Kurlberg G, Haglind E, Schön K, Törnqvist H, Lycke N
Departments of Surgery and Medical Microbiology and Immunology, University of Göteborg, S-413 45 Göteborg, Sweden.
Scand J Immunol. 2000 Mar;51(3):224-30. doi: 10.1046/j.1365-3083.2000.00725.x.
Allograft rejection involves T-cell activation, requiring T-cell receptor interactions with major histocompatibility complex (MHC) molecules and costimulatory signals delivered through the B7-CD28 pathway. We evaluated the effect of blocking this pathway on graft rejection and survival, in a rat experimental model of small bowel transplantation. Heterotopic small bowel transplantation was performed between PVG donor rats and DA recipient rats. The recipient animals were treated with CTLA4-Ig or irrelevant immunoglobulin (Ig)G as control and followed for 18, 30 or 90 days. The survival rate and degree of inflammation and accumulation of CD4+ T cells and macrophages were determined in the transplanted bowels. We found that administration of CTLA4-Ig significantly improved the survival rate compared to control rats: after 30 days 73% of the treated rats had survived and at 90 days 5/8 rats were still living, whereas in the control group only 2/8 rats had survived. The grafts showed preserved mucosal structure with only a mild degree of subacute inflammation and the accumulation of CD4+ T cells and macrophages was noticeably reduced in treated animals as compared to control rats. Necrosis was extensive in control rats, whereas CTLA4-Ig treated animals had grafts with at least some preserved villus morphology and no necrotic tissue. Although small bowel transplantation has proven exceptionally difficult, in this study we have shown that CTLA4-Ig treatment may provide a promising strategy to prevent rejection and induce long term tolerance and graft survival.
同种异体移植排斥反应涉及T细胞活化，这需要T细胞受体与主要组织相容性复合体（MHC）分子相互作用，以及通过B7 - CD28途径传递的共刺激信号。我们在大鼠小肠移植实验模型中评估了阻断该途径对移植排斥反应和移植物存活的影响。在PVG供体大鼠和DA受体大鼠之间进行异位小肠移植。受体动物接受CTLA4 - Ig或无关免疫球蛋白（Ig）G作为对照治疗，并随访18、30或90天。测定移植肠段的存活率、炎症程度以及CD4 + T细胞和巨噬细胞的聚集情况。我们发现，与对照大鼠相比，给予CTLA4 - Ig可显著提高存活率：30天后，73%的治疗大鼠存活，90天时8只中有5只仍存活，而对照组8只中只有2只存活。移植物显示出保留的黏膜结构，仅有轻度亚急性炎症，与对照大鼠相比，治疗动物中CD4 + T细胞和巨噬细胞的聚集明显减少。对照大鼠中坏死广泛，而CTLA4 - Ig治疗的动物的移植物至少有一些保留的绒毛形态且无坏死组织。尽管小肠移植已被证明异常困难，但在本研究中我们表明，CTLA4 - Ig治疗可能提供一种有前景的策略来预防排斥反应并诱导长期耐受和移植物存活。
