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Results for “Self Tolerance”

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At least 235 records · Page 13Linked to original sources
PubMed2001

Constitutive beta cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes.

To analyze the function of the Th1-promoting cytokine IL-12 in vivo, we generated transgenic (tg) mice (RIP-IL12 mice) whose pancreatic beta cells constitutively express bioactive IL-12 or one of its components, p35 or p40. In contrast to non-tg littermates or single-tg RIP-p35 and RIP-p40 mice, RIP-IL12 mice developed a marked pancreatic infiltration of lymphocytes and macrophages, mainly around islets. Expression of bioactive IL-12 primarily upregulated transcript levels of IFN-inducible protein-10 (IP-10), RANTES, IFN-gamma, and TNF-alpha in the pancreas. Despite the substantial recruitment of mononuclear cells, no biochemical or clinical disease was evident in the exocrine or endocrine pancreas. Coexpression of lymphocytic choriomeningitis virus (LCMV) proteins with IL-12 in the beta cells failed to spontaneously activate or expand antigen-specific anti-self/viral T cells in uninfected tg animals. However, when RIP-IL12 x RIP-LCMV tg mice were infected with LCMV, antigen-specific anti-self/viral T cells were induced, which led to an acceleration in the kinetics and severity of insulin-dependent diabetes mellitus (IDDM). Thus, the ectopic expression of IL-12 does not spontaneously break tolerance and activate antigen-specific T cells in the periphery, but it does worsen ongoing autoimmune disease.

Adoptive Transfer↗
PubMed1986

Self-tolerance to host and donor following HLA-mismatched bone marrow transplantation.

The transplantation of T cell-depleted HLA-haploidentical bone marrow can correct the severe combined immunodeficiency disease (SCID) caused by the inherited absence of T lymphocytes. Despite a different environment, no severe graft-vs.-host reaction occurred and engrafted T lymphocytes became functional. We have studied tolerance of engrafted T lymphocytes to donor and host HLA antigens in four SCID patients who have been transplanted with bone marrow from one of their HLA-haploidentical parents. Graft-vs.-host reaction was prevented by T cell depletion of infused bone marrow using E rosetting and by in vivo administration of cyclosporine A. Subsequent to bone marrow transplantation (BMT), the engrafted T lymphocytes were shown to be unresponsive in vitro towards host cells collected prior to BMT. Generally, this tolerance could not be explained by a suppressive mechanism. Nevertheless, in one patient suppressive cells were found transiently. In contrast to the early appearance of a tolerance towards host, a reactivity of engrafted donor cells towards donor was always observed within the first 300 days post-grafting. This autoreactivity was mediated by T cells of donor origin and its targets were HLA class II molecules (at least HLA-DR and DQ). The progressive disappearance of this autoreactivity was correlated with the engraftment of Ia-positive cells (monocytes plus B lymphocytes) of donor origin and the achievement of complete immunological reconstitution. In the patient showing the strongest autoreactivity, a donor-specific T cell line has been grown which was shown to specifically inhibit the proliferative response of donor lymphocytes. Concomittantly, the immunological reconstitution remains poor in this patient. These data suggest that tolerance to HLA class II molecules is dependent on the presence of the relevant HLA class II molecule-expressing cells allowing the elimination or the suppression of T lymphocytes specifically directed at these molecules.

Bone Marrow Transplantation↗
PubMed1992

Identification of an immunodominant type-II collagen peptide recognized by T cells in H-2q mice: self tolerance at the level of determinant selection.

The T cell recognition of type-II collagen (CII) in H-2q mice, susceptible to CII-induced arthritis, was analyzed. With the use of T cell hybridomas derived from rat CII-immunized mice, a peptide corresponding to amino acids 245-270 on chick CII was found to harbor a T cell epitope which is present on heterologous CII (chick, rat, human, and bovine CII) but not on autologous CII. It was shown that this epitope was located within amino acids 260-270, although flanking regions in either direction were necessary for proper recognition. A peptide corresponding to human CII (256-270) was used for further studies. A single amino acid difference at position 266 between mouse CII (aspartic acid) and heterologous CII (glutamic acid) strongly influenced recognition of this peptide. No response towards the mouse peptide was seen with any of the T cell hybridomas. Inhibition studies revealed that the mouse peptide did not bind as well to major histocompatibility complex as the corresponding heterologous peptide. Both peptides gave rise to a T cell response after immunization. However, immunization with the heterologous peptide resulted in a response strictly directed to rat CII and the immunogen while immunization with the autologous peptide elicited T cells which reacted in a heteroclitic fashion, with a stronger response to the heterologous peptide than to the autologous peptide, and did respond to rat CII but not to mouse CII. We suggest that aspartic acid in position 266 results in a cryptic determinant in mouse CII which is neither recognized after CII immunization nor capable of tolerance induction. A glutamic acid at position 266, however, gives rise to an immunodominant epitope which is recognized by a large proportion of the T cells activated after immunization with heterologous CII.

