MECHANISMS OF DRUG INDUCED LUPUS

University Of Michigan At Ann Arbor, Ann Arbor MI

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Linked publications & trials

Abstract

The application proposes funding with the specific intent of developing an independent research program by the principal investigator. For the past three and a half years, the applicant has been pursuing his interest in basic science research in the areas of T cell immunology and pathogenesis of lupus. Both the clinical and basic science training have prepared the applicant for an independent career in academic rheumatology/immunology in the near future. The proposal is a natural extension of the applicant~s current research. The applicant has shown that murine Th2 cells overexpress LFA-1 (CD11a/CD18) and become autoreactive following treatment with two distinct DNA hypomethylating agents. Adoptive transfer of these autoreactive cells will also induce a lupus-like disease in syngeneic mice. This proposal will first examine the relationship between different lupus-inducing drugs and T cell DNA hypomethylation. The role of LFA-1 in T cell autoreactivity and in vivo autoimmunity will be determined by overexpressing LFA-1 on T cells directly through transfection of murine LFA-1 constructs, and the use of ICAM-1 deficient mice in the murine system. The role of Th1 and Th2 cytokines in T cell autoreactivity in vitro and autoimmunity in vivo will also be examined. Finally, attempts will be made to knockout the murine T cell DNA methyltransferase gene by homologous recombination to definitively determine the role of the gene in the proposed hypothesis of environmental agents inhibiting T cell DNA methyltransferase , leading to DNA hypomethylation, LFA-1 overexpression, and T cell autoreactivity and in vivo autoimmunity. The murine model is likely to have relevance to human disease, as abnormal T cell DNA methylation, LFA-1 overexpression, and increased production of Th2 cytokines such as IL-6 have all been reported in human lupus patients. The application is now in the position to develop his own independent research program as a junior faculty member in the Department of Internal Medicine. It is expected that the applicant will be promoted to a tenure track position during the time of the award. The sponsor, Dr. Bruce Richardson, who is also head of the division of Rheumatology at the Ann Arbor Veteran Administration Hospital, is commited to contributing protected time and resources to the applicant. The collaborators, Dr. Rossler and Dr. Johnson, as well as the core facilities at the University of Michigan will also provide expert help where it is needed.