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Results for “Self Tolerance”

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At least 199 records · Page 11Linked to original sources
PubMed1996

Interleukin-2 is indispensable for development of immunological self-tolerance.

Interleukin-2-deficient mice (IL-2(-/-)) manifest severe immune system abnormalities characterized by an uncontrolled activation and proliferation of lymphocytes. A systemic autoimmune syndrome results, and hemolytic anemia leads to early death especially in mice derived from a BALB/c genotype. Remarkably, IL-2 treatment prevents both the activation of the immune system and the development of autoimmune disease. Moreover, adoptive transfer of lymphocytes from IL-2-treated IL-2(-/-) animals confers protection to IL-2(-/-) mice, suggesting that IL-2 induces a postnatal differentiation/maturation of regulatory cells necessary for self- and non-self-discrimination.

Anemia, Hemolytic, Autoimmune↗
PubMed2002

Bacterial motif DNA as an adjuvant for the breakdown of immune self-tolerance to pyruvate dehydrogenase complex.

Bacterial DNA containing unmethylated CpG dinucleotide motifs is immunostimulatory to mammals, skewing CD4(+) T-cell responses toward the Th1 phenotype. Autoreactive T-cell responses seen in primary biliary cirrhosis (PBC) are typically of the Th1 phenotype, raising the possibility that bacterial DNA might play a role in the generation of pathologic autoimmunity. We therefore studied the effects of CpG motif-containing oligodeoxynucleotides (ODN) on responses to pyruvate dehydrogenase complex (PDC, the autoantigen in PBC) in a murine model. Sensitization of SJL/J mice with non-self-PDC has been shown to result in induction of autoreactive T-cell responses to PDC sharing characteristics with those seen in patients with PBC. Administration of CpG ODN to SJL/J mice at the time of sensitization with PDC resulted in a significant skewing of splenic T-cell response to self-PDC, with significant augmentation of the Th1 cytokine response (interleukin [IL] 2 and interferon [IFN] gamma) and reduction of the Th2 response (IL-4 and IL-10). In fact, CpG ODN seemed to be more effective at biasing the response phenotype and as effective at inducing liver histologic change as complete Freund's adjuvant (CFA), the standard adjuvant used for induction of Th1 responses in murine autoimmune and infectious immunity models. In conclusion, our findings raise the possibility that bacteria play a role in the development of autoimmunity (in PBC at least) through the potential of their DNA to shift the T-cell responses toward the phenotype associated with autoimmune damage. Moreover, this study suggests caution in the therapeutic use of CpG ODN as vaccine adjuvants.

Adjuvants, Immunologic↗
PubMed2004

Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis.

Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4(+) T cells are selectively activated in the adventitia of affected arteries. In human GCA artery-severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83(+) dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia-media border. Adoptive T cell transfer into temporal artery-SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II-matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.

Adoptive Transfer↗
PubMed2001

Immune self-tolerance mechanisms.

Tolerance of both T and B cells to self-antigens can be achieved through a great variety of different routes, at the level of the primary lymphoid organs (thymus and bone marrow) and throughout the secondary lymphoid tissues. Whether self-reactive lymphocytes ignore their target autoantigen, or are tolerized by the various mechanisms discussed, depends on the circumstances.

Animals↗
PubMed1995

Breakdown of self-tolerance by intrathymic injection of a T-cell line inducing autoimmune gastritis in mice.

Autoimmune gastritis (AIG) develops spontaneously in BALB/c mice thymectomized 3 days after birth (3d-Tx). We first confirmed our previous observations that CD4+ splenic T cells in AIG mice induced AIG in nu/nu mice, while those in normal mice suppressed the development of the disease. In addition, we found that a quantitative balance between these effector (Te) and suppressor (Ts) T cells determined either onset or prevention of the disease. Peripheralization of Ts seemed to begin around 3 days after birth, since the incidence of AIG in mice that underwent Tx 6 days after birth (6d-Tx) decreased markedly, compared with that of 3d-Tx mice; 12% in the former, while 79% in the latter. Notably, Ts existed in the 6d-Tx mice that escaped AIG. We next examined the target specificity of such Ts using syngeneic parietal cells known as autoantigens and two kinds of T-cell lines established from an AIG mouse; one is gastritis inducible in vivo, termed A-II, while another is not, named AC-II. Intrathymic injection of parietal cells into mice 3 days after birth followed by 6d-Tx completely prevented the development of AIG. In contrast, injection of irradiated A-II, but not AC-II cells resulted in AIG in 67% of the mice. No autoimmune oophoritis (AIO) was induced in female mice, implying that the breakdown of tolerance is organ specific. Taken together, peripheral tolerance for organ-specific autoantigens seems to be maintained by CD4+ Ts responding to Te, which induces the disease.

