Mechanisms in immune tolerance

Self:nonself-discrimination is critical for the function of the immune system and survival of vertebrate species. The failure to respond to one's own antigens has been called self-tolerance. The mechanisms whereby such tolerance may be induced are reviewed herein. Emphasis is placed on the role of self-recognition involving suppressor T-cell pathways as well as on studies involving putative clonal deletion mechanisms. The important parameters for the induction of tolerance and the roles played by surface isotypes in discriminating immunogenic vs. tolerogenic signals will be emphasized. The possible involvement of multiple pathways for self or experimental tolerance is emphasized with the ultimate goal being the modulation of aberrant immune responses.     

Mechanisms of peripheral tolerance to allergens

The immune system is regulated to protect the host from exaggerated stimulatory signals establishing a state of tolerance in healthy individuals. The disequilibrium in immune regulatory vs effector mechanisms results in allergic or autoimmune disorders in genetically predisposed subjects under certain environmental conditions. As demonstrated in allergen‐specific immunotherapy and in the healthy immune response to high‐dose allergen exposure models in humans, T regulatory cells are essential in the suppression of Th2‐mediated inflammation, maintenance of immune tolerance, induction of the two suppressive cytokines interleukin‐10 and transforming growth factor‐β, inhibition of allergen‐specific IgE, and enhancement of IgG4 and IgA. Also, suppression of dendritic cells, mast cells, and eosinophils contributes to the construction of peripheral tolerance to allergens. This review focuses on mechanisms of peripheral tolerance to allergens with special emphasis on recent developments in the area of immune regulation.     

Mechanisms of immune tolerance induction through the thymic expression of a peripheral tissue-specific protein

A major process through which the immune system becomes tolerantto self proteins involves the deletion of self reactive cellsin the thymus. However, T cells reactive to peripheral tissue-specificproteins can escape this deletion and become tolerized in theperiphery by a variety of mechanisms. We report here, contraryto expectation, that the pancreas-specific protein, elastaseI, is also expressed at a low level in the thymus, and thatthis thymic expression contributes to tolerance induction. Tostudy the mechanism of this tolerance induction, we utilizeda double transgenic mouse model. In these mice the expressionof a model protein, SV40 T antigen, is directed by the elastaseI promoter and hence parallels elastase I expression in thepancreas and thymus. These mice were crossed with mice transgenicfor a TCR specific for T antigen, so the majority of thymocytesand T cells in these mice express the transgene. In double transgenicmice we find that thymic expression of T antigen results inanergic thymocytes which also show a reduction of T_h1 activitywith no decrease in T_h2 activity. These functional characteristicspersist in peripheral T cells, but there is also a depletionin the number of T antigen reactive T cells In lymph nodes.Chimeras were constructed which directly demonstrated that thethymus is the site of tolerance induction and that the tolerizingelement is thymic epithelium. We propose that the loss of T_h1activity as a consequence of the thymic epithelium being encounteredby tissue-specific proteins results in the functional tolerizationof CTL in vivo, despite the fact that CTL are fully functionalin vitro. In this way autoimmune destruction is contained. Thymicexpression of peripheral proteins may therefore be an additionalway in which tolerance to peripheral proteins can be achieved.     

Mechanisms of immune tolerance relevant to food allergy

The intestine has an unenviable task: to identify and respond to a constant barrage of environmental stimuli that can be both dangerous and beneficial. The proper execution of this task is central to the homeostasis of the host, and as a result, the gastrointestinal tract contains more lymphocytes than any other tissue compartment in the body, as well as unique antigen-presenting cells with specialized functions. When antigen is initially encountered through the gut, this system generates a robust T cell-mediated hyporesponsiveness called oral tolerance. Although seminal observations of oral tolerance were made a century ago, the relevant mechanisms are only beginning to be unraveled with the use of modern investigational techniques. Food allergy is among the clinical disorders that occur from a failure of this system, and therapies that seek to re-establish tolerance are currently under investigation.     

