This proposal is focused on understanding the regulation of lymphocyte trafficking as a fundamental therapeutic approach to autoimmunity and transplantation rejection. Immunosuppressive regimens generally impact upon both lymphoid and myeloid hemopoietic lineages, rendering patients highly susceptible to bacterial, fungal and viral infection, as well as to the long term toxicities of current drug classes, which include significant nephrotoxicity and bone loss. The project brings together chemical and biological approaches to activation of the receptors for the lysophospholipid sphingosine 1-phosphate (S1P) that result in the sequestration of lymphocytes by inhibiting their egress from lymphnodes. The reversible disappearance of lymphocytes from blood results in immunosuppression to peripheral antigen and protects from autoimmune tissue damage, transplant rejection and graft versus host disease. Potential advantages to autoimmune patients are based on broadening therapeutic window by retaining myelomonocytic cell function to enhance host defense, and the relative absence of nephrotoxicity or metabolic sequelae. This proposal will focus on improving the understanding of the mechanism by which S1P receptor agonism produces clinically useful immunosuppression, and will attempt to separate the mechanism of inhibition of lymphocyte egress from the pleiotropic effects of S1P upon pressor and cardiac function.
Specific aims of the proposal are to (1) Determine the detailed tissue expression of SIP receptors in lymphoid tissues. This will be done by in situ hybridization and immunohistology; (2) Determine receptor selectivity for alteration of lymphocyte trafficking using receptor selective agonists and S1P receptor subtype null mice. Receptor selective agonists will be defined and used in wild-type and S1P receptor deletant mice, to determine the role of specific receptors in producing lymphopenia and other physiological effects of S1P. (3) Identify the cellular site of action of S1P agonists in lymphocyte sequestration. The study on receptor distribution and evaluation of surrogate marker changes in situ in lymphoid organs will determine whether the effect of S1P receptor agonists is on lymphocytes, endothelium or both. (4) Establish the quantitative changes in immune responses induced by S1P receptor agonism. Local and systemic functional effects of S1P agonism will be studied quantitatively for immunosuppression or potentiation of immune responses in transgenic mice responding to ovalbumin peptide, to understand the roles of the S1P system in control of lymphocyte recirculation. These studies will yield an enhanced understanding of the basic mechanisms by which S1P receptor agonism induces clinically useful immunosuppression of potential use in autoimmunity.
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