Tolerance to Carbohydrate Antigens in Transplantation

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): There is a critical shortage of human organs and tissues for transplantation, which is particularly serious in infants requiring heart transplants. Recent work from Toronto indicates that, if an ABO- incompatible heart is transplanted into an infant human before that infant has developed natural anti-A and/or B antibodies (Abs), a state of B cell tolerance develops in which Abs directed against the incompatible blood type antigen never develop. The primary purpose of the proposed studies is to determine whether the transplantation of pig tissue into infant nonhuman primates (before the development of anti-pig Abs) can result in B cell tolerance to pig carbohydrate antigens. Secondarily, we shall investigate whether T cell tolerance can be induced under an anti-CD154 mAb-based immunosuppressive regimen. In Aim 1, we shall determine that the transplantation of a segment of carotid artery from an A/B- incompatible baboon (allograft) or from a pig (xenograft) into a non-immunosuppressed infant baboon will induce a T cell-dependent elicited Ab response. In Aim 2, we shall investigate whether a segment of artery transplanted from an ABO-incompatible baboon into an immunosuppressed infant baboon, before the development of natural anti-A or B Abs, will induce antigen-specific B cell tolerance to the A or B carbohydrate antigens expressed on that artery. In Aim 3, we shall investigate whether a segment of artery transplanted from a wild-type pig into an immunosuppressed infant baboon, before the development of natural anti-pig Abs, will induce antigen-specific B cell tolerance to the pig carbohydrate antigens expressed on that artery. The baboons in all groups will be monitored by hemagglutination assays to detect anti-A or B Abs, by flow cytometry to detect anti-carbohydrate Abs (anti-A/B, anti-pig, anti-Gal, anti-nonGal), by ELISA to detect anti-Gal Abs, and by ELISPOT to document B cell production of such Abs. Mixed lymphocyte response assays will determine the T cell response, and the donor artery graft will be biopsied at intervals. On the basis of preliminary studies, we anticipate that anti-A or B and anti-pig Abs will develop in the baboons in Aim 1 between 2 and 6 months of age. In Aim 2, no Abs will develop to the donor-specific A or B antigen, but anti-pig Abs will develop. In Aim 3, no anti-pig Abs will develop, but anti-A or B Abs will develop. In Aims 2 and 3, we anticipate that, in the presence of transplanted donor tissue, B cell tolerance will have developed to the specific carbohydrate antigens, but T cell tolerance may not have developed. After discontinuation of immunosuppressive therapy, therefore, elicited Abs to these (and other) antigens are likely to be associated with graft rejection. The studies will allow investigation of the outcome of organ grafts in the absence of natural (and elicited) anti-carbohydrate Abs, and on the possibility of inducing T cell tolerance to carbohydrate antigens through costimulation blockade in infancy, when the immune system is malleable. [unreadable] [unreadable] [unreadable]