Animals↗
PubMed1996

Mouse models of autoimmune disease suggest that self-tolerance is maintained by unresponsive autoreactive T cells.

Multiple organ-localized autoimmune diseases, such as thyroiditis and gastritis, spontaneously develop in BALB/c nu/nu (nude) mice receiving embryonic rat thymus grafts (TG) under their renal capsules (TG nude mice). When thyroid was grafted into the rat thymus of TG nude mice, development of autoimmune thyroiditis, but not other diseases, was completely prevented. However, when such mice received thyroid antigen plus complete Freund's adjuvant (CFA), severe autoimmune thyroiditis developed, suggesting that some thyroid-specific autoreactive T cells migrate into the periphery, but remain unresponsive. Development of autoimmune diseases, including thyroiditis, in TG nude mice was prevented by a single intraperitoneal injection of splenic CD4+ cells from normal BALB/c mice and also from mice with intrathymic thyroid grafts, indicating that thyroid-specific suppressor T cells are present in normal mice and that such T cells are neither deleted nor inactivated by the intrathymic thyroid grafts, in contrast to autoreactive T cells. Thus clonal deletion in the thymus, and clonal anergy and/or ignorance in the periphery, of autoreactive cells is important to maintain immune tolerance to organ-specific antigen, but CD4 suppressor T cells may play a more important role in tolerance, and the failure of education of this population may cause autoimmune diseases in the TG nude mouse model.

Animals↗
PubMed2005

Thymic cortical epithelium induces self tolerance.

Because of its role in positive selection, the ability of cortical epithelium to induce tolerance is controversial. On the one hand, experiments with transplanted thymuses showed that the recipients were functionally tolerant of all the antigens expressed by the cells of those thymuses, including cells of the cortical epithelium. On the other, the keratin 14 (K14) transgenic mouse strain, which expresses MHC class II on cortical epithelium under the control of the K14 promoter, does not seem to be tolerant of the transgenic MHC molecule. Here we tested whether the lack of tolerance in the K14 mouse might be more apparent than real. We found that K14 mice are indeed completely tolerant of K14 cortical thymic epithelium, whereas they remain reactive to tissues that express the same MHC allele under normal genetic control. These results establish the ability of cortical epithelium to induce central tolerance, and impinge on several of the models concerning positive selection of newly developing T cells.

Animals↗
PubMed1994

Capacity of simian virus 40 T antigen to induce self-tolerance but not immunological privilege in the anterior chamber of the eye.

Transgenic mice bearing the simian virus 40 (SV40) large T oncogene developed progressively growing intraocular tumors and displayed characteristics of immunological tolerance to SV40 T antigen. Transgenic mice failed to mount CTL responses to SV40 T antigen-bearing tumor cell lines derived from the transgenic intraocular tumors. Spleen cells from transgenic hosts were able to prevent the in vivo and in vitro generation of CTL responses by lymphocytes from normal syngeneic FVB/N mice. Adoptive transfer of spleen cells from tolerant transgenic donors temporarily inhibited the immunological rejection of SV40 T antigen-positive tumor cells transplanted to normal syngeneic FVB/N recipients. Thus, introduction of SV40 transforming sequences into the mouse germline induced tolerance to SV40 T antigen. However, in normal FVB/N mice, SV40 T antigen-bearing tumor cells failed to experience immune privilege in the anterior chamber and did not elicit systemic down-regulation of delayed-type hypersensitivity responses that characteristically occur when antigens are introduced into the anterior chamber. The results indicate that within the anterior chamber of the eye, SV40 T antigen-bearing cells are perceived by the host's immune system much differently than are other categories of antigen. Thus, SV40 T antigen effectively induces self-immunological tolerance when its gene is introduced into the host's germline but fails to experience immunological privilege in the anterior chamber of the eye in normal hosts.

