Tarumi K, Murakami M, Yagihashi A, Nakagawa I, Hirata K, Uede T
Section of Immunopathogenesis, Institute of Immunological Science, Hokkaido University, Sapporo, Japan.
Transplantation. 1999 Feb 27;67(4):520-5. doi: 10.1097/00007890-199902270-00005.
CTLA4 immunoglobulin (Ig)G that binds to B7 effectively inhibits the signaling of CD28/CTLA4-B7 pathway and induces antigen specific T cell unresponsiveness in vitro and in vivo. Using CTLA4IgG, we examined induction of long-term graft survival and the mechanism of maintenance of tolerance in rat allogeneic small bowel transplantation.
Small bowels of Brown-Norway rats (RT1n) were heterotopically transplanted into Lewis rats (RT1l). Recipients were treated with an i.p. injection of either CTLA4IgG or control IgG for 7 days.
Long-term survival was observed in rats treated with CTLA4IgG, whereas control rats died within 16 days after transplantation. To examine whether a tolerant state was established in long-term survival rats, secondary transplantation was performed using small bowels of Brown-Norway rats or ACI (RT1b) rats. It was demonstrated that small bowels of Brown-Norway rats were accepted; however, those of ACI rats were rejected within 10 days. Serum concentrations of interleukin (IL)-4 were maintained at >50 microg/ml for 7 days after transplantation in rats treated with CTLA4IgG but <15 microg/ml in control rats. IL-2 concentration was reduced to half in CTLA4IgG-treated rats compared with that in control recipients. Serum IFN-gamma in CTLA4IgG-treated recipients increased after transplantation and was not distinguishable from that of control recipients during the first 7 days after transplantation. Conclusion. We demonstrated that CTLA4IgG treatment alone for 7 days induced a long-term donor specific tolerance in rat allogeneic small bowel transplantation. The induction of long-term acceptance of small bowel allografts by CTLA4IgG is not caused by simply the shift of anti-alloimmune responses from Thl to Th2 cytokine production.
与B7结合的细胞毒性T淋巴细胞相关抗原4免疫球蛋白（Ig）G能有效抑制CD28/CTLA4 - B7途径的信号传导，并在体内外诱导抗原特异性T细胞无反应性。我们使用CTLA4IgG研究了大鼠同种异体小肠移植中长期移植物存活的诱导及耐受维持机制。
将棕色挪威大鼠（RT1n）的小肠异位移植到Lewis大鼠（RT1l）体内。受体经腹腔注射CTLA4IgG或对照IgG，共7天。
接受CTLA4IgG治疗的大鼠实现了长期存活，而对照大鼠在移植后16天内死亡。为检测长期存活大鼠是否建立了耐受状态，使用棕色挪威大鼠或ACI（RT1b）大鼠的小肠进行二次移植。结果显示，棕色挪威大鼠的小肠被接受；然而，ACI大鼠的小肠在10天内被排斥。接受CTLA4IgG治疗的大鼠在移植后7天内血清白细胞介素（IL）-4浓度维持在>50μg/ml，而对照大鼠中该浓度<15μg/ml。与对照受体相比，接受CTLA4IgG治疗的大鼠IL - 2浓度降低至一半。接受CTLA4IgG治疗的受体血清干扰素-γ在移植后升高，且在移植后的前7天与对照受体的无明显差异。结论。我们证明，单独使用CTLA4IgG治疗7天可在大鼠同种异体小肠移植中诱导长期供体特异性耐受。CTLA4IgG诱导小肠同种异体移植物长期存活并非仅仅是抗同种异体免疫反应从Th1型细胞因子产生向Th2型细胞因子产生转变的结果。