Central and peripheral autoantigen presentation in immune tolerance

Recent studies in both humans and experimental rodent models provide new insight into key mechanisms regulating tolerance to self-molecules. These recent advances are bringing about a paradigm shift in our views about tolerance to self-molecules with tissue-restricted expression. There is, indeed, mounting evidence that selected antigen-presenting cells (APCs) have the ability to synthesize and express self-molecules, and that such expression is critical for self-tolerance. Insulin is a key hormone produced exclusively by pancreatic beta-cells and a critical autoantigen in type 1 diabetes. It provides an excellent example of a molecule with tissue-restricted expression that is expressed ectopically by APCs. The fact that APCs expressing insulin have been demonstrated in both thymus and peripheral lymphoid tissues suggests that they may play a role in insulin presentation in both the central and peripheral immune system. Experimental mice, in which insulin expression was altered, provide functional data that help to dissect the role of insulin presentation by APCs of the immune system. This review addresses recent literature and emerging concepts about the expression of self-molecules in the thymus and peripheral lymphoid tissues and its relation to self-tolerance.     

Mechanisms of immune regulation in the peripheral nervous system

The peripheral nervous system (PNS) is a target for heterogenous immune attacks mediated by different components of the systemic immune compartment. T cells, B cells, and macrophages can interact with endogenous, partially immune-competent glial cells and contribute to local inflammation. Cellular and humoral immune functions of Schwann cells have been well characterized in vitro. In addition, the interaction of the humoral and cellular immune system with the cellular and extracellular components in the PNS may determine the extent of tissue inflammation and repair processes such as remyelination and neuronal outgrowth. The animal model experimental autoimmune neuritis (EAN) allows direct monitoring of these immune responses in vivo. In EAN contributions to regulate autoimmunity in the PNS are made by adhesion molecules and by cytokines that orchestrate cellular interactions. The PNS has a significant potential to eliminate T cell inflammation via apoptosis, which is almost lacking in other tissues such as muscle and skin. In vitro experiments suggest different scenarios how specific cellular and humoral elements in the PNS may sensitize autoreactive T cells for apoptosis in vivo. Interestingly several conventional and novel immunotherapeutic approaches like glucocorticosteroids and high-dose antigen therapy induce T cell apoptosis in situ in EAN. A better understanding of immune regulation and its failure in the PNS may help to develop improved, more specific immunotherapies.     

卵清蛋白免疫耐受因子转移免疫耐受活性的研究

目的:探讨卵清蛋白免疫耐受因子(OVA immune tolerance factors,OVA ITFs)转移抗原特异性外周免疫耐受的特性.方法:分别从OVA耐受鼠或空白小鼠的脾淋巴细胞裂解液中分离分子量小于3 kD的组分,即为OVA ITFs或OVA ITFscontorol.试验BALB/c小鼠分成5组,A、B、C、D组经尾静脉分别注射OVA ITFs、OVA ITFs control、OVA耐受鼠脾淋巴细胞或PBS给正常BALB/c小鼠,E组不做任何处理.流式细胞术检测转移前后受体鼠脾脏CD4+CD25+T细胞亚群的比例变化,MTT法检测受体鼠OVA特异性T淋巴细胞的增殖情况,夹心ELISA法测定培养上清中IL-10、TGF-β1的水平.结果:转移OVA ITFs或OVA耐受鼠脾淋巴细胞后,受体鼠脾脏CD4+CD25+T细胞亚群在总CD4+T细胞的比例分别为(15.32±1.03)%和(15.35±0.62)%,与转移前(9.97±1.38)%相比显著上升(P＜0.05);OVA特异性淋巴细胞增殖刺激指数(Stimulation Index,SI)分别为0.699±0.05和0.704±0.03,与PBS对照组(1.356±0.07)相比明显受到抑制(P＜0.05);培养上清中TGF-β1的分泌量分别为129.15±6.14和106.71±2.89 pg/ml,显著高于PKS对照组(52.82±3.68 pg/ml,P＜0.01),IL-10分泌量未检出.转移OVA ITFscontrol后,受体小鼠的CD4+CD25+T细胞比例、OVA特异性淋巴细胞增殖及TGF-β1、IL-10分泌量均无显著变化.结论:OVAITFs具有将OVA特异性免疫耐受传递给正常受体小鼠的特性.     

Mechanisms of immune tolerance to food antigens in humans.

