The long-term goals of this research are to define the abnormalities in T cell and B cell function in SLE which are critical to the initiation and maintenance of the disease, and ultimately to specifically modulate the immune system to prevent or overcome those abnormalities. The hypothesis to be tested in this grant is that there is defect in SLE in membrane receptor-mediated intracellular signalling in Th1 cells which results in defective Il-2 and gamma-IFN production by those cells. The resultant decrease in the inhibitory activity of gamma-IFN on Th2 cells. The results in an overproduction of B cell stimulatory factors (BSFs) by Th2 cells and an apparent hyperresponsiveness of lupus B cells to Th2 cell-derived BSFs. This hypothesis will be addressed using the Palmerston North mouse model of SLE.
The specific aims of this grant proposal are as follows: 1. To define whether there is a defect in the production of both IL-2 and gamma-IFN by PN Th 1 cells. 2. To determine whether the defect in lymphokine production by Th1 cells of PH is due to defective membrane receptor -mediated signalling. This will be accomplished by determining whether the abnormalities are present only when the cells are activated by membrane-dependent stimuli and not when they are activated by stimuli which do not require membrane receptor-mediated signalling. If these studies indicate that the abnormality in lymphokine production is due to defective membrane receptor- mediated signalling, we will determine if the defect in PH Th1 or Th2 cells is associated with a defect in protein kinase C activation. 3. To define whether there is increased production of IL-4 and IL-5 by PH Th2 cells and, if there is, whether the enhanced production of those BSFs can be inhibited by gamma-IFN. 4. To determine whether PN and control DBA/1 B cells hyperrespond to rIL-4, rIL-5 and the mixture of BSFs present in supernatants form Con A stimulated spleen cells compared to supernatants from control spleen cells, and if the response of PN and control B cells to these various BSFs can be inhibited by gamma-IFN. 5. To correlate the abnormalities in lymphokine production with the presence and progression of lupus-like disease.
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