Rachel R. Caspi, Ph.D.
Building 10, Room 10N222
10 Center Drive
Bethesda, MD 20892
The Section's interest is in cellular and molecular mechanisms involved in T cell-mediated, tissue-specific autoimmunity. The questions center on the development and maintenance of self-tolerance to immunologically privileged retinal antigens, and on defining the processes that lead to their pathological breakdown. The goal is to use this knowledge for designing novel and rational strategies for immunotherapy. Approaches and conclusions are generalizable to other tissue-specific autoimmune diseases.
The experimental approaches utilize the model of experimental autoimmune uveoretinitis (EAU) that resembles immune-mediated uveitic diseases in humans. EAU is induced in mice and in some cases in rats by immunization with retinal antigens or their fragments. Uveitogenic T cell lines and clones are developed and studied, with the aim of devising ways to target the autopathogenic cells in vivo. Genetically altered mice are used to evaluate the role of various components of the immune system in the immunopathogenesis of uveitis. We have recently developed a new model of spontaneous uveitis in mice expressing a transgenic T cell receptor specific to a major retinal antigen that serve to study basic mechanisms of pathogenesis and as donors of retina-specific T cells. Various strategies to induce long-lasting immunological tolerance to retinal antigens are explored as immunotherapy for EAU. Selected questions for which appropriate tools are not yet available in the EAU model are studied using related autoimmune disease models, e.g., experimental autoimmune encephalomyelitis (EAE). Lastly, EAU serves as a template for the preclinical evaluation of new drugs and compounds as to their effects on the various stages of immunopathogenesis and disease expression.
Dr. Rachel Caspi received her doctoral training in Israel and her postdoctoral training at the NIH. She is a tenured Senior Investigator at NIH and serves as a Section Head of the Immuoregulation Section and Deputy Chief of the Laboratory of Immunology, National Eye Institute. She also holds an Adjunct Professorship at the University of Pennsylvannia School of Medicine.
Dr. Caspi's research centers on tolerance and autoimmunity to immunologically privileged retinal antigens in animal models of autoimmune uveitis, a potentially blinding human disease. She developed the uveitis mouse model, now in use worldwide. Her studies have elucidated many basic mechanisms of pathogenesis and helped to devise clinically relevant immunotherapeutic approaches. She is particularly well known for her work on effector and regulatory T cells in pathogenesis of ocular autoimmunity. The work she and her group have published is broadly applicable to autoimmunity in general. She is the recipient of numerous honors and awards, most recent of which was the 2010 Friedenwald award, one of the two highest awards in the field of vision research, and has authored and co-authored more than 200 publications.
Agarwal RK, Kang Y, Zambidis E, Scott DW, Chan CC, Caspi RR. Retroviral gene therapy with an immunoglobulin-antigen fusion construct protects from experimental autoimmune uveitis. J Clin Invest. 2000;106(2):245-52.
Avichezer D, Grajewski RS, Chan CC, Mattapallil MJ, Silver PB, Raber JA, Liou GI, Wiggert B, Lewis GM, Donoso LA, Caspi RR. An immunologically privileged retinal antigen elicits tolerance: major role for central selection mechanisms. J Exp Med. 2003;198(11):1665-76.
Pennesi G, Mattapallil MJ, Sun SH, Avichezer D, Silver PB, Karabekian Z, David CS, Hargrave PA, McDowell JH, Smith WC, Wiggert B, Donoso LA, Chan CC, Caspi RR. A humanized model of experimental autoimmune uveitis in HLA class II transgenic mice. J Clin Invest. 2003;111(8):1171-80.
Horai R, Zárate-Bladés CR, Dillenburg-Pilla P, Chen J, Kielczewski JL, Silver PB, Jittayasothorn Y, Chan CC, Yamane H, Honda K, Caspi RR. Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site. Immunity. 2015;43(2):343-53.
Luger D, Silver PB, Tang J, Cua D, Chen Z, Iwakura Y, Bowman EP, Sgambellone NM, Chan CC, Caspi RR. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med. 2008;205(4):799-810.