Kidney xenotransplantation

Xenotransplantation using pigs as donors offers the possibility of eliminating the chronic shortage of donor kidneys, but there are several obstacles to be overcome before this goal can be achieved. Preclinical studies have shown that, while porcine renal xenografts are broadly compatible physiologically, they provoke a complex rejection process involving preformed and elicited antibodies, heightened innate immune cell reactivity, dysregulated coagulation, and a strong T cell-mediated adaptive response. Furthermore, the susceptibility of the xenograft to proinflammatory and procoagulant stimuli is probably increased by cross-species molecular defects in regulatory pathways. To balance these disadvantages, xenotransplantation has at its disposal a unique tool to address particular rejection mechanisms and incompatibilities: genetic modification of the donor. This review focuses on the pathophysiology of porcine renal xenograft rejection, and on the significant genetic, pharmacological, and technical progress that has been made to prolong xenograft survival

Quantitative and qualitative evaluation of proteinuria in non human primates recipients of porcine xenografts

Introduction: Immunological and histopathological features in pig-to-primate renal xenotransplantation are widely studied. However, only limited data have been reported on clinical-pathological findings in primate recipients of life supporting renal xenografts. In human medicine, proteinuria represents a common complication in kidney transplantation and is associated with impaired patient and graft survival. The detection of low molecular weight proteins of tubular origin such as \u3b11-microglobulin, \u3b22-microglobulin, retinol-binding protein, lysozime, is considered an early marker for predicting potential graft rejection. In the present study the presence and significance of quantitative and qualitative proteinuria were evaluated in xenotransplanted non-human primates in which kidney function is supported only by the transplanted organ. Material and methods: Eight captive-bred, bilaterally nephrectomized cynomolgus monkeys (Macaca fascicularis), recipient of a life-supporting transgenic porcine kidney, were included in the present study. Quantitative and qualitative analysis of proteinuria, evaluated with urinary protein to creatinine ratio (UPC ratio) and sodium dodecyl sulphate-agarose gel electrophoresis (SDSAGE) respectively, have been performed. Results: In urine samples, the measurement of UPC ratio was low before transplantation and increased after transplantation. Similarly, SDS-AGE was negative before transplantation but evidenced bands consistent with mixed (i.e. tubular and glomerular) proteinuria in all the samples collected posttransplantation. Proteinuria and presence of LMW proteins was consistently found in urine after transplantation, independently of the fluctuations of creatinine values and/or of the status of renal functions. Conclusions: The evaluation of UPC ratio and the use of SDS-AGE technique in urine samples of cynomolgus monkey recipients of a life-supporting renal xenograft, may be considered a valid, cheap and rapid technique to monitor proteinuria in the post-transplanted period

The Protective Effects of CD39 Overexpression in Multiple Low-Dose Streptozotocin-Induced Diabetes in Mice

Islet allograft survival limits the long-term success of islet transplantation as a potential curative therapy for type 1 diabetes. A number of factors compromise islet survival, including recurrent diabetes. We investigated whether CD39, an ectonucleotidase that promotes the generation of extracellular adenosine, would mitigate diabetes in the T cell-mediated multiple low-dose streptozotocin (MLDS) model. Mice null for CD39 (CD39KO), wild-type mice (WT), and mice overexpressing CD39 (CD39TG) were subjected to MLDS. Adoptive transfer experiments were performed to delineate the efficacy of tissue-restricted overexpression of CD39. The role of adenosine signaling was examined using mutant mice and pharmacological inhibition. The susceptibility to MLDS-induced diabetes was influenced by the level of expression of CD39. CD39KO mice developed diabetes more rapidly and with higher frequency than WT mice. In contrast, CD39TG mice were protected. CD39 overexpression conferred protection through the activation of adenosine 2A receptor and adenosine 2B receptor. Adoptive transfer experiments indicated that tissue-restricted overexpression of CD39 conferred robust protection, suggesting that this may be a useful strategy to protect islet grafts from T cell-mediated injury