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Rachel R Caspi

Publications and source records attributed to Rachel R Caspi.

23 records · Page 2Linked to original sources
PubMed2003

Methimazole protects from experimental autoimmune uveitis (EAU) by inhibiting antigen presenting cell function and reducing antigen priming.

Methimazole (methyl-mercapto-imidazole, MMI), a compound used clinically in therapy of Graves' thyroiditis, was found to inhibit development of several autoimmune diseases in animal models. It was suggested on the basis of in vitro data that inhibition is through down-regulation of interferon-gamma (IFN-gamma)-induced expression of major histocompatibility complex class I and class II molecules. Here, we investigate the effect of MMI on experimental autoimmune uveoretinitis (EAU) and study its mechanism(s). Treatment of EAU with MMI administered in drinking water inhibited induction of the disease and associated antigen (Ag)-specific proliferation and cytokine production by draining lymph node cells (LNCs). The treatment was protective only if administered during the first but not during the second week after immunization, suggesting an effect on the induction phase of EAU. It is interesting that MMI inhibited disease in IFN-gamma knockout mice, indicating that the in vivo protective effect is IFN-gamma-independent. Flow cytometric analysis of draining LNCs extracted 5 days after immunization showed that MMI partly to completely reversed the increase in Mac-1(+)/class I(+)/class II(+) cells induced by immunization and reduced the proportion of B7-1 and CD40-positive cells, suggesting a deficit in the Ag-presenting cell (APC) population. APC from untreated mice largely restored antigen-specific proliferation of MMI-treated LNCs. We suggest that MMI inhibits EAU at least in part by preventing the recruitment and/or maturation of APC, resulting in reduced generation of Ag-specific T cells.

Animals↗
PubMed2003

Regulation, counter-regulation, and immunotherapy of autoimmune responses to immunologically privileged retinal antigens.

Our interests revolve around the study of biological mechanisms regulating self-tolerance to immunologically privileged retinal proteins that serve as targets in sight-threatening autoimmune uveitic disease. These studies are aimed at understanding how selftolerance to these antigens develops during ontogeny and is maintained during adulthood, the processes involved in its pathological breakdown, the regulatory mechanisms that bring about remission and recovery, and, finally, how we can utilize knowledge of these processes for therapeutic restoration of tolerance. To answer these questions, we use the experimental autoimmune uveitis (EAU) model in rats and mice. Because of the commonality of underlying immunological mechanisms, lessons and concepts learned in experimental ocular models are applicable to other disease entities, and, conversely, data gleaned from other autoimmune diseases are applicable to the study of uveitis.

Animals↗
PubMed2002

Pertussis toxin alters the innate and the adaptive immune responses in a pertussis-dependent model of autoimmunity.

Pertussis toxin (PTX) is used to promote development of autoimmune diseases. The mechanism(s) are still incompletely understood. We dissected the innate and adaptive immune responses in a PTX-dependent model of autoimmune retinal disease, experimental autoimmune uveoretinitis (EAU), a Th1-driven disease of the neural retina elicited in F344 rats with a peptide derived from the retinal antigen interphotoreceptor retinoid binding protein (IRBP). Our results showed that optimal doses of PTX led to strongly increased innate cytokine responses, followed by enhanced adaptive Th1 immunity and disease. At supraoptimal doses of PTX, EAU was suppressed, the animals exhibited persistent lymphocytosis and had an inhibited chemotactic response to chemokines. We suggest that the suppressive effect of PTX at supraoptimal doses is due to inhibition of lymphocyte emigration from the blood into the target tissue, secondary to inhibition of Gi-protein-coupled chemokine receptor signaling, that persists into the effector phase of disease.

Adaptation, Physiological↗
PubMedDate not supplied

Th1 and Th2 responses in pathogenesis and regulation of experimental autoimmune uveoretinitis.

Experimental autoimmune uveoretinitis (EAU) in animals can be induced by immunization with retinal antigens or their fragments and represents human uveitis of putative autoimmune origin. The pathogenesis of EAU, and likely also of human uveitis, involves cell-mediated destruction of retinal tissues that is dependent on retinal antigen-specific T cells. Because in most cases a Th1-type response has been implicated in pathogenesis, the prevailing consensus has been that immunoregulatory manipulations designed to enhance the Th2 response at the expense of the Th1 response will be beneficial in clinical treatment of uveitis. This assumption may not always be correct. The present review will summarize the evidence that, despite a central role for Th1 response in uveitis, an unopposed Th2-like response can be equally or more destructive to the retinal tissues. Furthermore, the Th1 response itself triggers regulatory circuits that feed back and dampen further recruitment of antigen-specific T cells into the Th1 effector pool. Thus, although the Th1 effector response can and does result in retinal pathology, immunoregulatory strategies must take into account that immune deviation therapies designed to replace the Th1 with a Th2 response might result in exchanging one type of pathology for another rather than in achieving the desired therapeutic effect.

Animals↗