Both CIA and PGIA can be adoptively transferred to syngeneic immunocompromised mice by lymphocytes isolated from arthritic donors. Despite the autoimmune pathogenesis and development of robust and sustained inflammation of multiple joints in CIA or PGIA, the proportion of T cells present in the synovial fluid of these joints has been reported to be small. However, with regard to autoimmune dis eases, the consensus is that upon entry into the joints from the bloodstream, armed effector T cells can pro vide cytokinechemokine stimuli to surrounding cells and act in concert with these cells to trigger and main tain a local inflammatory process. To address the importance of joint homing versus lymphoid organ homing T cells in PGIA, we took two experimental approaches.
First, using in vivo two photon microscopy, we monitored the migration of fluorescence labeled T cells into the ankle joints and joint draining lymph nodes of syngeneic severe combined immunodeficient mice during the course of the adoptive transfer of PGIA. TPM has been successfully used to visualize the rapid influx of T cells into the central nervous system upon recommended reading induction of experimental allergic encephalomyelitis. an animal model of multiple sclerosis. However, in the adoptively transferred model of PGIA, we could MG-132 clinical trial hardly detect any T cells within the synovial tissue of the joints of SCID mice by TPM imaging either before or after arthritis development. The lack of synovial T cells was confirmed by immunohistochemistry performed on tissue sections of the same joints, but a small population of T cells could be identified in syno vial fluid samples of inflamed joints by flow cytometry.
Second, to determine whether the availability of T cells in the circulation affects their migration into the joints and arthritis development, we used FTY720, a drug known to deplete T cells in peripheral blood by inhibit ing their exit from lymphoid organs. FTY720, a sphingosine 1 phosphate receptor modulator, has been found to be effective in preventing or suppres sing EAE in rodents and shows a strong therapeutic potential in MS. In adoptively transferred PGIA, we found that FTY720 treatment of SCID mice, transferred with arthritic donor lymphocytes, effectively reduced T cell presence in both the circulation and synovial fluid but did not inhibit or delay the transfer of arthritis. In contrast, SCID mice receiving T cell depleted cells from the same arthritic donors failed to develop arthri tis, suggesting a strict requirement for substantial T cell presence for disease induction at locations other than the peripheral joints. Materials and methods Mice, immunization, and assessment of arthritis Adult female BALBc mice and female SCID mice were purchased from the National Cancer Institute.