FUNCTION OF CD40 ON FIBROBLASTS AND ENDOTHELIAL CELLS

DESCRIPTION: (Adapted from the applicant's abstract) -The principal investigator plans to study the functional consequences of CD40L- mediated T cell interactions with CD40+ fibroblasts and endothelial cells. CD40L is an activation-induced CD4+ cell surface molecule originally identified because of its importance in delivering contact-dependent activating signals to B cells. Recent studies demonstrate than monocytes, epithelial cells and dendritic cells also express functionally active CD40. The principal investigator has further explored the cellular distribution of CD40 and now shows that human fibroblasts and endothelial cells also express CD40. In addition, interferon(IFN)-gamma upregulates CD40 expression on fibroblasts and endothelial cells in vitro. Most importantly, CD40L-CD40 interactions induce fibroblast and endothelial cell activation. For example, CD40L+ Jurkat T cells of CD40L+ transfectants, but not control cells, upregulate the expression of CD54 (ICAM-1) and CD106 (VCAM-1) on fibroblasts and CD54, CD106 and CD62E (E-selectin) on production of interleukin( IL)-6. These effects on fibroblasts and endothelial cells are specifically inhibited by anti-CD40L monoclonal antibody(mAb) 5C8. Together, these findings suggest that CD40L+CD4+ T cells may interact with a variety of CD40+ target cells at inflammatory sites. It is therefore of interest that CD40 expression is markedly upregulated on many cell types in the kidney of patients with proliferative lupus nephritis. Because interactions of activated CD4+ T cells with fibroblasts and endothelial cells play important roles in the pathogenesis of autoimmune disease, the specific aims of this grant proposal are to study further the functional outcome of CD40L-mediated interactions with these cells. The investigators will study the role of CD40L-CD40 interactions in promoting leukocyte binding to endothelial cells. Additionally, they will determine if CD40L-mediated signals effect angioproliferation, induce endothelial cells to secrete pro-inflammatory molecules or alter hemostasis. With regard to the fibroblast, they will characterize the mechanism by which CD40L-mediated signals induce fibroblast proliferation and determine if CD40L-CD40 interactions induce fibroblasts to secrete additional cytokines, extracellular matrix proteins or collagenase. Together, these studies may provide new insights into the mechanisms by which activated CD4+ T cells functionally interact with fibroblasts and endothelial cells. Moreover, these studies may lead to better understanding of the immunopathogenesis of a variety of autoimmune or inflammatory diseases.