Pig Artery Patch Transplantation (Tx) as a Surrogate For Heart Tx in Baboons.

Abstract

Background: Pig heart Tx in baboons is time-consuming, expensive, and associated with complications. Graft failure can result from the development of (i) elicited anti-pig antibodies or (ii) thrombotic microangiopathy in the graft. We have developed a simple substitute model of pig artery patch Tx and have compared the results with those following heart Tx. Methods: Baboons received artery patch Tx into the wall of the abdominal aorta) (Gp 1; n=28) or heterotopic heart Tx (Gp 2; n=17) from GTKO pigs (+/- transgenes aimed at complement or coagulation regulation [n=22] +/- T cell regulation [a human mutant MHC class II transactivator, CIITA, n=9]). Nine recipients (patch 4, heart 5) received no immunosuppressive therapy (IS). The remainder (patch 24, heart 12) received IS based on blockade of either the CD40:CD154 pathway (anti-CD154 or anti-CD40 mAbs) or the CD28:B7 pathway (CTLA4-Ig - abatacept or belatacept) or of both pathways (anti-CD40mAb+belatacept). Monitoring was by MLR, anti-pig IgM and IgG, histopathology, and various coagulation (platelet count, fibrinogen, D-dimer) and inflammatory (C-reactive protein, CRP) parameters. Results: In both models, (i) with no IS, grafts induced a significant T cell response; (ii) anti-CD154mAb prevented a T cell response, whereas CTLA4-Ig did not; and (iii) anti-CD40mAb+belatacept prevented T cell proliferative and elicited antibody responses and cellular infiltration of the graft. Expression of CIITA in a patch graft reduced the elicited antibody response. Despite heparin therapy, thrombocytopenia, fall in fibrinogen, and increases in D-dimer and CRP were documented in baboons with heart grafts that did not express a human coagulation-regulatory transgene, but only increases in D-dimer and CRP were seen after patch Tx. Treatment with anti-CD40mAb+belatacept did not prevent the rise of D-dimer or CRP in either model. An IL-6R antagonist prevented a rise in CRP after patch Tx. Conclusions: Outcomes of patch and heart Tx are similar. Expression of CIITA reduces the elicited antibody response to a patch graft. To replace anti-CD154mAb, blockade of both the CD28 and CD154 pathways is essential. Patch Tx provides some (but not all) information on the coagulation and inflammatory responses to a heart graft. IL-6R blockade may reduce the inflammatory response. DISCLOSURE:Ayares, D.: Employee, Revivicor.