ラット同所性肺移植におけるforskolin誘導体NKH477の移植片生着延長効果に関する検討
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Forskolin and other cAMP-elevating agents have been reported to have immunosuppressive effects, and to inhibit interleukin-2 (IL-2) expression in vitro. NKH477 was recently identified as a water-soluble forskolin derivative. We investigated whether NKH477 inhibits acute rejection and prolong allograft survival in a rat orthotopic lung transplantation model as monotherapy or in combination with cyclosporine (CsA) and studies the mechanisms of this effecacy by means of immunohistochemical analysis of the associated inflammatory and proliferative cytokines (IL-2, IL-4, IL-10,) expression in lung transplant and recipient spleens. The left lung of a Lewis (RT11) recipient was orthotopically replaced by the left lung from a Brown-Norway (RT1n) donor at day 0. The recipient rats were untreated (control) or treated daily with different doses of NKH477 (orally, day 0-10) and/or CsA (intraperitoneally, day 0-6). NKH477 monotherapy at 1, 2 or 3 mg/kg/day significantly (p<0.01) extended MST from 4 days (untreated) to 6, 8.5 or 9.5 days respectively. Thus, NKH477 monotherapy prevented allograft rejection and caused dose-dependent prolongation of allograft survival. Analysis of graft survival time with combined treatment suggests that NKH477 interacts with CsA at least additively. In histological analysis, the average rejection scores for NKH477-treated groups (1.8±0.4 at day 3, 2.4±0.5 at day 5) were significantly lower than those for the untreated groups (2.6±0.5 at day 3, 3.6±0.5 at day 5) (p<0.05). Although NKH477 did not alter the patterns of cytokine expression (IL-2, IL-4, IL-10; immunohistochemical staining, ABC method) in the allografts, it significantly (p<0.05) decreased the expression of IL-2 and IL-10 of the recipient spleen at day 5. These results suggest that NKH477 alone or in combination with CsA exerts a beneficial effect to inhibit rat lung allograft rejection. The immunosuppressive effects of NKH477 appeared to be mediated by inhibition of IL-2 production.
- 札幌医科大学の論文
- 2000-04-01
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