Amino Acid Sequence↗
PubMed2004

HSP60 induces self-tolerance to repeated HSP60 stimulation and cross-tolerance to other pro-inflammatory stimuli.

In addition to their primary function as intracellular chaperone proteins, the immunomodulatory properties of heat shock proteins (HSP), including their role as adjuvants for vaccines, have become a focus of intense research interest. Interestingly, the effect of chronic exposure to an endogenous immunomodulator and initiator of inflammation such as autologous HSP60 has as yet remained uncharacterized. In this study, we demonstrate that pretreatment of monocytes with human HSP60 results in a suppression of TNF-alpha production on restimulation with HSP60. Furthermore, desensitization with HSP60 inhibits TNF-alpha expression in these cells in response to LPS stimulation, thereby inducing "cross-tolerance". In contrast to TNF-alpha suppression, IL-1beta expression was augmented in HSP60-pretreated monocytes on restimulation, while being suppressed in THP-1 cells. Addition of an anti-IL-10 neutralizing antibody had no significant effect on HSP60- or LPS-induced tolerance.HSP60 priming of monocytes also results in significant down-regulation of HLA-DR, CD86 and Toll-like receptor 4 expression, but minimally up-regulates CD80 expression, similar to that previously reported with LPS. By identifying a previously unrecognized "tolerizing" effect of extended exposure to autologous HSP60 on the innate immune system, as opposed to its recently identified pro-inflammatory stimulatory capacity, this study highlights a further level of complexity of our understanding of the biological activities of HSP.

B7-1 Antigen↗
PubMed2001

Pathways for self-tolerance and the treatment of autoimmune diseases.

Antigen delivers both immunogenic and tolerogenic signals to lymphocytes. The outcome of antigen exposure represents a complex integration of the timing of antigen binding with signals from many other immunogenic and tolerogenic costimulatory pathways. A road map of these signalling pathways is only beginning to be charted, revealing the mechansim of action and limitations of current immunotherapeutic agents and the points of attack for new agents. Ciclosporin and tacrolimus interfere with tolerogenic signals from antigen in addition to blocking immunogenic signals, thus preventing active establishment of tolerance. Corticosteroids inhibit a key immunogenic pathway, NFkappaB, and more specific inhibitors of this pathway may allow tolerance to be actively established while immune responses are blocked. New experimental therapies aim to mimic tolerogenic antigen signals by chronically stimulating antigen receptors with antigen or antibodies to the receptor, or aim to block costimulatory pathways involving CD40 ligand, B7, or interleukin 2. Obtaining the desired response with these strategies is unpredictable because many of these signals have both tolerogenic and immunogenic roles. The cause of autoimune diseases has been determined for several rare monogenic disorders, revealing inherited deficiencies in tolerogenic costimulatory pathways such as FAS. Common autoimmune disorders may have a biochemically related pathogenesis.

Animals↗
PubMed2002

The use of monoclonal antibodies to restore self-tolerance in established autoimmunity.

The author hopes to convince the reader that the data presented argue for a stage during the development of IDDM when beta-cell destruction can be counteracted and tolerance to beta cells restored, provided the immune aggression is arrested. This argument constitutes a solid rationale for immunointervention in established IDDM, especially by using potent agents such as CD3. The future for the application of monoclonal antibodies not only in autoimmunity but also in transplantation is exiting. With the development of humanized monoclonal antibodies, therapeutic uses for them are likely to expand. Enormous progress has been made in the last 15 years, and it is likely that before a similar time period has elapsed, monoclonal antibodies will have become standard tools that will dispense the need for long-term immunosuppression and its inherent dangers in various clinical arenas.

Animals↗