Animals↗
PubMed2004

Virus-induced activation of self-specific TCR alpha beta CD8 alpha alpha intraepithelial lymphocytes does not abolish their self-tolerance in the intestine.

TCRalphabeta CD8alphaalpha intestinal intraepithelial lymphocytes (IEL) represent an enigmatic subset of T cells, particularly, in regard to their potential functions and the apparent persistence of cells expressing self-specific TCR. We have used mice that are transgenic for the TCRalphabeta specific for the lymphocytic choriomeningitis virus (LCMV)-derived peptide gp33, and TCRalphabeta-transgenic mice that coexpress the gp33 Ag ubiquitously, to analyze the functional properties of TCRalphabeta CD8alphaalpha IEL in the presence, or absence, of their specific MHC-restricted Ag, and to assess the impact of molecular mimicry during a potent LCMV infection on potentially self-reactive TCRalphabeta CD8alphaalpha IEL. In this study, we show that the presence of the specific self-Ag results in reduced expression of IL-2, IFN-gamma, and IL-10 by resident TCRalphabeta CD8alphaalpha IEL while expression of mRNA for TGFbeta is not affected. We further demonstrate that despite their secluded location in the epithelium, TCRalphabeta CD8alphaalpha IEL are activated after infection of the intestinal mucosa with LCMV. Importantly, LCMV-induced activation of self-specific TCRalphabeta CD8alphaalpha IEL does not reverse their tolerance as no cytotoxic activity or up-regulated expression of proinflammatory cytokines is detected and no overt signs of autoimmunity are seen. Taken together, these results are in support of an immunoregulatory role for self-specific TCRalphabeta CD8alphaalpha in the intestinal mucosa and clearly speak against an involvement of this cell subset in inflammatory reactions and tissue destruction.

Animals↗
PubMed2006

Immunosurveillance of Erbb2 carcinogenesis in transgenic mice is concealed by a dominant regulatory T-cell self-tolerance.

To assess the role of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells in overcoming immunosurveillance of Erbb2 (HER-2/neu) mammary lesions, we studied the effects of their sustained removal in BALB/c female mice made transgenic for the rat Erbb2 (r-Erbb2) oncogene (BALB-neuT mice), which develop multiple mammary carcinomas. During the progression of these lesions, Treg cells expand in the spleen, tumor draining lymph nodes, and tumors. Repeated administration of anti-CD25 antibodies extends tumor-free survival, reduces carcinoma multiplicity, and leads to the manifestation of a natural antibody and CTL-mediated reactivity against r-Erbb2. Loss of Foxp3(+) Treg cells during anti-CD25 treatment remarkably caused the disappearance of Gr1(+) immature myeloid cells, suggesting a cross-talk between these two inhibitory immune cell types. Treg cell expansion associated with r-Erbb2 overexpression may be seen as a physiologic response to dampen the immune reaction elicited by local anomalous overexpression of a self-antigen.

Animals↗
PubMed2004

From the hemangioblast to self-tolerance: a series of innovations gained from studies on the avian embryo.

During the last decades of the 20th century, studies on the vertebrate hematopoietic and immune systems have largely been performed, on mammalian models. The mouse has been the preferred material for several cogent reasons: (i) numerous well defined genetic strains are available; (ii) this species has been and still is instrumental in the study of gene activity through transgenesis; and (iii) in vitro culture techniques and in vivo assays for blood cells together with a wide array of antibodies and nucleic acid probes have been developed to investigate the cellular interactions occurring during hematopoiesis and immune reactivity. However, important and fundamental notions have emerged from using another higher vertebrate model, the avian embryo. The distinction among small lymphocytes of two populations, the T and B lymphocytes, endowed with different roles in adaptive immunity and dependant on different environments for their specification, has relied on experiments carried out in birds. The avian model has been critical for the analysis of the origin and traffic of hematopoietic precursor cells. It allowed the demonstration that both hematopoietic and angioblastic lineages arise from a common precursor, a cell whose existence had been proposed but never undoubtedly proven, the hemangioblast. Finally a form of thymus-dependant 'dominant' tolerance was demonstrated on the basis of experiments in the avian embryo, which initiated a large current of studies on 'regulatory T-cells'. Work in this model during the last decades has relied strongly on the construction of chimeras between quail and chick embryos that allowed a refined analysis of cell behaviour during embryogenesis. The novel perception of developmental neuropoiesis and immunopoiesis that followed proved to be largely applicable to lower and higher vertebrates, notably mammals.

