Cellular and molecular mechanisms of T cell tolerance; Pathogenesis and regulation of T cell-mediated autoimmune and virus-induced diseases; Mechanisms of virus-induced autoimmunity; Molecular mechanisms of costimulatory molecule interactions in T cell activation; Role of glial cells in antigen processing and presentation in the CNS.
My laboratory investigates the cellular and molecular mechanisms of multiple aspects of the immunopathogenesis and specific immunoregulation of T cell-mediated autoimmune responses employing two mouse models of multiple sclerosis (MS) - Theiler's virus-induced demyelinating disease (a virus-induced model of MS) and Relapsing Experimental Autoimmune Encephalomyelitis (R-EAE) (an autoimmune model of MS).
Cellular and Molecular Mechanisms of T Cell Tolerance: In conjunction with the study of the effects of antigen-specific tolerance on the experimental T cell diseases described below, the laboratory utilizes transgenic and molecular approaches to study the cellular and molecular mechanisms of T cell tolerance induced by peptide-pulsed, chemically-fixed antigen presenting cells. This includes study of the differential effects of tolerance induction on specific immune functions mediated by the Th1 and Th2 subsets of CD4+ T cells, study of the effects of tolerance on expression of T cell lymphokine-specific mRNA and protein levels, and determination of the role of CTLA-4 and the mechanisms of tolerance in experimental animals (clonal deletion, clonal anergy, and/or induction of specific immunoregulatory T cells) employing both conventional and T cell receptor transgenic mice.
Immunopathology of Theiler's Murine Encephalomyelitis Virus (TMEV)-Induced Demyelinating Disease: MS is a T cell-mediated autoimmune demyelinating disease which is thought to be initiated by a virus infection. TMEV, a natural mouse pathogen, is a picornavirus which induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic-progressive MS. Demyelination in TMEV-infected mice is initiated by a mononuclear inflammatory response mediated by virus-specific CD4+ T cells targeting virus which chronically persists in the CNS of susceptible mouse strains. Beginning 3-4 weeks after onset of clinical disease, autoimmune T cell responses to multiple myelin epitopes arise in an ordered progression and play a major pathologic role in the progression of chronic disease. Recent kinetic and functional studies have shown that T cell responses to the myelin epitopes arise due to de novo priming of self-reactive T cells to sequestered autoantigens released secondary to virus-specific T cell-mediated demyelination (i.e., epitope spreading) and are not a consequence of cross-reactivity between TMEV and self epitopes (i.e., molecular mimicry). Epitope spreading represents an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases. We have also recently developed a molecular mimicry model of virus-induced CNS demyelination wherein mice infected with recombinant Theiler’s viruses encoding encephalitogenic myelin epitopes leads to a rapid onset paralytic disease which can be prevented by the prior induction of tolerance to the expressed myelin peptide. Current studies are directed toward: identification of the relevant immunodominant determinants on the viral capsid proteins responsible for induction of DTH and antibody responses in susceptible and resistant hosts; characterization of immunopathologic T cells isolated from the periphery and CNS of affected mice as to antigen-specificity, cytokine profile, and T cell receptor usage; isolation and molecular characterization of virus-specific Th1 and Th2 clones with the potential to produce and/or inhibit disease in vivo; immunoregulation of the demyelinating disease using antigen-nonspecific (monoclonal antibody therapies directed against costimulatory molecules) and antigen-specific (induction of virus-specific and myelin epitope-specific tolerance) mechanisms; and further characterization of the molecular mimicry model by determining the ability of TMEV expressing ‘mimics’ of myelin antigens to induce T cell-mediated demyelinating disease.
Immunopathology of Murine Relapsing-Remitting EAE (R-EAE): Following immunization with myelin antigens or the adoptive transfer of myelin-specific Th1 lines/clones, SJL/J mice develop a paralytic demyelinating disease characterized by a relapsing-remitting clinical course. The laboratory is using this model to determine the mechanisms of pathogenesis and intrinsic regulation of a Th1-mediated autoimmune disease and to study the efficacy various immunoregulatory strategies as potential therapies for human autoimmune diseases. Recent studies have revealed that progression of this relapsing-remitting disease involves epitope spreading, i.e. the induction of T cell responses to endogenous encephalitogenic epitopes exposed to the immune system subsequent to acute CNS damage mediated by T cells specific for the inducing epitope. Current studies are directed toward: identification of the relative contribution of immune responses to various CNS antigens [myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG), etc.] in R-EAE induction and relapses; study of the intrinsic regulation of T cell-mediated autoimmune processes by signals delivered via the B7/CD28/CTLA-4 family of T cell costimulatory molecules and by the Fas/Fas-L system; cellular and molecular characterization of the fine specificity, T cell receptor usage, and cytokine synthesis patterns of CNS-infiltrating T cells at varying times during the relapsing-remitting disease process; study of the molecular mechanisms of antigen processing and presentation of self myelin epitopes by CNS-resident antigen presenting cells (i.e., astrocytes, microglia, and cerebrovascular endothelial cells); determination of the cellular and molecular mechanisms of specific T cell tolerance using chemically-fixed antigen presenting cells and antagonists of B7/CD28-mediated costimulation; and determination of the immunoregulatory effects of other relevant monoclonal antibodies which can potentially interfere with the induction or expression of neuroantigen-specific Th1 responses.