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PubMed1997

Acquired transplant tolerance.

Increasing the acceptance rate of organs is the central goal of transplantation research. Long-term survival of vascularized organs without chronic immunosuppressive therapy has been achieved in experimental animals. In humans, the possibility of achieving immunological tolerance and a drug-free state has been reported occasionally in patients who after withdrawal of immunosuppressants because of major toxicity still carry a functioning graft. It has been proposed that organ transplant implies a migratory flux of donor 'passenger' leukocytes out of the graft into the recipient tissue or organs, to establish a persistent condition of 'microchimerism'. Although there is evidence that the same migratory mechanisms apply to all organ grafts, migration of 'passenger' leukocytes is less in kidney and heart than in liver. To enhance the acceptance of organs less tolerogenic than liver, perioperative infusion of donor bone marrow has been attempted to increase the donor 'passenger' leukocyte load. It has been suggested that the established microchimerism is not only associated with long-term acceptance of the graft, but it also plays an active role in induction and maintenance of donor-specific unresponsiveness. However, the intimate mechanism(s) responsible for prolonged graft survival in this setting remain speculative. Experimental evidence is also available that the thymus plays a major role in the development of self-tolerance and is critical in the induction of acquired tolerance to exogenous antigens. It has been reported that after intrathymic injection of donor cells clonal deletion of maturing thymocytes occurs and is the major mechanism in the induction of donor-specific tolerance, since peripheral T-cell component would be devoid of alloreactive population. Studies are warranted in the near future to explore whether the thymus technique can be employed to prolong survival or induce tolerance to allograft in humans. An interesting novel strategy for transplant tolerance is also the oral administration of alloantigens, which has been recently applied to the cardiac transplant model in rat. All these approaches will have a major impact in the near future on transplant medicine, opening new perspectives to obtain indefinite graft survival.

Animals↗
PubMed2001

Some quantitative aspects of T-cell repertoire selection: the requirement for regulatory T cells.

How the adaptive immune system achieves self-non-self discrimination is not well understood, and in this article consideration is given to some of the quantitative aspects of this problem. In particular, the modification of the T-cell repertoire as a result of clonotypic deletion in the thymic cortex is discussed and shown to make a major contribution to the achievement of self-tolerance. An evaluation is also made of the benefit of MHC restriction in preventing clonal deletion in MHC heterozygotes from being more profound than it is in homozygotes, despite the approximately twofold increase in the presentation of self-peptides in the thymus in heterozygotes. The effect that receptor editing may have on the efficiency of positive selection is estimated. Finally, the conclusions from these considerations are used to suggest why a subset of T cells, the regulatory T cells, are required to control immune responses to certain self-antigens. The potential value of regulatory T cells to the control of inflammation induced by pathogens is also briefly discussed.

Animals↗
PubMed1995

Novel packages of viral and self-antigens are generated during apoptosis.

Immune context is an essential determinant of the host response to potential autoantigens. The clustering of the autoantigens targeted in systemic lupus erythematosus within surface blebs of apoptotic cells generates high concentrations of autoantigen within discrete subcellular packages. We demonstrate here that when apoptosis is induced by Sindbis virus infection, viral antigens and autoantigens cocluster exclusively in small surface blebs of apoptotic cells. The surface of these blebs is rich in viral glycoproteins, and virions can be seen blebbing from their surface. We propose that these blebs of mixed foreign and self-origin define a novel immune context that may challenge self-tolerance.

Antigens, Viral↗
PubMed2005

B-cell tolerance checkpoints in healthy humans and patients with systemic lupus erythematosus.

Antibodies are protective effector molecules in the body's immune defense against pathogens. However, if directed against the body's own tissues or organs, antibodies can also play a role in the pathogenesis of autoimmune disease. Here, we discuss our data on how autoreactive antibodies are regulated in healthy humans and how a failure to establish self-tolerance during early B-cell development in patients with systemic lupus erythematosus may predispose to the development of this autoimmune disease.

B-Lymphocyte Subsets↗
PubMed1992

Cellular and molecular mechanisms of B lymphocyte tolerance.

