| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥3,200,000 (Direct Cost: ¥3,200,000)
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| Research Abstract |
Due to species disparities, direct cellular interaction between donor antigen-presenting cells (APC) and recipient T lymphocytes is not strong in xenotransplantation. Indirect recognition, in which recipient T cells recognized processed donor antigens on the MHC class II cell surface molecules of recipient self APC, appears more significant than direct recognition in xenoantigen recognition. Cathepsin B is one of the determinant protease responsible for foreign antigen processing by APC. CA074 reported to be a potent specific inhibitor of cathepsin B. In the present study, immunosuppressive effect of cathepsin B inhibitor CA074 on indirect xeno-antigen recognition was investigated.
One way mixed lymphocyte reaction (MLR) was performed in rat-to-mouse combination. B cell depleted B6 mouse splenocytes (2 x 10^5), including T cell and APC population, were used as responder. Irradiated (3000 rad) F344 rat erythrocytes (40 x 10^5) and splenocytes (4 x 10^5) were used for 'indirect' (Ind-MLR) and 'direct plus indirect' (Both-MLR) stimulation, respectively. CA074 100 mg/ml concentration suppressed xenogenic erythrocyte stimulated MLR (Ind-MLR), which is evoked by exclusively indirect recognition, to the control level. Xenogenic splenocyte stimulated MLR (Both-MLR), which include direct and indirect recognition was partially suppressed by CA074. By adding various concentrations, from 10 to 100 mg/ml, of CA074 to the culture, a dose-dependent inhibition was observed in Ind-MLR, and mitogenic responses by ConA were not affected by CA074. In conclusion, CA074 suppressed indirect xeno-antigen recognition on rat-to-mouse MLR by blocking the donor antigen processing in recipient APC. It will be a novel strategy for immunosuppression of xeno cellular response.
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