| Experimental autoimmune encephalomyelitis (EAE), a murine model for Multiple Sclerosis, is a CD4+ T cell mediated demyelinating disease that can be induced in susceptible strains of mice by immunization with myelin antigens. For complete activation, CD4+ T cells require the delivery of two signals by antigen-presenting cells (APC); the antigen-specific signal and the costimulatory signal. The CD28 molecule on T cells delivers the major costimulatory signal upon its ligation with the B7 family of molecules, B7-1 or B7-2, expressed on APCs. Subsequently, activated neuroantigen-specific T cells migrate to the central nervous system (CNS) where they are reactivated and the inflammatory, demyelinating disease of the CNS progresses. As the B7/CD28:CTLA-4 costimulatory system plays a critical role in determining the fate and magnitude of immune responses, it is a promising therapeutic target for regulating immunopathological responses.; These studies were designed to examine the roles of CD28 and its individual ligands, B7-1 and B7-2, in EAE. EAE induction in CD28- or B7-deficient NOD mice was compared with the effects of B7/CD28 blockade using antibodies in wildtype NOD mice. Disease severity was significantly reduced in CD28-deficient as well as anti-B7-1/B7-2-treated NOD mice, indicating a critical role for CD28 costimulation in EAE induction. However, EAE can be induced in CD28-deficient mice following two immunizations. After reimmunization, CD28-deficient mice develop EAE with myelin-specific responses equal to those of wildtype controls. Additionally, I have demonstrated that CD40L-mediated costimulation is required for the activation of CD28-deficient T cells. Thus, sufficient T cell costimulation is critical for full activation and EAE induction.; CNS-resident glia are inducible APCs and efficiently activate T cells. However, the immune function of cerebrovascular endothelial cells (CVEs) during CNS inflammatory responses remains controversial. I have compared the effector phenotype, expression of costimulatory molecules and the functional antigen presenting capacity of SJL/J CVEs and astrocytes in response to the pro-inflammatory cytokines IFN-γ and/or TNF-α. Both astrocytes and CVEs produce pro-inflammatory cytokines upon activation. However, unlike astrocytes and microglia, CVEs are not competent APCs. Furthermore, T cell-induced changes to CVE monolayers may have important implications for the integrity of the blood brain barrier during EAE and MS. |
