Prolonged Survival of Pig Skin on Baboons After Administration of Pig Cells Expressing Human CD47

Abstract

Background Successful xenotransplantation will likely depend, in part, on the induction of immunological tolerance, since the high levels of immunosuppression otherwise required would likely have unacceptable side effects. Rapid clearance of administered porcine hematopoietic stem cells by primate macrophages has hampered previous attempts to induce tolerance through mixed hematopoietic chimerism across a pig-to-primate barrier. Phagocytosis is normally inhibited by binding of cell surface protein CD47 to macrophage SIRPα receptors. However pig CD47 has previously been shown to be ineffective in transducing signals through primate SIRPα. Methods Mobilized peripheral blood hematopoietic cells from transgenic swine expressing high or low levels of human CD47 were infused into conditioned baboons at 3 time points over a 9-week period. Xenogeneic peripheral blood chimerism was assessed following each infusion. Split thickness skin grafts from the hematopoietic cell donor swine were placed on recipients 5 weeks following the last cell infusion and 7 weeks following the discontinuation of all immunosuppression to test immune response. Results The level and duration of transient chimerism were substantially greater in baboons receiving hematopoietic cells from a pig expressing high levels of human CD47. Skin graft survival on high CD47 recipients was prolonged as well, in one case showing no signs of rejection at least 53 days following placement. Conclusions Prolongation of transient porcine chimerism via transgenic expression of human CD47 in a primate model is associated with an immune modulating effect, leading to markedly prolonged survival of donor swine skin xenografts that may be applicable to clinical solid organ xenotransplantation.

Advances in the immunology of heart transplantation

“…80 Encouragingly, such prolongation has been associated with markedly prolonged donor swine skin xenografts. 81 …”

Tolerance in xenotransplantation

“…Skin grafts on both baboons that received HSC from 18286 showed markedly prolonged survivals (70 and >23 days, respectively), while skin grafts on both baboons that received HSC from 18289 showed no difference in survival from the control baboon (14 days). These results therefore indicate a strong correlation between hCD47 expression, prolonged peripheral porcine chimerism, and marked prolongation of porcine skin grafts in the absence of concurrent immunosuppression(62). .…”

“…In order to test the ability of human CD47 (hCD47) to similarly improve engraftment of porcine cells in baboons, transgenic swine were produced on the GalT-KO inbred miniature swine background (62). Two swine expressing markedly different levels of the hCD47 transgene on peripheral blood mononuclear cells were produced, one expressing high levels (18286) and one expressing very low levels (18289).…”

“…There was no evidence for sensitization of the recipient baboons at either the antibody or T-cell levels (62). To test for effects of the HSC transplants on recipient responses, split-thickness skin grafts (STSG) from the transgenic PBSC donors were placed onto full-thickness graft beds at 14 weeks after the cell transplants, by which time all exogenous immunosuppression had been discontinued for over four weeks.…”

Xenotransplantation

“…Tena et al demonstrated that pig cells expressing human CD47 are associated with an immune-modulating effect, which leads to markedly-prolonged survival of pig skin grafts in NHPs [60]. …”