Prevention of graft-versus-host disease following allogeneic bone marrow transplantation in rats using FK506

Abstract

FK506 and cyclosporine were used for the prevention of acute graft-versus-host disease. Acute GVHD was induced in Lewis rats by total-body irradiation and subsequent reconstitution with allogeneic (ACI) bone marrow and spleen cells (BMTx). GVHD was assessed by both clinical and histologic parameters during the experiment duration of 60 days, and longer for selected animals. All untreated BM recipients died within 26 days from severe acute GVHD. GVHD was prevented with CsA during the period of immunosuppressive therapy, but it appeared within a few days afterward. FK506-treated BM recipients were also protected, but they had a markedly prolonged GVHD-free period after therapy was discontinued. Most such animals eventually developed GVHD but with notable exceptions. Maintenance therapy with doses of FK506 as low as 0.1 mg/kg every other day (1/20 of daily induction dose) was infallible insurance against delayed GVHD. The relevance of these findings to GVHD caused by lymphoid-containing solid organs such as the intestine was discussed.

Figure 1

Flow cytometric analysis of cell phenotypes from control (Lew, left and ACI, middle) and a representative chimeric bone marrow transplant rat (right).

Figure 2

Effect of low-dose continuous treatment with FK506 on the development of GVHD. Histology of target organs from an animal treated with FK506 at 1.0 mg/kg followed by 0.1 mg/kg/q.o.d. (group 7). Biopsies of (A) ear, (B) tongue, (C) liver, and (D) small bowel were taken 60 days after BMTx. There was no histological evidence of GVHD, except for foci of lymphocytic exocytosis, seen in the tongue.