Immune responses and the mechanisms of tolerance to the common dietary antigens bovine gamma globulin (BGG), ovalbumin (OVA), and soybean protein were evaluated in normal human volunteers. Humoral and T cell proliferative responses to these antigens were measurable but low, consistent with immune tolerance. There were limited correlations between responses in the systemic and mucosal compartments, and in general the responses to one dietary antigen could not predict the response to another. T cell proliferation to dietary antigens increased significantly by addition of recombinant human interleukin-2 (rhuIL-2). Peripheral blood mononuclear cells stimulated with BGG or OVA expressed IL-2Ralpha chain but not IL-2 mRNA, consistent with T cell anergy. Incubation with exogenous IL-2 alone did not restore T cell proliferation to BGG or OVA. In some individuals T cell proliferation to an unrelated vaccine antigen was suppressed by addition of BGG or OVA, but could be reversed with low doses of rhuIL-2. We conclude that in humans anergy is the major mechanism of tolerance to chronic antigen feeding, and we propose that such anergic, antigen-specific T cells actively contribute to maintenance of homeostasis in the intestine in the face of massive antigen challenge.     

Mechanisms of allergic sensitization to foods: bypassing immune tolerance pathways

The default response of the mucosal immune system to antigens derived from food is one of active immune tolerance carried out by regulatory T cells and induced by dendritic cells residing in the intestinal mucosa. This tolerance response must be inhibited or bypassed to generate allergic sensitization in experimental food allergy and this has been achieved by 3 main approaches: genetic modifications, experimental adjuvants, and bypassing oral tolerance by administering the antigen through alternative routes. This article discusses the implications of these approaches for understanding the mechanisms of sensitization to food allergens in human disease.     

Analysis of peripheral immune tolerance uncovers a mouse strain-dependent in situ type of graft tolerance

We screened various mouse strains [C57BL / 6, BALB / c, DBA / 2, CBA / Ca, (CBAxC57L / 6)F1, SJL, C3H] for induction of peripheral immune tolerance. Only CBA / Ca mice treated with anti-CD4 + CD8 monoclonal antibodies and grafted with allogeneic skin showed long-term graft survival (150 to > 200 days). Interestingly, T cells from the tolerant CBA / Ca mice rejected bone marrow / spleen cells of the skin graft donor strain and caused lethal graft-versus-host disease when transplanted to the donor strain. Furthermore, peripheral tolerance was easily broken: CBA / Ca mice could be reactivated to reject their tolerated grafts via immunization with (graft donor x recipient strain)F1 bone marrow cells. Thus, in contrast to the generalized nature of central tolerance, our experiments show that peripheral immune tolerance is strain dependent and locally restricted to graft tissue.     

Mechanisms preventing allergen-induced airways hyperreactivity: role of tolerance and immune deviation

BACKGROUND: Aeroallergens continuously enter the respiratory tract of atopic individuals and provoke the development of asthma characterized by airway hyperreactivity (AHR) and inflammation. By contrast, nonatopic individuals are exposed to the same aeroallergens, but airway inflammation does not develop. However, the mechanisms that prevent allergen-induced respiratory diseases in nonatopic subjects are poorly characterized. OBJECTIVE: In this study we compared the role of allergen-specific T-cell tolerance and immune deviation in conferring protection against the development of allergen-induced AHR. METHODS: We exposed mice to intranasal ovalbumin (OVA) to induce T-cell tolerance and examined its effects on the subsequent development of AHR and inflammation. RESULTS: We demonstrated that exposure of mice to intranasal OVA resulted in peripheral CD4(+) T-cell unresponsiveness that very efficiently prevented not only the development of AHR but also greatly inhibited airway inflammation and OVA-specific IgE production. The induction of peripheral T-cell tolerance and protection against AHR were not dependent on the presence of IFN-gamma or IL-4. The development of AHR was also prevented by an OVA-specific T(H)1-biased immune response induced by inhalation of OVA in the presence of IL-12. However, the OVA-specific T(H)1 response was associated with a significant degree of pulmonary inflammation. CONCLUSION: These results indicate that both allergen-specific T-cell tolerance and T(H)1-biased immune deviation prevent the development of AHR, but T(H)1 responses are associated with significantly greater inflammation in the lung than is associated with T-cell unresponsiveness. Therefore CD4(+) T-cell unresponsiveness critically regulates immune responses to aeroallergens and protects against the development of allergic disease and asthma.     

Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance

The lack of immune response to an antigen, a process known as immune tolerance, is essential for the preservation of immune homeostasis. To date, two mechanisms that drive immune tolerance have been described extensively: central tolerance and peripheral tolerance. Under the new nomenclature, thymus-derived regulatory T (tT_reg) cells are the major mediators of central immune tolerance, whereas peripherally derived regulatory T (pT_reg) cells function to regulate peripheral immune tolerance. A third type of T_reg cells, termed iT_reg, represents only the in vitro-induced T_reg cells¹. Depending on whether the cells stably express Foxp3, pT_reg, and iT_reg cells may be divided into two subsets: the classical CD4⁺Foxp3⁺ T_reg cells and the CD4⁺Foxp3⁻ type 1 regulatory T (Tr1) cells². This review focuses on the discovery, associated biomarkers, regulatory functions, methods of induction, association with disease, and clinical trials of Tr1 cells.     

Mechanisms of antigen-induced blockade of immune response and cyclophosphamide-promoted tolerance to Salmonella typhi Vi antigen

Blockade of the immune response, caused by a high dose of Salmonella typhi Vi antigen (200 microgram i.v.) and cyclophosphamide (CY)-induced tolerance to Vi antigen, were analyzed. The results of the study show that blockade of the immune response cannot be attributed to masking of the response resulting from neutralization of antibodies by the excess of non-cell-bound antigen. A high dose of Vi-antigen induced triggering and proliferation of specific B precursors but reversibly suppressed synthesis or secretion of antibody by plaque-forming cells. A single injection of CY (200 mg/kg i.p.) 2 days after a high dose of Vi antigen markedly prolonged the antigen-induced state of unresponsiveness. CY-induced tolerance to Vi antigen is due to elimination or long-term inactivation of specific B precursors. Dissimilarities in the characteristics of immune response blockade and CY-induced tolerance are discussed as well as their possible implications for the mode of action of CY.     

关于免疫耐受的重新思考

传统免疫学认为机体免疫系统对“自身”及“异己”的识别是免疫学的中心内容。本文对经典的免疫耐受概念作了重新认识，扩大其内涵及外延，提出免疫耐受与不耐受为免疫应答的两个重要方面，如果对免疫耐受有一个清楚的认识，有可能对整个免疫学有一个新的认识并使免疫学的发展呈现新的面貌。     

Mechanisms of tolerance to self

Several mechanisms exist to prevent lymphocytes from reacting against self-antigens. As T cells develop in the thymus and express antigen-specific receptors, those with high-affinity to self-antigens existing within the thymus are deleted. Low-affinity self-reactive T cells and T cells with receptors against antigens not represented intrathymically will mature and join the peripheral T cell pool. They may either ignore self-antigens expressed by tissues unable to activate T cells through a lack of the appropriate costimulator signals, or they may, under certain conditions, be deleted or rendered anergic and unable to respond. Likewise, B cells that express surface Ig receptors with high binding affinity to membrane-bound self-antigens present in the bone marrow will be rescued by receptor editing or will be deleted, whereas those of lower affinity will migrate to the periphery in either an anergic or indifferent state depending on the degree of receptor engagement by antigen. Once there, their ultimate fate is determined by the availability of T cell help.     

Mechanisms of self tolerance.

The redundancy of biological systems minimizes the probability that isolated molecular and cellular defects entail deleterious consequences. This notion also applies to the establishment and maintenance of tolerance to self antigens. Thus, immune homeostasis is attributed to multiple distinct safety valves that are connected in series and intervene at defined control points of the life cycle of the developing lymphocyte to guarantee the physical elimination, functional inactivation, or regulated inhibition of self-reactive, potentially autoaggressive, B and T cells.     

HLA-G与免疫耐受

HLA-G是一种非经典人类主要组织相容性复合物Ⅰ类分子,与器官移植、生殖及肿瘤等多种免疫反应有关,是引起免疫耐受的一种因子.