*Purpose: We have recently reported that both CD80 upregulation and the degradation of SMPDL-3b on glomerular podocytes are involved in the development of post kidney xenotransplant (XKTx) proteinuria in a pig-to-baboon model. In this study, we assessed (1) if the incompatibility of porcine CD47 and baboon macrophages (CD47/SIRPα pathway) was involved in the development of post XKTx proteinuria, and (2) if transgenic (Tg) expression of human CD47 (hCD47) caused negative effects via a CD47/TSP-1 pathway following pig-to-baboon K+VT Tx.

*Methods: Study 1: Phagocytosis of porcine endothelial cells (EC) as well as podocytes with/without hCD47 was assessed in co-culture assays with baboon macrophages. Study 2 (to assess the effect of hCD47 Tg in vivo): Five baboons received porcine Kidney plus vascularized thymus (K+VT) in which hCD47 was expressed at high levels. All 5 received ATG and rituximab followed by anti-CD40 or CD40L mab +MMF. One of the 5 additionally received anti-IL6 receptor ab weekly from the 3^rd week. Graft renal function, immunologic assays as well as graft expression of hCD47 and TSP-1 were assessed.

*Results: Co-culture phagocytosis assays: Statistically significant reductions of phagocytosis of both porcine EC and podocytes were observed when hCD47 was expressed on porcine ECs or podocytes. Expression of hCD47 and TSP-1: One animal expressed hCD47 only on glomerular cells while the others (n=4) expressed hCD47 on glomerular cells as well as vascular ECs and arterial median layers (widespread hCD47). Widespread hCD47- expressing kidneys also expressed TSP1, although weakly, in vascular median layers while no TSP1-expression was observed on kidneys with glomerular hCD47 or naïve pig or baboon kidneys. Following XK+VT Tx: Historic controls of GalTKO K+VT without hCD47Tg uniformly developed proteinuria 2+ within 14 days (n>10), while all recipients of hCD47Tg GalTKO K+VT displayed minimal (1+ or 0) Uprot. However, although the recipient of a kidney graft in which hCD47 was expressed only in the glomeruli maintained function >4 months, three of 4 animals that received widespread hCD47 K+V were euthanized due to systemic edema with evidence of up-regulation of TSP-1 in grafts, without evidence of immunologic rejection within 8 weeks. These had circulating pig CD3+ T thymic emigrants >5% following Tx with increased serum levels of IL6. One animal that received weekly anti-IL6r ab maintains stable renal function without systemic edema (Cr<1mg/dl currently on POD 86).

*Conclusions: These results demonstrate that (1) high expression of hCD47 on porcine glomerular cells prevented the development of proteinuria; however, (2) widespread expression of hCD47 upregulates TSP-1 which might play a role in increased vascular permeability leading to systemic edema. These effects may be inhibited by anti-IL6r treatment.

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