Introduction: We have recently reported pig xenograft survival of more than 2.5 years in a heterotopic cardiac xenograft model. Some of the animals exhibited local and systemic inflammatory response to the xenograft, which aided in graft rejection. This inflammatory response also resulted in massive adhesions in the abdominal cavity. Here we report benefits of additional human gene expression on graft survival and prevention of an inflammatory response. In these experiments we used pigs expressing a combination of 5 human genes along with one gene knockout to evaluate their role in graft survival and suppressing the inflammatory response.

Methods: Three specific pathogen free baboons (8-12Kg) received heterotopic cardiac xenografts from either Group 1 (GTKO.CD46.EPCR.DAF.CD39.CD47) (n=2) or Group 2 (GTKO.CD46.EPCR.DAF. TFPI.TBM) (n=1) pigs. Recipient baboons were treated with a short course of anti CD20 antibody, cobra venom factor, anti thymocyte globulin, and were maintained on anti CD40 antibody (clone 2C10R4), mycophenolate mofetil and tapering doses of steroids. Graft survival was monitored with telemetry, periodic echocardiography and manual palpation. Blood work (CBC, chemistry, troponin and ACT) was performed at regular intervals.

Results: One of the grafts in-group 1 stopped contracting on day 46 and was explanted. The remaining grafts are still surviving for 143 and 68 days. No signs of any inflammatory reaction were observed. One baboon that needed laparotomy for graft evaluation and biopsy, displayed absolutely no adhesions due to the inflammatory process. All hematologic parameters were maintained within normal limits except for a brief phase of infection after exploratory laparotomy. No thrombocytopenia or consumptive coagulopathy was observed. Normal overall animal health was maintained without any complications and only one incidence of infection was observed in a baboon subsequent to laparotomy for telemetry implant extraction.

Conclusion: The expression of multiple human genes prevented xenograft rejection for the extended period of time and also helped in avoiding inflammatory reaction. Absence of inflammation was demonstrated on laparotomy and blood analyses. The expression of CD47 and TBM with known anti-inflammatory properties may have contributed in avoiding the inflammation but needs further evaluation.

CITATION INFORMATION: Mohiuddin M, Singh A, Chan J, Corcoran P, Thomas III M, Lewis B, Ayares D, Horvath K. Long Term Heterotopic Cardiac Xenograft Survival from Donor Pigs with Six Gene Modifications. Am J Transplant. 2016;16 (suppl 3).

« Back to 2016 American Transplant Congress