There is compelling evidence that cellular immunity plays a role in the pathogenesis of glomerulonephritis (GN). Our recent data indicate that both alpha/beta and the less common gamma/delta T cells, are required for the development of experimental GN in mice. Mice deficient in either of these two T cell subsets developed minimal glomerular injury and interstitial macrophage accumulation in an anti-glomerular basement membrane (GBM) model of GN. This demonstrates that both T cell subsets are required for the progression of disease and is the foundation of our hypothesis that regulatory interactions between alpha/beta and gamma/delta T cells culminates in the production of cytokines, that regulate macrophages, the immune effector cells in GN. The effector phase of specific immunity requires the recruitment of T cells to sites of antigen exposure. Members of the selectin family of leukocyte adhesion receptors are important in alpha/beta and gamma/delta T cell interactions with endothelial cells, in vitro. In vivo, our studies during the current funding period revealed a hitherto unexpected complexity for the role of selectins in GN. Mice deficient in P-selectin, had increased indices of glomerular injury and leukocyte accumulation following experimental GN. This was associated with an absence of endothelial derived soluble P-selectin, which is anti- inflammatory in vitro. On the other hand, L- or E-selectin deficient mice had a significant reduction in disease and in renal alpha/beta T cell and macrophage accumulation suggesting a role for selectins in alpha/beta T cell recruitment/function. We will critically test the hypothesis that L-selectin and the selectin ligands on alpha/beta T cells play a dominant role in T cell recruitment and that soluble P-selectin is a potent stop signal for continued leukocyte influx in GN. Like alpha/beta T cells, gamma/delta T cells may also be recruited into the kidney in GN, although this is not known and will be directly examined in this application.
The specific aims are to I) Examine the determinants of alpha/beta and gamma/delta T cell recruitment, and functional cooperation in GN, II) Determine the role of alpha/beta and gamma/delta T cell derived effector cytokines in GN, and III) Examine the contribution of selectins in alpha/beta T cell mediated glomerular injury. The unique advantages of knock-out mice, transgenic mice with green fluorescent protein (GFP) labelled alpha/beta and gamma/delta T cells and adoptive transfer experiments will be emphasized in these studies. The information gained from these studies will help delineate the T cell subpopulations, and mechanisms that downregulate injurious T cell mediated responses in GN and may thus define new targets for therapeutic intervention in the treatment of human glomerulonephritides.
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