The long-term objective of this research is to improve treatment of rheumatoid arthritis (RA) by developing cell-based therapies that target auto reactive T cells. The hypothesis to be tested is that defined subsets of activated B cells can mediate down-regulation of inflammation by inhibiting the activity of T helper cells. This hypothesis is based on the preliminary finding that a subset of B cells from immunized mice is capable of mediating T cell death in an antigen-specific and Fas ligand (CD178)-dependent manner. These 'regulatory'B cells have been observed in other models of inflammation in mice, as well as in human diseases.
Aim 1 : Study the induction and/or down-regulation of immune regulatory molecules on B cell subsets following in vitro and in vivo stimulation.
Aim 2 : Analyze the cell-cell interactions required to induce cell death or regulation of Th cells following coculture of activated B cell subsets with arthritis antigen-specific Th cells.
Aim 3 : Study the ability of antigen-loaded, 'regulatory'B cells to maintain regulatory phenotype, skew the ThlL-17 response, and prevent or treat arthritis in mice.
Aim 4 : Determine the relative contribution of endogenous CD178+ B cells to the in vivo regulation of ThlL-17 response and joint inflammation.
These aims will be achieved using established models of arthritis in mice. B cells from these mice will be analyzed for expression of regulatory molecules after various modes of stimulation. Assays for T cell activation and death will be carried out by coculture of T cells from immunized mice and antigen-pulsed purified B cells. Cell-cell interactions between B and T cells will be blocked by neutralizing antibodies to determine which interactions are critical to T cell regulation. Expansion of murine B cells for adoptive transfer will be achieved using CD40L-transduced fibroblasts, and culture parameters will be optimized to produce large numbers of regulatory B cells. B cells will be injected into mice prior to or during established arthritis to study in vivo regulatory effects. An arthritis model involving injection of arthritogenic antigens will be tested in B cell deficient mice in order to further substantiate the importance of regulatory B cells. Relevance: Regulatory B cells have potential in treating RA because of their ability to specifically identify, interact with, and eliminate the T cells involved in arthritis progression. Elimination of disease-causing T cells, while sparing bystander T cells would be a significant improvement over current non-specific therapeutic strategies.
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