The use of FK-506 for small intestine allotransplantation. Inhibition of acute rejection and prevention of fatal graft-versus-host disease

Abstract

Small intestine allotransplantation in humans is not yet feasible due to the failure of the current methods of immunosuppression. FK-506, a powerful new immunosuppressive agent that is synergistic with cyclosporine, allows long-term survival of recipients of cardiac, renal, and hepatic allografts. This study compares the effects of FK-506 and cyclosporine on host survival, graft rejection, and graft-versus-host-disease in a rat small intestine transplantation model. Transplants between strongly histoincompatible ACI and Lewis (LEW) strain rats, and their F1 progeny are performed so that graft rejection alone is genetically permitted (F1----LEW) or GVHD alone permitted (LEW----F1) or that both immunologic processes are allowed to occur simultaneously (ACI----LEW). Specific doses of FK-506 result in prolonged graft and host survival in all genetic combinations tested. Furthermore, graft rejection is prevented (ACI----LEW model) or inhibited (rejection only model) and lethal acute GVHD is eliminated. Even at very high doses, cyclosporine did not prevent graft rejection or lethal GVHD, nor did it allow long-term survival of the intestinal graft or the host. Animals receiving low doses of cyclosporine have outcomes similar to the untreated control groups. No toxicity specific to FK-506 is noted, but earlier studies by other investigators suggest otherwise.

Figure 1

Donor small intestine, fully allogeneic bidirectional model: A. control animal (group IA) at 8 days showing cryptitis and inflammation of the lamina propria (H&E; × 100); B. FK-506–treated animal (group IIA) at 22 days showing normal villi and crypts (H&E; ×63); and C. CsA-treated animals (group VII) at 26 days demonstrating severe cryptitis and inflammation in the lamina propria (H&E; ×100).

Figure 2

Host small intestine, control animal (group IA, fully allogeneic model) at 8 days with GVHD that is characterized by cryptitis and lamina propria inflammation (H&E; ×100).

Figure 3

Postoperative weight change following small intestine transplantation in the rat. A. Fully allogeneic model—progressive weight gain is noted in the FK-506–treated rats (group IIA). Following a several-month period of well-being, chronic rejection resulted in weight loss and death of the animals. Only high doses of CsA (group VII) resulted in weight gain in the recipients. The remaining survivor is alive and thriving at >3 months posttransplantation. B. Semiallogeneic model of rejection after an initial period of slight loss, the surviving FK-506–treated animals gained weight. Control animals lost weight and died in a short period of time. C. Semiallogeneic model of GVHD—the FK-506–treated animals show progressive weight gain. The CsA-treated group gained weight until the late onset of lethal GVHD resulted in weight loss and death.

Figure 4

Donor small intestine, semiallogeneic rejection model: A. control animal (group IB) at 8 days showing severe rejection with villous blunting, cryptitis, and inflammation (H&E; ×100); and B. FK-506–treated animal (group IIB) at 12 days demonstrating rare singlecell necrosis (arrow) and minimal inflammation (H&E; ×125).

Figure 5

Sections of ear, semiallogeneic GVHD model: A. control animal (group IC) at 25 days with apoptosis throughout the basal layer and lymphocytic infiltrate in the dermis; and B. FK-506–treated animal (group IIC) at 21 days with normal skin (H&E; ×125).