Immune responses in the central nervous system (CNS) can be protective when mounted against foreign invaders, such as meningococcus, or tumors that arise in the brain, such as gliomas. However, they can be pathogenic and lead to autoimmune diseases if directed against "self" peptides that are normally expressed in CNS white matter, such as myelin basic protein (MBP). In our laboratory we investigate the cellular and molecular mechanisms underlying protective as well as destructive immune-CNS interactions in different disease states.

We study a mouse model of multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE), mediated by CD4+ T cells specific for MBP. We have previously demonstrated that production of the pro-inflammatory cytokine, IL-12, promotes development of EAE, whereas production of the immunosuppressive cytokine, IL-10, is protective. Current experiments are directed at manipulating antigen presenting cells via gene therapy so that they deliver negative or apoptotic signals rather than growth factors to disease-causing T cells. Our goal is to devise new strategies for the treatment of autoimmune diseases such as MS.

A second project is to develop immunotherapies against glial brain tumors. Current experiments are directed at identifying the phenotype and functions of the immune cells responsible for rejection of a mouse glioma. Against our expectations, CD4+, but not CD8+, T cells and IL-10, but not IFN-gamma or IL-12, are critical for the generation of the anti-glioma protective immune response. Future experiments will assess the role of NK cells and B cells and investigate the mechanism underlying the tumoricidal effects of IL-10.

Bagaeva LV, Williams LP, Segal BM. IL-12 dependent/IFN gamma independent expression of CCR5 by myelin-reactive T cells correlates with encephalitogenicity. J Neuroimmunol. 137:109-16, 2003.

Segal BM. Experimental Autoimmune Encephalomyelitis: Cytokines, Effector T Cells, and Antigen-presenting Cells in a Prototypical Th1-mediated Autoimmune Disease. Curr Allergy Asthma Rep. 3:86-93, 2003.

Schwid SR, Covington M, Segal BM, Goodman AD. Fatigue in multiple sclerosis: current understanding and future directions. J Rehabil Res Dev. 39:211-24, 2002.

Segal BM, Glass DD, Shevach EM. IL-10-Producing CD4+ T cells mediate tumor rejection. J Immunol. 168:1-4, 2002.

Segal BM, Cross AH. Fas(t) track to apoptosis in MS: TNF receptors may suppress or potentiate CNS demyelination. Neurology 55:906-7, 2000.

Segal BM, Chang JT, Shevach EM. CpG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo. J Immunol. 64:5683-8, 2000.

Chang JT, Segal BM, Nakanishi K, Okamura H, Shevach EM. The costimulatory effect of IL-18 on the induction of antigen-specific IFN-gamma production by resting T cells is IL-12 dependent and is mediated by up-regulation of the IL-12 receptor beta2 subunit. Eur J Immunol. 30:1113-9, 2000.

Chang JT, Segal BM, Shevach EM. Role of costimulation in the induction of the IL-12/IL-12 receptor pathway and the development of autoimmunity. J Immunol. 164:100-6, 2000.

Chang JT, Shevach EM, Segal BM. Regulation of interleukin (IL)-12 receptor beta2 subunit expression by endogenous IL-12: a critical step in the differentiation of pathogenic autoreactive T cells. J Exp Med 189:969-78, 1999.