Targeting a dendritic cell-stromal axis in lupus
Lymphoid tissues are the sites of lymphocyte stimulation and autoantibody generation, and one potential strategy for dampening autoimmune responses in SLE is to target the stromal infrastructure that provides survival, guidance, and regulatory signals within the lymphoid tissues. We have recently shown that abnormal CD4-CD8- T cells in the MRL-lpr/lpr model of lupus are sequestered within ectopic follicles away from the normal regulatory T cell zone stromal microenvironment and that treatment with the receptor tyrosine kinase inhibitor SU5416 results in disruption of the ectopic follicles, normalization of CD4-CD8- T cell localization with T zone stroma, altered T cell phenotype, and reduction of anti-dsDNA titers. SU5416 can target dendritic cells, and preliminary data in wild-type mice suggest that dendritic cells maintain proper function of the the stromal cells that delineate the boundaries of compartments and promote plasma cell survival. We propose to test the hypothesis that dendritic cells maintain stromal integrity in mouse models of lupus and targeting of this dendritic cell-stromal axis can be used to disrupt ongoing autoimmune responses. We will test the hypothesis via the following Our aims are to 1) Examine the extent to which dendritic cells maintain stromal integrity, lymphocyte phenotype, and plasmablast survival in MRL/lpr mice, 2) Understand the roles of gp38 and LTbR in maintaining stromal integrity, lymphocyte phenotype, and plasma cell survival, 3) Examine the utility of orally available, FDA-approved, SU5416-related Sutent for treatment of MRL/lpr and B6.DEF-/-SWAP-/- lupus mice. These experiments have the potential to provide novel insights into stromal regulation and the control of autoimmune responses. This proposal also has the potential to lead to the rapid repurposing of an FDA-approved drug for novel use in lupus.