Bone marrow transplantation is used to treat neoplastic, certain genetic, and even autoimmune diseases. The need to transplant across MHC barriers due to the lack of MHC-identical siblings for patients. It is important to devise approaches to prevent rejection, and induction of tolerance is a logical strategy. Because NK cells are major effectors that reject BMC grafts by recognizing class I Ag by positive signaling Ly49 receptors, but that ability is regulated by negative signaling Ly49 receptors. The mechanism requires co-existence of donor and host type NK cells to allow such 'alteration' of the NK cell repertoire. Moreover, T cells are not required. To test these notions marrow chimeras will be generated, e.g., F1 hybrid to parent strain, and NK cells will be examined for expression of positive and negative expression of receptors for class I Ag, such as D4. Marrow grafts will validate tolerance induction, and use of T cell deficient marrow donors and hosts will critically test the importance of T cells to induction of NK cell tolerance.
In Aim 2, experiments are designed to develop clinically applicable approaches to inducing tolerance to marrow grafts that involve T cells and/or NK cells. These approaches include 1] infusion of marrow derived dendritic cells in immunosuppressed mice (low dose irradiation, antibodies to CD4 and CD8 T cells and to NK cells, 2] blockade of CD4 and CD8 cells with non-depleting antibodies to induce a tolerance that is maintained by T suppressor cells, 3] interference with co-stimulatory signals between CD28 or CD40L, on T cells with B7 or CD40 on dendritic cells, 4] interruption of CD2 or 2B4-CD48 interactions that regulate alloreactivity, 5] polarization of effector cells to a 'Th2-like' phenotype with anti-IL-12 and IL-4, or combinations of these. These approaches will be tried in sequence from minor H antigen mismatches, F1 to parent mismatches, HS mismatches that do or do not involve host NK cells, and parent to F1 hybrid grafts (hybrid resistance). The results of these studies will hopefully lead to clinical marrow engraftment.
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