Harvard Catalyst Profiles

Contact, publication, and social network information about Harvard faculty and fellows.

IMMUNOREGULATION IN EAE--ROLE OF T CELL COSTIMULATION


Biography

Overview
Experimental autoimmune encephalomyelitis (EAE), an animal model for the study of multiple sclerosis, is an inflammatory disease of the central nervous system (CNS) that can be induced in a number of species by immunization with myelin proteins and adjuvant. The disease is initiated by antigen-specific encephalitogenic T cell activation. The first signal is provided by engagement of the T cell receptor with the antigenic peptide plus major histocompatibility complex on antigen-presenting cells (APCs), and thus provides antigen-specificity to the immune response. The second "costimulatory" signal is provided by binding of specific receptors on T cells with their ligand/s on APCs. The best characterized costimulatory pathway is that provided by CD28 on T cells binding to B7-1 and B7-2 on professional APCs. Preliminary data in the Lewis rat model show that blocking CD28-B7 costimulation by systemic administration of CTLA4Ig a fusion protein which binds B7, prevents the development of EAE. In addition, the investigators found that professional APCs such as splenic dendritic cells, can deliver a tolerogenic signal when they are preincubated in vitro with encephalitogenic peptide in the presence of CTLA4Ig before injection into naive recipients. They plan to study the following:

First, the investigators plan to study the role of CD28-B7 T cell costimulation in generating encephalitogenic T cells, and whether a costimulatory signal (B7-1 versus B7-2) is necessary after these cells enter the CNS. This will be done by studying the effects in both active and passive disease. They will give CTLA4Ig (a fusion protein which binds to B7), or mutant forms of CTLA4Ig which binds only to B71 or B72. This will be given peritoneally and intravenously. Various effects such as cell proliferation, cytokines, etc. will be determined. Th2 cells will be cloned and then adoptively transferred to study a protective role.

Second, the investigators plan to study the mechanisms of how antigen presentation by dendritic cells in the absence of costimulation prevents EAE in vivo. Effector mechanisms will be studied by in vitro lymphocyte proliferation studies and in vivo delayed type hypersensitivity responses, by cytokine analysis using ELISA or polymerase chain reaction, and by immunohistology for specific inflammatory and activation markers, expression of Th1 and Th2 cytokines, and the presence of V beta 8.2 CD4+ T cells in the CNS. Thirdly, the investigators will investigate whether costimulatory signals are required for the generation of tolerizing signals such as the generation of Th2 cells after oral tolerization, and whether a second signal is also needed for the effector function of these cells.

These studies should have important and relevant clinical implications for the role of costimulatory T cell activation in multiple sclerosis, and may provide the rationale for development of novel therapies targeted at blocking T cell costimulation in this disease as well as in other immunologically mediated neurologic diseases.
R29AI040945
KHOURY, SAMIA J.

Time
1996-08-01
2002-04-30
Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.