A paradox of immunology is that the immune system is distributed so widely in the body, as a large number of cells that discharge most of their effector functions as single cells; but, at the same time, the elements of the system are so very interdependent, not only via specialized cell clusters and microenvironments, but also by mobile feedback loops, cellular and molecular. The end result is that one cannot really understand one element of the system without understanding every other, at least to a degree. Certainly, tolerance cannot be isolated from immune activation, nor B cell from T cell tolerance, rendering the task of the reviewer somewhat thankless. This being said, the last few years have seen wonderful progress in our grasp of B cell tolerance, to which the transgenic revolution has contributed a great deal. The fact that B cell tolerance exists as an important component of self-tolerance has been firmly established, as have the limits of the process in terms of both the survival of low-affinity antiself clonotypes and the question of location and concentration of antigen required for tolerance induction. Two processes have been identified as key alternatives: clonal abortion/maturation arrest/deletion and induction of clonal anergy. The latter requires a less strong Ig receptor crosslinking signal, may be partial, and is reversible. Recognition of these facts has prompted both experimentation and speculation on possible functions of the anergic cell. One unsatisfactory area, which we have not addressed because nothing like a consensus has been reached, is T cell-mediated suppression and its possible effects on tolerant states, including anergy induction in B cells. The phenomenology of suppression is too striking to sweep under the carpet, and suppressor T cell memory in particular (Adelstein et al., 1990) requires much more investigation; however, suppression has not been shown to play a major role in any of the best-studied transgenic models. These can readily be explained on the basis of direct interactions between the B cell target for abortion or anergy and the self antigen in question. The biochemical basis of discrimination between immunity and tolerance has also progressed, but not as fast. This is understandable, as so many signaling pathways have to come together for full immune induction, and as immaturity of the signal transduction pathway plays a profound role that must be studied in normal cells, with all the attendant difficulties of cell separation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Self-antigen presentation by thymic stromal cells: a subtle division of labor.

Self-antigen-MHC complexes expressed by thymic stromal cells serve as ligands for TCR-mediated positive and negative selection, resulting in a self-MHC-restricted, self-tolerant T cell repertoire. It has recently become apparent that thymic stromal cells differ in their accessibility to antigen as well as their ability to process and present antigen. These differences result in the sampling by thymic stromal cells of largely nonoverlapping self-antigen pools and the display of self-peptide profiles specific for each cell type. In conjunction with single or serial cell-cell interactions between thymocytes and stromal cells, such differences in self-antigen display allow for maximal (re)presentation of 'self' in the thymus and optimize the efficacy of positive and negative selection.

Acute-Phase Proteins↗
PubMed2001

Slow proliferation as a survival advantage: an attempt to resolve a paradox.

A model is proposed for immunological high zone- and self-tolerance that is based on the concept of overstimulation of replication: It is demonstrated that if proliferation is hindered by delayed response to nutritional deficiency, then under competitive conditions slower proliferation can become a survival advantage. This offers a resolution of the paradox that self-antigens promote both positive and negative selection in the development of lymphocytes. It also suggests that maintaining nutrition and caloric intake at a minimal level can prolong the survival of cancer patients if the cancer cells replicate more rapidly than healthy ones.

Cell Division↗
PubMed1989

Tolerance of class I histocompatibility antigens expressed extrathymically.

Although convincing evidence has been obtained for the imposition of self-tolerance by the intrathymic deletion of self-reactive T cells, the development of tolerance to antigens which are expressed only in the periphery is not so well understood. We have approached this question by creating transgenic mice which carry a class I major histocompatibility complex (MHC) gene (H-2Kb) linked to the rat insulin promoter. Mice expressing the transgene develop diabetes, but do not appear to mount an immune response against the transgene-expressing pancreatic beta-cells, even when the transgene is allogeneic with respect to the endogenous host H-2 antigens. We have now explored the mechanism of this tolerance further. We find that spleen cells from pre-diabetic transgenic (RIP-Kb) mice do not kill targets bearing H-2Kb, whereas thymus cells from the same mice do. The unresponsiveness of these spleen cells can be reversed in vitro by providing recombinant interleukin-2 (rIL-2). In older, diabetic mice, responsiveness develops as the pancreatic beta-cells are lost. Our results point to an extrathymic mechanism of tolerance induction, dependent on the continuous presence of antigen and the lack of IL-2 in the local environment of potentially reactive T cells.

