The lysophospholipid growth factor sphingosine 1-phosphate (S1P) is derived from macrophages, mast cells and platelets, and regulates lymphocyte migration, homing and other functions through the T and B cell-predominant S1P1 G protein-coupled receptor (R). The major effect of the 0.3 ?M to 3 ?M S1P in plasma, lymph and inflamed tissues transduced by S1P1 Rs is inhibition of lymphocyte chemotactic responses to chemokines. Rat anti-S1P1 R monoclonal antibodies and small heterocyclic compounds inhibitory for S1P1 Rs, but not S1P4 Rs, suppress all T cell migration effects of S1P. Non-suppressible overexpression of S1P1 Rs selectively by T cells in a transgenic mouse (TG) and loss of T cell S1P1 Rs in a conditional knock-out mouse (KO) both alter T cell traffic, T cell effector responses, and isotype-specific antibody production. The newly-developed anti-S1P1 R antibodies and pharmacological probes, and the TG and KO mouse models now will be applied in studies designed to: 1. Elucidate the nature and control of post-translational modifications of lymphocyte S1P1 Rs that affect their expression and functions, 2. Characterize the transcriptional mechanisms and biochemical pathways used by the S1P- S1P1 R axis to increase the Th2/Th1 cytokine and activity ratios sufficiently to suppress delayed-type hypersensitivity and promote allergic reactions, 3. Define roles of the S1P- S1P1 R axis in controlling tissue-specific distribution and traffic of T cells, including rolling-adhesion on endothelial surfaces, tissue homing at distinct stages of differentiation, interactions with other immune cells in intact lymph nodes by 2-photon microscopy, and compartmental responses to antigen, and 4. Evaluate involvement of the S1P- S1P1 R axis in central nervous system influx and pathogenetic reactions of T cells in mouse experimental autoimmune encephalitis (EAE). Suppression of T cell S1P1 R expression or signaling is predicted to inhibit T cell entry into sites of transplanted organ rejection and autoimmunity with attendant therapeutic benefits and without compromise of host defense against microbial infections. ? ? ? ?
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