Immunotoxin-treated rhesus monkeys: A model for renal allograft chronic rejection

Background. Unlike acute and hyperacute rejection, chronic rejection (CR) still constitutes a poorly understood process. The onset is insidious, occurs in a period of months to years and, because the pathophysiology is not well understood, is untreatable. A reliable large-animal model for renal allograft CR is needed and has not been reported in the literature yet. Methods. CR biopsy changes were studied in major histocompatibility complex-mismatched renal allografts performed in nine rhesus monkeys that received CD3 T-lymphocyte depletion therapy with immunotoxin on the day of the transplantation (n = 7) or 7 days before transplant (n = 2). Results. Mean graft survival time was 613.77 days. Biopsy changes of CR were identified as soon as 84 days after transplant (mean, 336 days; range, 84-896 days). Most of the experimental animals had severe interstitial fibrosis, tubular atrophy, chronic transplant glomerulopathy, and chronic vascular rejection changes at the time of necropsy. A significant positive correlation between the severity of CR and the degree of CD68⁺ macrophage infiltrate of renal parenchyma and the degree of anemia and serum creatinine level elevations were also observed. Conclusions. Our findings are similar to those seen in human renal chronic allograft nephropathy, but in contrast, our model excludes all the nonimmune factors associated with chronic allograft nephropathy, including donor disease, injury from prolonged preservation, drug toxicity, and underlying recipient disease. Immunotoxin-treated rhesus monkeys emerge as an outstanding animal model for assisting us in understanding the pathophysiology of CR.