Transplantation Biology Research Center
Massachusetts General Hospital
Prolonged survival of porcine skin on baboons following administration of porcine cells expressing human CD47
Aseda Tena1, David H Sachs1, Christopher Mallard1, Yong-Guang Yang2, Masayuki Tasaki1, Evan Farkash2, Robert B Colvin2, David A Leonard1, Robert Hawley1.
1Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA, United States; 2Columbia Center for Translational Immunology, Columbia University, New York, NY, United States; 3Pathology, Massachusetts General Hospital, Boston, MA, United States
Background: To inhibit phagocytosis of porcine cells by primate macrophages in a mixed chimerism protocol, we generated hCD47/GalT-KO transgenic swine. We report the results of hematopoietic stem cell (HSC) transplantation from these swine into baboons with respect to cell survival and immune response.
Methods: Five baboons underwent a conditioning regimen consisting of non-myeloablative irradiation and lymphocyte depletion. Two baboons received mobilized HSC from a pig expressing high levels of hCD47 (CD47hi), two received cells from a hCD47low donor and one baboon received no cells. Immunosuppression consisted of FK506 daily for 30 days and anti-CD154 antibody weekly for 7 weeks. Cell recipients received challenge infusions of mobilized HSC from the same donor swine 7 and 10 weeks following the initial infusion. All baboons received split thickness porcine skin grafts onto full thickness wound beds at 14 weeks, without any additional conditioning or immunosuppression.
Results: Baboons receiving hCD47hi HSC had a 5X greater level of peripheral macrochimerism than the hCD47low group 5 hours post-infusion. At 24 hours, chimerism in the hCD47hi recipients remained greater than 10%, whereas chimerism was undetectable in the hCD47low recipients. No evidence of humoral or cellular sensitization was observed prior to skin grafting. A xenogeneic donor skin graft on one of the baboons receiving hCD47hi HSC developed healthy, confluent porcine skin over the entire wound bed by 6 weeks after graft placement, with slow rejection over the following 4 weeks. Histological examination at7 weeks showed normal epidermis and superficial dermis, with eosinophil-rich granulomatous inflammation in the deep dermis and host junction. The xenogeneic donor skin graft on the second baboon receiving hCD47hi HSC, showed a similar course for about 40 days but was then lost to wound infection. In contrast, xenogeneic skin grafts were rejected by day 14 in the both recipients of hCD47low HSC and in the control baboon.
Conclusions: High transgenic expression of human CD47 increased the level and duration of porcine hematopoietic chimerism in non-human primates. This prolongation was associated with markedly prolonged survival of donor swine skin grafts in the absence of concurrent immunosupression, suggesting that the transient chimerism had a potent tolerizing effect.
17:30 - 18:30
|Young Investigators Best Mini-Orals Session||Prolonged survival of porcine skin on baboons following administration of porcine cells expressing human CD47||Plenary Room 1|