Yuichi Takama, Shuji Miyagawa, Takehisa Ueno, Masahiro Fukuzawa

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

Small intestinal transplantation has become one of the most commonly utilized treatments for patients with irreversible intestinal failure. The control of leukocyte migration depends on the combined actions of various adhesion molecules, chemokines and their receptors. The chemokine receptors CCR5 and CXCR3 are markers for T cells associated with Th1 type reactions. The effects of FK506, and TAK-779, antagonists of CCR5 and CXCR3, were investigated using a rat intestinal transplantation model.

Methods: Small intestines from DA rats were heterotopically transplanted into LEW rats. The recipients were treated with FK506 (1 mg/kg/day, day 0–5) and TAK-779 (10 mg/kg/day, day 0–10). Graft survival and immunological responses were estimated by mixed lymphocyte reactions and IFN-γ production. The expression of chemokine receptors on lymphocytes was also examined.

Results: The average duration of survival was 7.0 ± 0.3, 12.0 ± 1.0, 9.8 ± 0.5 and 18.0 ± 1.5 days in the allogeneic, FK506, TAK-779 and the two-drug combined groups, respectively. Cell proliferative responses and IFN-γ production were suppressed to a significant extent in the FK506 group compared with the TAK-779 group. The two-drug combination showed a tendency for stronger suppression than FK506 alone, correlated with in vivo and histopathological data. The numbers of both CD4⁺and CD8⁺cells were significantly suppressed in the blood of the recipients of both the FK506 and the TAK-779 groups, and in Peyer's patches of the graft of the TAK-779 group, but the FK506 group was not, as evidenced by FACS analysis. Double-staining of graft-infiltrating lymphocytes showed a significant reduction in lymphocyte numbers, expressing CCR5 and CXCR3 in the TAK-779 group, but not evident in the FK506 group, compared to the allogeneic group.

Conclusion: This study indicates that combined therapy with FK506 and TAK-779 promises to prolong allograft survival to a much greater extent than a single therapy.