The use of FK506 and RS61443 for reversal of small-bowel rejection

Abstract

Successful clinical small-bowel transplantation is still difficult to achieve [3, 6]. Two features render the small intestine unique among vascularised solid organ grafts. First, the bowel contains a large amount of lymphoid tissue within the Peyer's patches, mesenteric lymph nodes, and intraepithelial lymphocytes, which are thought to mediate graft-versus-host disease and provide a major stimulus for the recipient's immune system [10]. Unfortunately, mere surgical reduction of these tissues, by using segmental allografts, does not furnish any immunological advantage [12]. Second, the small bowel lacks specific serum markers such as blood urea nitrogen (BUN) in the kidney or bilirubin in liver transplantation. Clinical signs such as fever, pain, or tenderness of the abdomen may indicate an already advanced destruction of the graft. Therefore, very potent immunosuppressive regimens are necessary to avoid small-bowel allograft rejection or even to reverse an ongoing rejection process. Cyclosporin was shown in small and large animal models to control rejection reactions sufficiently [4, 13]. However, there are two even more promising immunosuppressive agents currently under investigation. FK506, a macrolide lactone isolated from Streptomyces tsukubaensis, leads to long-term survival of small-bowel allografts in a rodent model and has already been used in a few clinical small-bowel transplantations [11, 14]. RS61443, a mycophenolic acid morpholinoethylester, selectively inhibits T- and B-cell proliferation [9]. We have investigated the use of FK506 and RS61443 for the reversal of small-bowel allograft rejection in a small animal model.