Animals↗
PubMed1993

An evaluation of mechanisms by which tolerance to organ-specific antigens is lost using a transgenic mouse model.

Patients with type I diabetes lose immunologic tolerance to beta cell Ag and produce anti-self (beta cell) antibodies. We have examined mechanisms by which this self tolerance is lost using transgenic mice in which islet cells express human CD4. These mice are immunologically tolerant to this human protein; the tolerance appears to be characterized by the presence of self reactive B cells and nonresponsive T cells. Autoantibodies can be induced by immunization with CD4 in CFA; this autoantibody response is accompanied by minor peri-islet inflammation but diabetes is not induced. Tolerance can also be broken by provision of an independent covalently linked T cell epitope. Although this mimic can lead to the appearance of an autoantibody response, the autoimmune response can not be maintained by the endogenous Ag. We have also demonstrated that an inflammatory lesion leading to death of the CD4-containing beta cells may not be sufficient to break tolerance. These results have implications for potential mechanisms relating to the appearance of autoantibodies in patients with type I diabetes.

Animals↗
PubMed1995

Breaking tolerance leads to autoantibody production but not autoimmune liver disease in hepatitis B virus envelope transgenic mice.

Hepatitis B virus (HBV) transgenic mice containing the HBV envelope open reading frame under the transcriptional control of the mouse albumin promoter express hepatitis B surface Ag (HBsAg) in all of their hepatocytes and secrete HBsAg (10 to 40 ng/ml) into the circulation. Because these transgenic mice show no signs of spontaneous liver cell injury or autoimmunity toward the viral (self-) Ag, we asked whether the state of self-tolerance could be reversed by the induction of an acute necroinflammatory liver disease or by immunization with HBV envelope proteins, with the aim of creating a transgenic model for chronic, immune-mediated hepatitis. Our studies indicate that repetitive administration of bacterial LPS, IFN-gamma, or HBsAg-specific CTL, all of which were previously shown to cause liver cell injury and inflammation, does not break tolerance at the T or B cell level, suggesting that the intrahepatic lymphomononuclear cell infiltrate induced by these agents consists of HBsAg-nonspecific cells. The adoptive transfer of HBsAg-primed nontransgenic CD4+ T cells into transgenic mice did not induce anti-HBs autoantibody production by transgenic B cells, even though transgenic B cells were fully responsive to immunization with HBsAg when appropriate T cell help was provided in a nontransgenic environment. Immunization of transgenic mice with purified HBsAg in CFA and repetitive infection with rHBV envelope vaccinia virus led to production of T cell-dependent anti-HBs autoantibodies that cleared HBsAg from the serum, but not to activation of HBsAg-specific CTL. We conclude that HBV envelope transgenic mice are largely tolerant to the transgene product at the T cell but not at the B cell level, and that the activation of an anti-HBs response was not sufficient to induce an autoimmune liver disease in this HBV envelope transgenic mouse model.

Animals↗
PubMed2004

Systemic administration of antigen-loaded CD40-deficient dendritic cells mimics soluble antigen administration.

The decision to mount a T cell response to antigen (Ag) is dependent on the cellular context in which the Ag is presented. Activated dendritic cells (DC) are potent stimulators of immune responses, an ability which is linked to their high expression of several costimulatory molecules. In contrast, resting DC have been implicated in the generation of self tolerance, presumably due to their reduced costimulatory capacity. However, the precise molecular basis for the choice between Ag-induced immunity and unresponsiveness remains unclear. We show here that CD40 plays an important rolein this decision. Systemic administration of Ag-loaded, CD40-deficient DC failed to induce a productive primary T cell expansion and rendered mice relatively unresponsive to subsequent immunization with Ag in adjuvant. Using a TCR-transgenic T cell transfer system, we found that CD40(-/-) DC triggered an initial T cell activation that could not be sustained, resulting in loss of Ag-reactive T cells and reduced cytokine production by those T cells that did persist. Furthermore, administration of CD40(-/-) DC that had been loaded with a central nervous system autoantigen was found to protect mice from autoimmune pathology. These data implicate the CD40:CD40L interaction as a key checkpoint in the development of T cell immunity rather than tolerance.

