Role of Intrinsic (Graft) Versus Extrinsic (Host) Factors in the Growth of Transplanted Organs Following Allogeneic and Xenogeneic Transplantation

Abstract

In our studies of life-supporting GalT-KO pig-to-baboon kidneys, we have found that some recipients developed increased serum creatinine with growth of the grafts, without histologic or immunologic evidence of rejection. We hypothesized that the rapid growth of orthotopic pig grafts in smaller baboon recipients may have led to deterioration of organ function. To test this hypothesis for both kidneys and lungs, we have assessed whether the growth of outbred (Yorkshire) organ transplants in miniature swine is regulated by intrinsic (graft) or extrinsic (host environment) factors. Yorkshire kidneys exhibited persistent growth in miniature swine, reaching 3.7x their initial volume over 3 months vs. 1.2x for miniature swine kidneys over the same time period. Similar rapid early growth of lung allografts was observed and, in this case, led to organ dysfunction. For xenograft kidneys, a review of our results suggests that there is a threshold of 25cm3/kg for kidney graft volume/recipient body weight that induces cortical ischemia in transplanted GalT-KO kidneys in baboons. These results suggest that intrinsic factors are responsible, at least in part, for growth of donor organs and that this property should be taken into consideration for growth-curve mismatched transplants, especially for life-supporting organs transplanted into a limited recipient space.

Advances in the immunology of heart transplantation

“…78 More recently, thymokidney survival was extended to 193 days without evidence of rejection. 79 Attempts to induce mixed hematopoietic chimerism in primates using GalT-KO bone marrow have been advanced recently by generating hCD47 transgenic GalT-KO miniature swine. CD47 expression has prolonged the duration of porcine hematopoietic chimerism in baboons by inhibiting the phagocytosis of donor cells by primate macrophages.…”

Bringing Home The Bacon: Update on The State of Kidney Xenotransplantation

“…It is not yet certain whether pig erythropoietin is functional in primates but, if not, human recombinant erythropoietin can be administered or the organ-source pig can be rendered transgenic for human erythropoietin. A rapid increase in size of the pig kidney graft has been documented during the first few weeks in some (but not all) NHP studies [20, 28], and it is uncertain whether this is related to (i) the transplantation of a single immature kidney into a more mature NHP, or (ii) retained pig growth hormone in the kidney. It is known that human growth hormone is active in pigs.…”

Tolerance in xenotransplantation

“…Thus far, thymic transplantation has proven to be a powerful strategy to induce T cell tolerance across both allogeneic and xenogeneic barriers in pig-to-pig, pig-to-mouse, pig-to-humanized mouse and pig-to-baboon models (19, 21, 22, 30–33). T-cell education occurs in the thymus and the thymus is known to play an integral role in self-tolerance.…”

“…In initial studies, recipients of GalT-KO kidneys and vascularized thymic grafts from the same donors maintained normal creatinine levels up to 83 days, while GalT-KO kidneys without thymic grafts were rejected by 34-days, even with potent immunosuppression (41) (31). Recently, further modification of the induction regimen facilitated survival of life-supporting thymokidneys for over 6 months (30). Notably, multiple recipients bearing functional thymokidneys for over 3 months developed T cells with the phenotype of new thymic emigrants (CD4+/CD31+/CD45+) as well as donor-specific unresponsiveness at the T and B cell levels.…”

“…Notably, multiple recipients bearing functional thymokidneys for over 3 months developed T cells with the phenotype of new thymic emigrants (CD4+/CD31+/CD45+) as well as donor-specific unresponsiveness at the T and B cell levels. Because recipients were completely thymectomized prior to transplantation, these thymic emigrants most likely developed in the vascularized thymic grafts of the composite thymokidneys (30). …”