TOLERANCE TO BONE MARROW TRANSPLANTS

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This project has two overall goals: 1] understanding the mechanism(s) of transplantation tolerance to parental strain bone marrow cell (BMC) incompatible grafts, when the major effector cell that eliminates donor stem cells is an NK cell; and 2] Developing 'clinically applicable' method(s) of inducing tolerance to incompatible BMC grafts. The research is aimed clinically at accomplishing successful bone marrow transplants without graft-versus-host disease (GVHD) even when the door is not matched perfectly at HLA (H2 in the mouse). Removal of donor marrow T cells helps ameliorates GVHD, but it increases the likelihood of rejection of the BMC graft. To accomplish these goals, we have created two specific aims, the first one aimed at goal 1] and the second aimed at goal 2]. In aim 1, we will analyze the mechanisms of tolerance induction in NK cells in murine (BALB/c X C57BL/6)F1 (cB6F1)-to BALB/c (C) radiation BMC chimeras. In the CB6F1-to-C model, the effector cells are 5E6+ NK cells. This model can be used to determine the mechanism of tolerance if 'missing self' hypothesis for NK cell mediated BMC graft rejection is correct, i.e., NK cell receptors receive negative signals from certain class I Ags. A failure to detect those class I Ags allows NK cells to kill. In contrast, the 'Hh" hypothesis suggests that NK cells use NK receptors to recognize Ags on stem cells in a positive fashion. The Ags themselves are under a peculiar regulation such that homozygosity is required for expression. In aim 2, we will try three approaches to induce tolerance to BMC grafts that are 'clinically applicable'. The first is oral tolerance, induced by feeding donor-type BMC prior to challenge with marrow grafts; the second is induction of anterior chamber-associated immune deviation (ACAID) by injection of BMC into the anterior chamber of the eye prior to challenge with BMC; the third is us of ultraviolet light B (UVB) irradiation of antigen-presenting cells, e.g. Langerhans cells (LC) of the skin. UVB treated LC not only fail to stimulate immune responses) but actually lead to 'tolerance'. Success in this aim could benefit patients undergoing bone marrow transplants.