AUTOREACTIVE T CELLS IN MURINE LUPUS NEPHRITIS

The long-term objectives of this proposal are to develop a better
understanding of the cellular events leading to the production of
pathogenic autoantibodies in Systemic Lupus Erythematous. Ultimately
through this understanding a more rational approach to alter these events
can be planned. For these purposes the role of an autoreactive T cell
clone, termed ARTC-1 and derived from the lupus prone MRL-1pr/1pr mouse, in
murine lupus will be examined. This will include analysis of the events
involved in activation of ARTC-1 and the factors responsible for ARTC-1
induced B cell proliferation and immunoglobulin production. Particular
emphasis will be devoted to the capacity of ARTC-1 to induce B cells to
produce immunoglobulin with nephritogenic properties. This work will
involve six approaches: 1) Further characterization of the requirements for
activation of ARTC-1 using L cell transfectants expressing class II
molecules; 2) Analysis of the capacity of ARTC-1 to induce B cell
proliferation and immunoglobulin production, using both T cells and
membranes isolated from activated T cells; 3) Examination of the
lymphokines produced by ARTC-1 by determination of soluble lymphokines
ARTC-1 produces and the lymphokine mRNA expressed by ARTC-1 after
activation; 4) Characterization of the immunoglobulin products resulting
for ARTC-1 induced B cell activation by analysis of the class, subclass,
charge and ligand binding properties of Ig products derived from ARTC-1 B
cell interaction; 5) Production and characterization of an ARTC-1
hybridoma, and 6) Production and characterization of a monoclonal anti-
clonotypic antibody specific for ARTC-1. The result of these studies (1-4) will be compared to those performed with
other T cell lines derived form MRL-1pr/1pr mice. Ultimately, the probes
derived from the latter studies of (V-VI) will be used to examine the role
of cells like ARTC-1 in the pathogenesis of murine lupus in vivo, if these
cells are prominent in vivo, strategies using the reagents derived for the
proposed studies, will be planned to either delete or alter the function of
cells line ARTC-1 in vivo.