Allantois↗
PubMed1993

Hormones in self tolerance and autoimmunity: a role in the pathogenesis of rheumatoid arthritis?

Recent studies indicate that pituitary hormones play an important role in immunoregulation. The evidence that endocrine abnormalities are associated with, and may contribute to the development of autoimmune disease is reviewed and discussed. Patients suffering from rheumatoid arthritis show a number of endocrine abnormalities that indicate altered pituitary function. The decreased bioactivity of prolactin and possible inadequate glucocorticoid response to inflammation found in patients may have an etiological role in rheumatoid arthritis. The further clarification of the possible role of endocrine factors in the etiology of autoimmune disease is needed urgently.

Arthritis, Rheumatoid↗
PubMed2003

Mechanisms, manifestations, and failures of self-tolerance.

We have developed transgenic (Tg) mice that express the influenza virus A/PR/8/34 hemagglutinin (PR8 HA) as a well-characterized model antigen with which to analyze factors governing tolerance and autoreactivity among CD4+ T and B cells. To analyze how the expression of self-antigens in varying amounts and in different cell types and tissues affects these processes, we have used a variety of promoters and enhancers to drive HA expression. By mating these HA Tg mice with Tg mice-expressing HA-specific major histocompatibility complex (MHC) class II-restricted T cell receptors (TCRs), we have shown that variations in the expression of the HA in different HA Tg lineages can cause CD4+ T cells with identical specificity for a self-peptide either to be deleted (to varying degrees) or to undergo selection to become CD4+ CD25+ regulatory T cells. In addition, a high intrinsic affinity of the TCR for a self-peptide appears to be required for thymocytes to undergo selection to become CD4+ CD25+ regulatory T cells. We have also shown that separate populations of HA-specific B cells that participate at distinct phases of the immune response to the HA in BALB/c mice differ significantly in their sensitivity to negative selection by the neo-self HA. Together, these studies demonstrate that both the diversity of the CD4+ T cell and B cell responses to the HA and variations in the expression of the HA in HA Tg mice can significantly affect the mechanisms and extent of CD4+ T and B cell tolerance induction.

Animals↗
PubMed1996

The post-activation refractory phase: a mechanism to measure antigenic complexity and ensure self-tolerance among mature peripheral T lymphocytes.

This paper outlines a model describing how the post-activation refractory phase of mature T cells may promote adaptive self/nonself-discrimination among mature peripheral T cells in extrathymic tissues. This model is based on the following experimental observations. First, activation of myelin basic protein-specific T-helper cells elicits a single episode of interleukin 2 production followed by a 7-10 day refractory phase during which antigenic restimulation elicits proliferation but without interleukin 2 production or reexpression of encephalitogenic activity. Secondly, T lymphoblasts exhibiting post-activation refractoriness are substantially more susceptible to anergy as compared to resting T cells. Third, myelin basic protein-induced activation at low T-cell densities elicits a refractory phase that is prolonged as compared to that of high T-cell density cultures. These results support a model by which a pioneer T-cell encountering peripheral antigen produces a limited supply of interleukin 2. This T cell will upregulate effector functions or will become anergic, depending on continual immigration of additional antigen-reactive clones, each of which makes a limited supply of interleukin 2 before entering into the post-activation refractory phase. By this model, immune responses will be sustained in areas with high degrees of antigenic complexity (infectious process) but will falter in regions of low antigenic complexity (unaltered self tissues).

Animals↗
PubMed2006

Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance.

T cell homeostasis is crucial for a functional immune system, as the accumulation of T cells resulting from lack of regulatory T cells or an inability to shut down immune responses can lead to inflammation and autoimmune pathology. Here we show that Blimp-1, a transcriptional repressor that is a 'master regulator' of terminal B cell differentiation, was expressed in a subset of antigen-experienced CD4(+) and CD8(+) T cells. Mice reconstituted with fetal liver stem cells expressing a mutant Blimp-1 lacking the DNA-binding domain developed a lethal multiorgan inflammatory disease caused by an accumulation of effector and memory T cells. These data identify Blimp-1 as an essential regulator of T cell homeostasis and suggest that Blimp-1 regulates both B cell and T cell differentiation.

Animals↗