An approach to induction of tolerance to pig cardiac xenografts in neonates

Abstract

There is a continuing need for donor hearts for infants with complex congenital heart defects. The transplantation of hearts from neonatal pigs would be an alternative to human organs, particularly if donor-specific immunological tolerance could be achieved. The great majority of infant humans do not make natural (preformed) antibodies against triple-knockout (TKO) pigs (that do not express any of the three known pig antigens against which humans have natural anti-pig antibodies). The transplantation of a heart from a TKO pig into an infant would therefore minimize any risk of early antibody-mediated rejection, and, with adequate immunosuppressive therapy, prolonged graft survival may well be achieved. Total host thymectomy (commonly carried out at the time of orthotopic heart transplantation in this age group) ± residual T-cell depletion and donor-specific pig thymus tissue transplantation might induce T-cell tolerance and allow immunosuppressive therapy to be discontinued (if there is in vitro evidence of T-cell and B-cell nonresponsiveness to donor-specific pig cells). Even if tolerance were not achieved, with continuing immunosuppressive therapy, the graft would likely "bridge" the patient until a suitable allograft became available or be associated with prolonged xenograft function.

The immune system in infants: Relevance to xenotransplantation

“…Additionally, the activation of complement and innate immune cells is weak, thus negating or minimizing the risk of early antibody-mediated rejection. 54…”

“…The excellent long-term outcomes of ABO-incompatible heart allotransplantation in infants provide encouragement that, with an effective tolerance-inducing regimen, both B and T-cell tolerance to a cardiac allograft may be achieved. 24,54 The lack of availability of hearts from deceased human donors remains a major barrier to allotransplantation. Xenotransplantation using genetically engineered pigs as sources of organs offers a realistic alternative, at least as a bridge until a suitable cardiac allograft becomes available.…”

“…We hypothesize that the induction of tolerance to a transplanted pig heart may be possible using a combination of (a) pretransplant T-cell depletion and thymectomy, (b) a genetically engineered pig as the source of the heart, (c) costimulation blockade-based immunosuppressive therapy, and (d) donor-specific pig thymic transplantation. 54 The possibility of achieving a state of tolerance is greater in infants than in adults due to the relatively immature immune system in infants. Even if tolerance cannot be achieved, prolonged survival of a genetically engineered pig heart in a recipient receiving maintenance immunosuppressive therapy would enable the heart to be employed either as a short-term "bridge" to allotransplantation, or as destination therapy.…”

Toward a solution for cardiac failure in the newborn

“…The governance of B cell responses and tolerance to saccharides is incompletely understood. Antibodies specific for some saccharide antigens, such as blood groups A and B and Galα1–3Gal, are usually absent at birth (2, 3, 43, 55–57) but after months or years appear spontaneously in all immune-competent individuals who lack the corresponding antigen (58). Introduction of polymerized saccharide antigens or cells expressing those antigens in the newborn does not spark immunity to the saccharides, and organs bearing those antigens are not subject to hyperacute or acute antibody-mediated rejection that otherwise might be induced by those antibodies (56, 59).…”

“…Viewed from a distance, then, xenotransplantation appears to be engaged in a marathon with alternative medical and surgical treatments, including allotransplantation, all potentially slowed by regulatory hurdles. The course of this marathon is eloquently brought into focus by David Cooper et al, who discuss the prospects for applying neonatal tolerance to advance xenotransplantation as a treatment for congenital structural heart disease and cardiomyopathies.…”