The livers from h-DAF transgenic pigs did not undergo hyperacute rejection after orthotopic xenotransplantation in baboons. When HAR is abrogated, the porcine liver maintains sufficient coagulation and protein levels in the baboon up to 8 days after OLT.

In the largest series of pig-to-primate solid organ transplants performed thus far, the presence of the hDAF transgene fully prevents HAR of cynomolgus monkey kidney transplants and partially inhibits HAR of heart grafts in cynomolgus monkeys or baboons. The incidence of HAR in control grafts is significantly higher.

Transgenic pigs, which express levels of functional HDAF even greater than those observed in humans, have successfully been produced. Pigs transgenic for human complement inhibiting molecules could represent a source of organs for future clinical xenotransplantation.

Background: The widely adopted Jablonski scoring system for reporting histological damage in kidney ischaemia reperfusion injury (IRI) provides a limited score documenting the degree of necrosis within tubular cells. IRI is a complex process that involves damage to various cellular components of the renal cortex and therefore there is a need to develop a more detailed scoring system. The aims of this study were to evaluate a new comprehensive histology scoring system (comprising Endothelial, Glomerular, Tubular, and Interstitial (EGTI)components), in rat models of IRI. Methods: Twenty-seven adult male Lewis rats underwent surgery: Left unilateral IRI (45-minutes left renal pedicle cross-clamping)(n=5); Left unilateral sham(n=5); Bilateral IRI (45-minutes bilateral renal pedicle cross-clamping)(n=9); and Bilateral sham(n=8). Kidney tissue was retrieved at 48 hours. Paraffin sections were examined under H&E staining. RNA extraction and RT-qPCR analysis were performed for acute kidney injury (AKI) markers. Serum creatinine was measured before and at 48 hours post reperfusion for the bilateral model rats. Results: Forty-five minutes of IRI in the rat caused marked histological damage at 48 hours when compared with sham controls. This was characterized by acute tubular necrosis, endothelial cell disruption and loss, interstitial damage with inflammation, cast formation and necrosis, and glomerular capsule thickening. The EGTI scores correlated significantly with serum creatinine at 48 hours, and expression of AKI markers (NGAL and KIM-1). In addition to this, each individual component on the EGTI histology scoring system correlated significantly with serum creatinine at 48 hours, and expression of NGAL and KIM-1. Discussion: The EGTI histology scoring system appears reliable and more informative in assessing the degree of damage observed in kidney IRI. Separate scoring parameters for Endothelial, Glomerular, Tubular, and Interstitial injury showed sensitivity to IRI, and permit quantitative analysis of injury and protection in different segments of the kidney.

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A pig line transgenic for human membrane cofactor protein (hMCP) has been established. Offspring from the founder were produced by crossing the founder with pigs heterozygous for the human decay accelerating factor (hDAF) transgene. As a result, pigs transgenic for both hMCP and hDAF have been produced. Ribonuclease protection assay (RPA) indicated that hMCP was expressed in all the tissues analysed. In addition, immunohistochemical results indicated a high level of expression of hMCP on neural tissues and islets where hDAF was absent or weakly expressed. C3 fragment deposition and cytotoxicity assays indicated that hMCP expression alone on pig endothelial cells and peripheral blood lymphocytes (PBLs) provided protection against human complement mediated damage. However, we did not find that porcine endothelial cells expressing both hDAF and hMCP were better protected than those expressing hDAF alone. The expression of hMCP on tissues where hDAF is not expressed could provide these tissues with protection against human complement mediated lysis.

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