. "Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo." Blood 103, no. 1 (January 1, 2004): 177–84. http://dx.doi.org/10.1182/blood-2003-06-2184.

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Abstract T-cell anergy is a tolerance mechanism defined as a hyporesponsive status of antigen-specific T cells upon prior antigen encounter and is believed to play a critical role in the evasion of tumor immunity and the amelioration of allogeneic transplant rejection. Molecular mechanisms in controlling T-cell anergy are less known. We show here that administration of an agonistic monoclonal antibody (mAb) to CD137, a member of the tumor necrosis factor receptor superfamily, prevents the induction of CD8+ cytolytic T-lymphocyte (CTL) anergy by soluble antigens. More importantly, CD137 mAb restores the functions of established anergic CTLs upon reencountering their cognate antigen. As a result, infusion of CD137 mAb inhibits progressive tumor growth that is caused by soluble tumor antigen-induced tolerance in a P815R model. CD137 mAb also restores proliferation and effector functions of anergic alloreactive 2C T cells in a bone marrow transplantation model. Our results indicate that ligation of CD137 receptor delivers a regulatory signal for T-cell anergy and implicate manipulation of the CD137 pathway as a new approach to break T-cell tolerance.

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42

Ghorashian, Sara, Ben Carpenter, Angelika Holler, Emma Nicholson, Maryam Ahmadi, Mathias Zech, Clare Bennett, et al. "CD4 Cells Engineered to Express an MHC Class I Restricted TCR Can Rescue CD8 Cells Tolerized to Tumour-Associated Antigens." Blood 120, no. 21 (November 16, 2012): 952. http://dx.doi.org/10.1182/blood.v120.21.952.952.

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Abstract Abstract 952 Background: The efficacy of T cell therapies for cancer may be limited when targeting tumour-associated antigens (TAA) which are also self-antigens. Ongoing exposure to TAA on normal cells may lead to tolerance via anergy or exhaustion of antigen-specific T cells. Methods: We have designed a model of tolerance to TAA in which T cell receptor (TCR)-transduced CD8 T cells recognise pMDM2, a TAA that is also a ubiquitous self-antigen. CD8+ T cells were transduced with pMDM2-specific TCR (MDM-CD8) and transferred to sub-lethally irradiated B6 mice that express pMDM2 in the context of MHC Class I (H2-Kb). MDM-CD8 cells are detectable 4 weeks after transfer but show defective in vivo killing of target cells pulsed with MDM2 peptide. We have used this model to determine the mechanism of tolerance and to evaluate whether tolerant CD8+ T cells can be rescued by CD4 help. Results: To determine whether tolerance of MDM-CD8 cells was dependent upon recognition of cognate antigen, we transferred MDM-CD8 cells into mice of a different MHC background (BALB/c) which lack H2-Kb required for presentation of the TCR-recognised MDM2 peptide. When BALB/c MDM-CD8 cells were transferred to BALBc hosts their functions were preserved and they retained efficient antigen-specific cytolysis. To determine whether tolerance could be modified by provision of CD4+ T cell help, we co-transferred MDM-CD8 with transgenic OT-II CD4+ cells. OT-II cells were primed with dendritic cells (DCs) loaded with cognate pOVA323-339 or irrelevant peptide. When activated through their TCR, OT-II cells increased both the frequency of MDM2-specific CD8 cells and their cytotoxic functions, indicating that CD4 help can overcome CD8 tolerance to TAA. Ineffective antigen presentation to CD4 cells and lack of known MHC class II-restricted TAA are major limitations to providing CD4 help in T cell therapy for cancer. We therefore tested whether transfer of the MHC Class I-restricted MDM2 TCR into CD4 cells could provide help upon transfer to antigen-expressing hosts. Co-transfer of MDM2-TCR-transduced CD4 cells with CD8 cells improved antigen-specific killing of target cells when compared to single transfer of either TCR-transduced CD8 or CD4 cells. Conclusion: CD4 cells rendered capable of responding to an MHC class I restricted TAA by TCR transfer can rescue tolerance developing in a CD8 population with the same specificity. This is potentially a novel way to circumvent defective immune responses arising in adoptively transferred effector cells due to prolonged exposure to cognate antigen on normal host cells. Disclosures: Stauss: Cell Medica: Scientific Advisor Other.

