抗ICOS免疫疗法抑制鼠心脏移植的加速性和慢性排斥反应

背景：在DA鼠移植给路易鼠模型中，用AdCTLA-4Ig免疫球蛋白阻断B7-CD28共刺激信号可以诱导心脏同种异体移植的长期免疫耐受。然而这种耐受是不完全的，并最终发生排斥。尤其是在心脏移植后功能良好时将供体皮肤移植给受体可以引发加速性移植心脏的排斥反应。 目的：重新评价抗ICOS抗体疗法与AdCTLA-4Ig疗法相结合在同种异体移植中的作用。验证抗ICOS疗法无论是否应用AdCTLA-4Ig疗法都起到阻断心脏加速性排斥的作用。 方法：在DA(供体)→LEW(受体)鼠之间进行心脏移植手术。心脏移植给予受体鼠一次静脉注射109 pfu AdCTLA-4Ig。生存期> 50 d的受体鼠接受全厚皮片移植到侧胸壁，第50天开始静脉注射抗ICOS抗体(1 mg/kg)或者IgG，隔天注射1次，共2周。完全移植排斥被定义为心脏停止跳动，或者组织学上通过单核细胞浸润和心肌细胞坏死的苏木精-伊红染色证实。 结果与结论：AdCTLA-4Ig处置受体生存大于100 d的心脏切片可见典型的ICOS+单核细胞浸润，并表现出血管病理性改变。AdCTLA-4Ig疗法与抗ICOS抗体结合可介导出对慢性排斥稳定的耐受。抗ICOS疗法明显减少了ICOS阳性炎性细胞浸润，并阻断了皮肤二次移植引发的心脏加速性免疫排斥反应。实验结果表明了ICOS在慢性及急性心脏移植免疫排斥中的重要作用，并揭示出阻断血管化器官同种异体移植慢性排斥的革命性观点。

Anti-inducible costimulator immunotherapy inhibits accelerated and chronic cardiac allograft rejections in rats

BACKGROUND: In a DA (RT1a) to LEW (RT1l) rat model, inhibition of B7-CD28 co-stimulatory signal blockade by adenovirus-mediated cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (AdCTLA-4Ig) induces long-term acceptance of cardiac allografts. However, allograft tolerance is incomplete and rejection eventually occurs. In particular, donor-type skin grafting to recipients with functional cardiac allografts causes accelerated heart rejection. OBJECTIVE: To evaluate the combined effects of inducible co-stimulator (ICOS) therapy and AdCTLA-4Ig treatment on preventing accelerated cardiac rejection caused by donor-strain skin grafting and validate that ICOS therapy can block accelerated cardiac rejection, no matter with or without AdCTLA-4Ig treatment. METHODS: DA hearts were transplanted into the abdominal cavity of LEW recipients. The recipients intravenously received a single dose of 109 plaque-forming units of AdCTLA-4Ig immediately after transplantation. Recipients with grafts surviving > 50 days were given a full-thickness donor-type skin graft to the lateral thoracic wall. These recipients received intravenous injection of anti-ICOS antibody (1 mg/kg) or control IgG from the 50th day, once every other day, for 2 weeks. Complete graft rejection was defined as cessation of beating and was histologically confirmed by mononuclear cell infiltration and cardiac myocyte necrosis using hematoxylin and eosin staining of graft sections. RESULTS AND CONCLUSION: Cardiac sections of AdCTLA-4Ig-treated recipients surviving > 100 days showed typical ICOS-positive mononuclear cell infiltration and vasculopathy. AdCTLA-4Ig treatment combined with anti-ICOS therapy induced stable tolerance to chronic rejection. Anti-ICOS therapy significantly reduced ICOS-positive inflammatory cell infiltration, and prevented accelerated cardiac graft rejection following secondary skin grafting. These findings identify a critical role of ICOS in chronic and accelerated cardiac allograft rejection and suggest a novel approach to prevent chronic rejection of vascularized organ allografts.