Tolerance in xenotransplantation

Abstract

This review describes recent progress in tolerance-inducing strategies across xenogeneic immunological barriers as well as the potential benefit of a tolerance strategy for islets and kidney xenotransplantation. Recent findings Using advanced gene editing technologies, xenotransplantation from multi-transgenic alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of renal xenograft survival, ranging from days to greater than several months for life-supporting kidneys, and >2 years in a heterotopic non-life-supporting cardiac xenograft model. Continuous administration of multiple immunosuppressive drugs has been required and attempts to taper immunosuppression have been unsuccessful. It appears likely that low levels of T cell-dependent antibodies and activation of innate responses are responsible for xenograft loss. Mixed chimerism and thymic transplantation approaches have achieved xenogeneic tolerance in pig-to-mouse models and both have recently been extended to pig-to-baboon models. Encouraging results have been reported, including persistence of macrochimerism, prolonged pig skin graft survival, donor-specific unresponsiveness in vitro and detection of recent T cell emigrants in vivo. Summary Although tolerance induction in vivo has not yet been achieved in pig-to-baboon models, recent results are encouraging that this goal will be attainable through genetic engineering of porcine donors.

The immune system in infants: Relevance to xenotransplantation

“…110 Since the early studies of Billingham and his colleagues, 111 many studies suggest a role for thymectomy in the induction of tolerance. [112][113][114] Although the clinical consequences of thymectomy are not certain, some studies suggest there is higher risk for autoimmune disease and a reduced response to vaccines. 98,115 (Table 5).…”

“…The induction of donor-specific tolerance is the ultimate goal in organ transplantation, as the recipient would no longer require longterm immunosuppressive therapy. 114,123,124 Tolerance to maternal antigens develops naturally in the fetus and is retained throughout life.…”

The Veterinary Immunological Toolbox: Past, Present, and Future

“…For example, pigs are emerging as a very powerful model to predict human influenza vaccine responses but to achieve the maximum benefit of such models a complete toolkit is required (58). Gene editing is already providing pig organs for future human xenotransplantation, a biomedical application that has helped drive reagent development in pigs (59,60).…”

Toward a solution for cardiac failure in the newborn

“…They propose including measures such as thymus xenotransplantation and blockade of co-stimulation that are being pursued for induction of xenogeneic tolerance in mature individuals (19, 22, 63), reasoning, we think correctly, the deliberate induction of tolerance would be more effective in newborns than in adults.…”