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Morlacchi, Sara, Cristiana Soldani, Antonella Viola, and Adelaida Sarukhan. "Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion." Blood 118, no. 4 (July 28, 2011): 984–91. http://dx.doi.org/10.1182/blood-2011-02-336115.

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Abstract Multiple mechanisms operate to ensure T-cell tolerance toward self-antigens. Three main processes have been described: clonal deletion, anergy, and deviation to CD4+ regulatory T cells (Tregs) that suppress autoreactive T cells that have escaped the first 2 mechanisms. Although it is accepted that dendritic cells (DCs) and B cells contribute in maintaining T-cell tolerance to self-antigens, their relative contribution and the processes involved under physiologic conditions remain only partially characterized. In this study, we used different transgenic mouse models to obtain chimeras where a neo self-antigen is expressed by thymic epithelium and/or by DCs or B cells. We found that expression of cognate ligand in the thymus enhances antigen-specific FoxP3+ cells independently of whether the self-antigen is expressed on thymic epithelium or only on DCs, but not on B cells. On the contrary, self-antigen expression by B cells was very efficient in inducing FoxP3+ cells in the periphery, whereas self-antigen expression by DC led mainly to deletion and anergy of antigen-specific FoxP3− cells. The results presented in this study underline the role of B cells in Treg induction and may have important implications in clinical protocols aimed at the peripheral expansion of Tregs in patients.

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Soroosh, Pejman, Taylor A. Doherty, Wei Duan, Amit Kumar Mehta, Heonsik Choi, Yan Fei Adams, Zbigniew Mikulski, et al. "Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance." Journal of Experimental Medicine 210, no. 4 (April 1, 2013): 775–88. http://dx.doi.org/10.1084/jem.20121849.

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Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3+ iTreg cells is unclear. Here, we show that lung-resident tissue MØs coexpress TGF-β and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3+ Treg cells. Treg cell induction in this model depended on both TGF-β and retinoic acid. Transfer of the antigen-pulsed tissue MØs into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue MØs to allergens suppressed their ability to generate iTreg cells coincident with blocking airway tolerance. Suppression of Treg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue MØs have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma.

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Esprit, Arthur, Wout de Mey, Rajendra Bahadur Shahi, Kris Thielemans, Lorenzo Franceschini, and Karine Breckpot. "Neo-Antigen mRNA Vaccines." Vaccines 8, no. 4 (December 18, 2020): 776. http://dx.doi.org/10.3390/vaccines8040776.

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The interest in therapeutic cancer vaccines has caught enormous attention in recent years due to several breakthroughs in cancer research, among which the finding that successful checkpoint blockade treatments reinvigorate neo-antigen-specific T cells and that successful adoptive cell therapies are directed towards neo-antigens. Neo-antigens are cancer-specific antigens, which develop from somatic mutations in the cancer cell genome that can be highly immunogenic and are not subjected to central tolerance. As the majority of neo-antigens are unique to each patient’s cancer, a vaccine technology that is flexible and potent is required to develop personalized neo-antigen vaccines. In vitro transcribed mRNA is such a technology platform and has been evaluated for delivery of neo-antigens to professional antigen-presenting cells both ex vivo and in vivo. In addition, strategies that support the activity of T cells in the tumor microenvironment have been developed. These represent a unique opportunity to ensure durable T cell activity upon vaccination. Here, we comprehensively review recent progress in mRNA-based neo-antigen vaccines, summarizing critical milestones that made it possible to bring the promise of therapeutic cancer vaccines within reach.

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Gallegos, Alena M., and Michael J. Bevan. "Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation." Journal of Experimental Medicine 200, no. 8 (October 18, 2004): 1039–49. http://dx.doi.org/10.1084/jem.20041457.

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Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs.

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Cheng, Fengdong, Hongwei Wang, Alex G. Cuenca, Pedro Horna, Lldefonso Suarez, Jason Brayer, James Turkson, Richard Jove, and Eduardo M. Sotomayor. "Disruption of STAT3 Signaling in Antigen Presenting Cells Represents a Novel Strategy To Overcome Tumor-Induced Antigen-Specific CD4+ T-Cell Tolerance." Blood 104, no. 11 (November 16, 2004): 109. http://dx.doi.org/10.1182/blood.v104.11.109.109.