Animals↗
PubMed2001

Thymus and tolerance. Is regulation the major function of the thymus?

This paper will serve as a contribution to the current reassessment of the relative roles of clonal selection and regulation in specific immunologic tolerance. We review basic studies in the Waksman laboratory that first established the importance of the thymus in tolerance and the possible contribution of regulatory cells generated in the thymus to self-tolerance. Experimental evidence is presented to suggest that there exists a wide range of immunoregulatory mechanisms, many of which deserve more intensive investigation in relation to the tolerance question. These include regulation based on idiotype-specific recognition, multiple forms of immune deviation, two well-described and quite distinct forms of T-cell receptor alphabeta "suppressor cell", and several regulatory systems involving multiple cells acting in concert. We do not comment on more recently described regulatory cells, such as certain gammadelta T-cell subsets, natural killer T cells, CD4-CD8- T cells, and others. Basic studies in our laboratory and in other laboratories pointed to antigen-presenting cells (APC) generated in the thymus as possible mediators of tolerance. Certain cytokines, first described in our laboratory, including lymphotoxin and the "inhibitor of DNA synthesis" produced by T cells and interleukin-1 produced by macrophages, also may act as significant components of regulatory systems. The rapid entry of exogenous and self-antigens into the thymus and the free migration of specific regulatory T cells and of APC in both directions between thymus and periphery are also stressed.

Animals↗
PubMed2006

Influence of p53 on anti-tumor immunity (review).

Self-tolerance and tumor-induced peripheral tolerance may be responsible for the limitations of the immune system in controlling tumor growth in cancer patients. It is known, that self-proteins are continuously processed and presented by antigen presenting cells. During development, auto-reactive T cells encountering self peptide/self-MHC complexes are being eliminated in the thymus. This process called 'negative selection' results in the removal of nascent auto-reactive T cells thus preventing an autoimmune attack of our own tissues. Many self-peptides (e.g. parts of p53), despite their high affinity for self-MHC, remain cryptic in the thymus and do not mediate cell deletion. Under conditions that favor up-regulation of cryptic self-determinants, one or more of these subsets of the 'protected' T cell repertoires, can be stimulated by these self-determinants, leading to induction of autoreactivity. The latter could eventually result in auto-immunity under permissive conditions governed by MHC and non-MHC genes. Thus, considering tumor tissue a 'modified self-tissue', this process that may have evolved to prevent excessive purge of the T cell repertoire, providing the potential for the development of autoimmune responses and therefore for anti-cancer therapy in adults.

Animals↗
PubMed2004

Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger.

Stimulation of certain cytokine and pattern recognition receptors enhances adaptive immune responses, and in chronic situations, may play a role in the loss of self-tolerance. We hypothesized that in addition to upregulating positive immune receptors (i.e. co-stimulatory molecules), certain cytokine and pattern recognition signals might downregulate negative immune receptors, removing a potential barrier to lymphocyte responsiveness. The newly identified CD28 family member Programmed Death-1 (PD-1) is an inhibitory receptor involved in peripheral tolerance, as evidenced by the frank autoimmunity and autoantibody formation found in PD-1-deficient mice. Here we report that antigen-receptor induced PD-1 expression on murine B cells is markedly reduced by certain signals associated with immune system danger, including LPS, CpG oligodeoxynucleotides and several pro-inflammatory cytokines, through distinct signaling pathways. We further report for the first time that engagement of PD-1 inhibits cell cycle progression in primary B cells and that modulation of PD-1 expression by CpG or IL-4 significantly reverses such inhibition. Our data suggest a novel mechanism for enhancement of normal immune responses and disruption of normal tolerance mechanisms.

