PREVENTING ANTI-GAL PRODUCTION AGAINST XENOGRAFTS

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DESCRIPTION (verbatim from the applicant's abstract) The use of pig heart xenografts in humans may solve in the future the problem of paucity of heart allografts. Currently, binding of the human natural anti-Gal antibody to alpha-gal epitopes (Gal al-3Gal p14GlcNAc-R) on pig cells results in the immune rejection of xenografts. This obstacle can not be overcome by removal of anti-Gal by affinity columns, because this antibody returns to its normal level within few days. Furthermore, the xenograft recipient produces large amounts of high affinity anti-Gal IgG in response to alpha-gal epitopes on the xenograft. This elicited anti-Gal effectively mediates delayed and chronic rejection of xenografts. We propose to prevent anti-Gal production in xenograft recipients by specific elimination of B cells producing this antibody (designated anti-Gal B cells). This may be achieved by in vivo targeting of an alpha-gal coupled toxin, ricin A, (a-gal-ricin) to B cell receptors (BCR) on anti-Gal B cells, subsequent endocytosis of the toxin and death of these cells. Furthermore, the elimination of mature anti-Gal B cel}s may create a window of opportunity for long term prevention of maturation of these cells. Circulating glycoproteins expressing alpha-gal epitopes, continuously released from the xenograft, may bind to BCR on immature anti-Gal B cells and induce specific apoptosis of these B cells. We will test this hypothesis in alpha-l,3-galactosyltransferase knock-out (KO) mice . Our aims are 1) to define the optimal a-gal-ricin treatment protocol for elimination of mature anti-Gal B cells and plasma cells, 2) to determine whether infused alpha-gal glycoproteins, or such glycoproteins released from wild type mouse heart allografts, can induce long term elimination of immature anti-Gal B cells, and 3) to determine whether a-gal-ricin treatment can affect survival of pig single cell xenografts in KO mice. Success in these studies will help in planning effective treatments for preventing anti-Gal response in primate xenografts recipients. |