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Abstract Tumor antigen-specific T-cell tolerance imposes a significant barrier to the development of effective therapeutic cancer vaccines. Bone marrow-derived antigen presenting cells (APCs) are critical in the induction of this unresponsive state. Recently, we have identified STAT3 signaling in APCs as an important regulatory pathway that determines the functional outcome of antigen-specific CD4+ T-cells in response to cognate antigen. Indeed, while disruption of this signaling pathway in APCs led to effective T cell priming, enhanced STAT3 activity resulted in the induction of T cell unresponsiveness1. Given the above results, we explored in this study whether disruption of STAT3 signaling in APCs may preserve the responsiveness of antigen-specific CD4+ T-cells during the growth of a tumor that induces antigen specific T-cell tolerance. First, mice with a genetic disruption of Stat3 in macrophages, neutrophils and a sub-population of myeloid DCs (LysMcre/Stat3flox/− mice) or control C57BL/6 mice were given subcutaneously 1x106 B16 melanoma tumor cells engineered to express Ovalbumin as a model tumor antigen (B16-OVA). Four days later, naive CD4+ T-cells (1x106) specific for a MHC class II-restricted epitope of Ovalbumin (OT-II cells) were adoptively transferred intravenously into tumor bearing mice as well as into tumor-free controls. Two weeks later animals were sacrificed and antigen-specific CD4+ T-cell responses to in vitro re-stimulation with OVA-peptide were evaluated. As expected, antigen-specific T cells re-isolated from tumor-bearing C57BL/6 mice were fully tolerant (lack of HA-specific proliferation and cytokine production). In sharp contrast, anti-OVA CD4+ T-cells isolated from tumor bearing LysMcre/Stat3flox/− mice remained fully functional as determined by their capacity to proliferate and produce IL-2 and IFN-gamma in response to cognate OVA-peptide. The demonstration that tumor-induced antigen-specific CD4+ T-cell tolerance occurs in mice with an intact STAT3 signaling in APCs, but not in mice with genetic disruption of this signaling pathway, led us next to evaluate the efficacy of pharmacologic inhibitors of STAT3 in preventing and or overcoming tumor-induced T-cell tolerance. In vivo treatment of tumor bearing mice with Tyrphostin AG490 (0.5 mg/ i.p. /twice a day x 5 days), a well-known inhibitor of STAT3 signaling, also resulted in preservation of the responsiveness of tumor-antigen specific CD4+ T-cells. Furthermore, in vitro treatment of APCs with this compound led to effective priming of naive antigen-specific T cells and breaking of antigen-specific T-cell anergy. More recently, we have evaluated the efficacy of a novel STAT3 inhibitor, compound 295558, which efficiently inhibits the DNA-binding activity of STAT3. Treatment of DCs or macrophages with this specific inhibitor led to the generation of inflammatory APCs capable of restoring the responsiveness of tolerized CD4+ T-cells isolated from tumor bearing mice. Taken together, our findings establish a critical role for STAT3 signaling in the induction of tolerance to tumor antigens in vivo. Inhibition of this signaling pathway in APCs provides a novel molecular target to overcome the remarkable barrier that tolerance to tumor antigens imposes to cancer vaccination strategies.

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Sebille, Fabien, Bernard Vanhove, and Jean-Paul Soulillou. "Mechanisms of tolerance induction: blockade of co–stimulation." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1409 (May 29, 2001): 649–57. http://dx.doi.org/10.1098/rstb.2001.0842.

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Induction of tolerance to transplantation antigens is believed to be a promising way to achieve long–term allograft survival without a deleterious immunosuppressive regimen. T–cell activation, which is an essential feature of graft rejection, requires a first signal provided by T–cell receptor (TCR) ligation and a second signal provided by engagement of co–stimulatory molecules with their respective ligands on antigen–presenting cells. The coordinated triggering of these two independent signalling systems ensures the full T–cell activation, including proliferation and acquisition of effector function. TCR occupancy in the absence of co–stimulatory signals leads to a sustained loss of antigen responsiveness called clonal anergy, which could be of major importance in transplantation. In vivo , co–stimulation blockade was indeed shown to allow for long–term allograft survival in several transplantation models. However, the current continuous identification of new co–stimulatory molecules suggests that a functional redundancy of the system exists and that tolerance to transplantation antigens might be achieved more easily through the combined blockade of two or several co–stimulatory signals. In this review, we analyse the biological effects of the disruption of some co–stimulation pathways in vitro and in vivo and discuss their potential interest for tolerance induction.