Animals↗
PubMed1996

Interferon-gamma in autoimmunity.

Autoimmune disorders are characterized by abrogation of self-tolerance, resulting in emergence of activated self-reactive lymphocyte clones that trigger or maintain inflammatory reactions in specific organs. Interferon-gamma (IFN-gamma), as well as other cytokines, plays an important role as a regulator of the activation of self-reactive lymphocytes and of bystander and accessory cells that are involved in the autoimmune inflammatory response. In experimental models of autoimmunity, endogenous IFN-gamma has invariably been found to profoundly affect the disease course. However, it acts in one way in some diseases and in the opposite way in others.

Animals↗
PubMed2004

Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection.

Regulatory T (T(R)) cells consist of phenotypically and functionally distinct CD4(+) and CD8(+) T cell subsets engaged both in maintaining self-tolerance and in preventing anti-non-self effector responses (microbial, tumor, transplant, and so on) that may be harmful to the host. Here we propose that the proinflammatory function of virus-specific memory effector CCR7(-)CD8(+) T cells, which are massively recruited in the liver, are inefficient (in terms of IFN-gamma production) in patients with chronic hepatitis C virus (HCV) infection because of the concomitant presence of virus-specific CCR7(-)CD8(+) T(R) cells producing considerable amounts of IL-10. These CD8(+) T(R) cells are antigen specific, as they can be stimulated by HCV epitopes and suppress T cell responses that are in turn restored by the addition of neutralizing anti-IL-10. This study provides for the first time to our knowledge direct evidence of the existence of virus-specific CD8(+) T(R) cells that infiltrate the livers of patients with chronic HCV infection, identifies IL-10 as a soluble inhibitory factor mediating suppression, and suggests that these cells play a pivotal role in controlling hepatic effector CD8(+) T cell responses.

Adult↗
PubMed2002

[Regulatory phenomena in tolerance induction].

The implication of regulatory T cells in self-tolerance induction was shown in experimental models based on construction of thymic chimera and peripheric T cell transfers. The role played by the epithelial stroma of the thymus in CD4+ regulatory T cell selection was demonstrated. In the NOD (Non Obese Diabetic) strain, protection again diabetes was obtained by grafting supplementary thymuses injected with allogeneic pancreatic islets. This result suggest that the NOD thymuses are defective in the production of T regulatory cells.

Animals↗
PubMed1982

The specificity of in vivo tolerance to haptens in NZB and normal mice after exposure to hapten-modified syngeneic spleen cells.

We have evaluated hapten-specific hyporesponsiveness induced by in vivo administration of TNP-modified syngeneic spleen cells (TNP-SC). Pretreatment of non-autoimmune mice led to hyporesponsiveness to challenge with either TNP or the closely related hapten DNP coupled to Ficoll. There was also a significant reduction of the direct PFC response after challenge with TNP-HGG. In tolerized mice challenged with TNP-HGG, the IgM portion of the serum response was similarly suppressed; however, the total serum antibody as well as the indirect PFC response was not suppressed. There was no tolerance at all when the mice were challenged with DNP-HGG. Thus, exposure to TNP-SC results in an incomplete form of hapten-specific B cell tolerance. This tolerance is selective for the IgM isotype and does not extend to the cross-reactive hapten DNP on a thymic-dependent carrier, although it does extend to a DNP on a thymic-independent carrier. Autoimmune NZB mice were defective with regard to tolerance after injection of hapten-modified syngeneic spleen cells. They did manifest a reduced direct PFC response to the challenge with TNP-Ficoll, but failed to demonstrate cross-tolerance to DNP-Ficoll challenge. Moreover, they did not have suppression of the hapten-specific IgM response after challenge with TNP on the thymic-dependent carrier. These abnormalities in tolerance induction in NZB mice to modified self may help to explain the loss of self-tolerance that occurs spontaneously and is expressed as autoimmune disease.

Animals↗