Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects about 1 percent of the general population worldwide. The disease is characterized by inflammation of the synovial joints leading to destruction of cartilage and bone. The initiating events and the mechanisms that perpetuate the inflammation remain obscure. Although the role of CD4+ T cells has been established, the function of cytotoxic lymphocytes in this disease has not been entirely elucidated. Some studies suggest that cytotoxic lymphocytes may decrease the incidence or suppress inflammation in murine models of arthritis. Cytotoxic lymphocytes exert their effects mainly through target cell apoptosis. One of the major mechanisms utilized by these cells to kill their targets is the granule exocytosis pathway. Activated lymphocytes contain a family of highly related serine proteases termed granzymes. Recent evidence suggests that granzymes are required for cell-mediated cytotoxicity. We recently created a mouse with a null mutation in the cysteine protease dipeptidyl peptidase I (DPPI) and showed that this enzyme is required for the activation of granzymes A and B in vivo. Furthermore, we showed that DPPI-deficient cytotoxic lymphocytes have a severe defect in their ability to induce DNA fragmentation and apoptosis from different target cells. The objective of this proposal is to evaluate the role of DPPI/granzymes in models of murine arthritis. We hypothesize that cytotoxic lymphocytes, through the action of granzymes, may have a -protective role in murine inflammatory arthritis. To explore this hypothesis, we propose the following aims: 1. We will explore the role of DPPI and granzymes in models of murine arthritis. Since there is no single animal model that recapitulate all the features of RA, we will study 3 distinct murine arthritis models that differ in the degree and type of cartilage damage [zymosan-induced arthritis (ZIA), antigen-induced arthritis (AIA), and collagen-induced arthritis (CIA)]. 2. We will explore the role of CD8+ I cells and granzymes in CIA We hypothesize that CD8+ T cells may exert a protective role in CIA, through the actions of granzymes. In this aim, we propose to generate chimeric animals using severe combined immunodeficient (SCID) mice. Spleen cells from arthritic mice will be depleted of CD4+ or CD8+ T cells prior to transfer into SCID mice to elucidate the specific role of T lymphocyte subsets (and granzymes) in the induction and progression of arthritis.
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