Uniformed Services University of the Health Sciences
Department of Medicine
4301 Jones Bridge Road, C1094
Bethesda, Maryland 20814-4799
Phone: (301) 295-3606
Fax: (301) 295-1996
The pathology of organ-specific autoimmune diseases occurs in the context of increased reactivity of CD4 T cells against self-antigens. Type 1 diabetes mellitus (T1DM) is an example of organ-specific autoimmune disease widely-spread around the word. Its incidence is continuously increasing. In T1DM, the CD4 T cells mediate the destruction of pancreatic ?-islets, and the loss of insulin secretion. At present, there is no effective therapy for T1DM.
One line of our undergoing investigations aims at studying the cellular and molecular mechanisms by which our "in home" engineered MHC II-peptide chimeras prevent and reverse T1D. Several immunospecific therapeutics for T1D in mice have been genetically and enzymatically engineered in the lab, i.e., highly polymerized, recombinant MHC II-peptides, and drug-carrying MHC II peptides. The mechanisms by which these reagents can negatively regulate the function and development of diabetogenic CD4 T-cells in thymus and peripheral lymphoid organs are under investigation. Parallel studies are aimed at deciphering negative regulatory mechanisms by which CD4+25+ T regulatory cells (Treg) suppress the function of diabetogenic T cells, and the extent to which our recombinant MHC II-peptide chimeras induce clonal expansion of Treg cells in the thymic and extrathymic environment.
A second line of research refers to the neonatal development of autoreactive T-cells. We are particularly investigating the thymic and extrathymic conditions of development that foster clonal expansion of diabetogenic CD4 T-cells. The function of lipid rafts microdomains in plasma membrane of diabetogenic T-cell precursors (as primordial foci of signal transduction) during the neonatal development of diabetogenic T-cells is currently under investigation.