The effect of immunoglobulin immunoadsorptions on delayed xenograft rejection of human CD55 transgenic pig kidneys in baboons

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Abstract
Delayed xenograft rejection (DXR) remains a major obstacle in discordant xenotransplantation. As strategies of complement inhibition and xenogeneic natural antibody (Ab) removal have been shown to give prolonged xenograft survival, we endeavored to determine whether combining these two strategies would lead to an additive effect in terms of graft survival. The study was initiated with two groups, A and B, where group A received normal kidneys and group B received hCD55 transgenic kidneys. Both groups underwent pre‐transplant (day − 1) total immunoglobulin (Ig) immunoadsorption (IA) and received an immunosuppression of cyclophosphamide, cyclosporine A, mycophenolate mofetil and corticosteroids. Two subsequent groups (C and D) receiving hCD55 transgenic pig kidneys were then performed with an ‘optimized’ immunosuppression (Cyclophosphamide starting 1 day earlier) but only group D recipients were immunoadsorbed. Biopsies taken during the post‐transplantation period were analyzed for Ab deposition, complement activation and cellular infiltration. No hyperacute rejection was observed. In the initial immunoadsorbed groups A and B, all baboons underwent DXR, which started surprisingly early (day 5 in most cases). In the subsequent two groups, the immunoadsorbed group D baboons also underwent DXR, again as early as day 5. In contrast, group C baboons did not show any signs of DXR on their day 6 biopsy or at their time of death. Analysis of graft biopsies from the kidneys undergoing rejection or with stable function showed strong deposition of anti‐Gal IgM in all cases whereas strong complement C5b‐9 deposits were only observed in biopsies at rejection. Cellular infiltration consisted mostly of monocytes/macrophages, was more pronounced in biopsies taken at rejection and was associated with a pro‐inflammatory environment involving interleukins 1α, 6 and 8. Our findings suggest that non‐specific Ig (anti‐Gal and non‐Gal Ig of all isotypes) IA or even incomplete IA in immunosuppressed baboon recipients of transgenic pig kidneys is detrimental to graft survival by being associated with an Ab and complement driven rejection. We speculate that the IA were insufficient in terms of Ig depletion or frequency inducing an Ab rebound or that this total Ig depletion also removed components facilitating graft survival.