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Menne, Stephan, Carol A. Roneker, Brent E. Korba, John L. Gerin, Bud C. Tennant, and Paul J. Cote. "Immunization with Surface Antigen Vaccine Alone and after Treatment with 1-(2-Fluoro-5-Methyl-β-l-Arabinofuranosyl)-Uracil (l-FMAU) Breaks Humoral and Cell-Mediated Immune Tolerance in Chronic Woodchuck Hepatitis Virus Infection." Journal of Virology 76, no. 11 (June 1, 2002): 5305–14. http://dx.doi.org/10.1128/jvi.76.11.5305-5314.2002.

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ABSTRACT Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) were treated with the antiviral drug 1-(2-fluoro-5-methyl-β-l-arabinofuranosyl)-uracil (l-FMAU) or placebo for 32 weeks. Half the woodchucks in each group then received four injections of surface antigen vaccine during the next 16 weeks. Vaccination alone elicited a low-level antibody response to surface antigen in most carriers but did not affect serum WHV DNA and surface antigen. Carriers treated first with l-FMAU to reduce serum WHV DNA and surface antigen and then vaccinated had a similar low-level antibody response to surface antigen. Following vaccinations, cell-mediated immunity to surface antigen was demonstrated in both groups, independent of serum viral and antigen load, but was significantly enhanced in woodchucks treated with l-FMAU and was broadened to include other viral antigens (core, e, and x antigens and selected core peptides). Cell-mediated immunity and antibody responses to surface antigen were observed after drug discontinuation in half of the carriers that received l-FMAU alone. Surface antigen vaccine alone or in combination with drug broke humoral and cell-mediated immune tolerance in chronic WHV infection, but the combination with drug was more effective. This suggested that a high viral and antigen load in carriers is important in maintaining immunologic tolerance during chronicity. The humoral and cellular immunity associated with the combination of l-FMAU and vaccine resembled that observed in self-limited WHV infection. Such combination therapy represents a potentially useful approach to the control of chronic hepatitis B virus infection in humans.

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Kuiper, Johan, and Saskia de Jager. "Vaccination strategies in atherosclerosis." Thrombosis and Haemostasis 106, no. 11 (2011): 796–803. http://dx.doi.org/10.1160/th11-05-0369.

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SummaryThe treatment of atherosclerosis is currently based on lipid lowering in combination with anti-inflammatory therapies that slow the progression of atherosclerosis. Still, we are not able to fully inhibit the formation or progression of atherosclerotic lesions. A very effective strategy in other disease pathologies is vaccination, in which the body is challenged with the culprit protein or micro-organism in order to create a highly specific humoral immune-response. Immunisation can typically be divided into active or passive immunisation. Active immunisation occurs naturally when the body is exposed to certain microbes or antigens, but also artificially in the case of vaccination. Exposure to a microbe or antigen will result in the production of (antigen specific) antibodies. Passive immunisation is defined as the transfer of humoral immunity (as a result of antibody transfer). Another mechanism to ensure immune-protection is tolerance induction. Immune tolerance occurs naturally to prevent immune responses to ‘self-antigens’, but can also be induced to non-self antigens. Acquired tolerance to foreign antigens is accompanied by suppression of cellular and/or humoral immune response to the introduced antigen. In its most effective way, vaccination can result in a lifelong protection against the targeted pathology, and therefore the development of an atherosclerosis-specific vaccination is of high importance in the future prevention of atherosclerosis. One of the difficulties in developing effective vaccination strategies for atherosclerosis is the selection of a specific antigen to target. So far vaccination strategies have been based on targeting of lipidantigens, inflammation-derived antigens, and recently cell-based vaccination strategies have been employed; but also the cardiovascular ‘side-effects’ of infection-based vaccines are worthy of our attention. This review describes the current status-quo on classical antibody associated vaccination strategies but also includes promising immunemodulation approaches that may lead to a clinical application.

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Journal articles on the topic 'Antigen tolerance'

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