Overview

Research Description

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.

Research Abstract

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.










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