Class II (Ia) major histocompatibility complex molecules are normally expressed only-on cells of the immune system. However, during immune renal injury class II molecules spontaneously appear on proximal tubules (PT) in the kidney. We propose to use molecular and cellular approaches in two murine models, spontaneous autoimmune lupus nephritis and renal transplant rejection, to test the hypothesis that the expression of class II antigens on PT is required for renal injury. First, the temporal sequence of class II induction on PT during renal injury will be determined and the nature of the signals responsible for Ia induction on PT (i.e. secreted cellular products of T lymphocytes or substances present in serum) will be identified. Second, the functional consequences of class II expression on PT will be determined. We will ask 1) whether PT can and do serve as antigen-presenting cells to T cells in vivo and in vitro 2) whether nephrotoxic antibodies to PT- specific antigens and class II are produced and 3) whether renal tubule cell function is altered by class II expression. Third, the molecular basis for class II expression in PT will be studied and compared to the induction of class II in lymphoid cells. The chromatin configuration of class II genes in PT and the existence of unique sequence-specific DNA proteins will be determined. Finally, binding to facilitate the cellular and molecular studies, long term clonal lines of PT will be produced by transfection with SV40 origin defective DNA. The proposed experiments should help to establish the role of class II antigens in the progression of renal injury.
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