This proposal will investigate the immunologic mechanisms responsible for experimental allergic encephalomyelitis (EAE) in nonhuman primates. EAE is an autoimmune demyelinating disease of the central nervous system that, in most species studied, is mediated by T-cells reactive to myelin basic protein (MBP). Models of EAE in 2 different primate species, common marmosets and cynomolgus monkeys, have been developed over the past 4 years. Common marmosets develop in utero as genetically distinct twins or triplets who share a cross-circulation of bone marrow derived elements, resulting in a permanent and stable chimeric state. Lymphocytes can therefore be transferred between members of these sibling groups without generating an alloresponse. T-cell clones reactive to MBP will be prepared from one animal and adoptively transferred to an unimmunized chimeric sibling. In so doing, it will be possible to directly identify the encephalitogenic T-cell repertoire in an outbred species phylogenetically close to humans. The repertoire of MBP-reactive clones will be studied by epitope mapping, analysis of T-cell receptor chain usage and encephalitogenic potential. It will also be possible to assess the role of the astrocyte in adoptive transfer EAE by experiments in which the transferred T-cell clones are syngeneic or fully allogeneic to host astrocyte MHC determinants. In additional studies, the role of """"""""promiscuous"""""""" T-cells, i.e., T-cells that recognize antigen in an MHC dependent but allele-independent fashion, will be assessed. In other experiments, chronic, relapsing-remitting EAE in the cynomolgus monkey will be studied to define the role of polymorphism of genes of the major histocompatibility complex on the clinical course of EAE. Nonhuman primates offer unique advantages for the study of EAE, including the clinical similarity of the induced disease to the human disease multiple sclerosis (MS), the outbred genetic characteristics, and the extensive conservation of immune and nervous system genes and proteins between human and nonhuman primate species. As MS is, excluding trauma, the most important acquired neurologic disease of early to mid adulthood, affecting 250,000 Americans, it is essential that useful model systems for this tragic illness be developed and studied. These studies will define nature of the T-cell response in autoimmune demyelination and the effects of genetic differences in the background of affected individuals on the disease course in the hope that results will directly lead to improved understanding of, and treatment for, MS.
