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DENDRITIC CELLS AND SECOND SIGNAL BLOCKADE: A STEP TOWARD ALLOGRAFT TOLERANCE?

The ultimate goal of clinical organ transplantation is to induce immunological tolerance to the allograft. Dendritic cells, the main antigen-presenting cells, are a complex system including numerous subsets, capable of inducing T-cell activation, and thus initiating an immune response, but also of inducing tolerance. In organ transplantation, the problem is even more complex because of the coexistence of dendritic cells from the donor, responsible for direct recognition of foreign antigens by T cells, and dendritic cells from the recipient, responsible for indirect antigen presentation to host T cells. Among the various methods of immunomanipulation aiming at inducing tolerance, blockade of the second signal pathway by monoclonal antibodies (anti-CD28, anti-B7, anti CD40, anti-CD40L, CTLA4-Ig) has yielded promising but incomplete results. Viral transfection of recipient immature dendritic cells encoding for immunosuppressive or apoptotic molecules, such as interleukin 10, transforming growth factor-&bgr;, CTLA4-Ig, or Fas ligand, is also able to induce hyporesponsiveness. Another very promising method consists of associating donor cells (bone marrow cells, CD34+ cells, dendritic cells) and polyclonal or monoclonal antibodies (anti-CD4, anti-CD40L, CTLA4-Ig) to induce microchimerism and partial tolerance. Reflecting on these data would seem to be an interesting direction for future prospects.