The role of the CD134-CD134 ligand costimulatory pathway in alloimmune responses in vivo
The role of the CD134-CD134 ligand costimulatory pathway in alloimmune responses in vivo
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DOI：
10.4049/jimmunol.170.6.2949
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发表时间：
2003-03-15
影响因子：
4.4
通讯作者：
Sayegh, MH
中科院分区：
文献类型：
--
作者：
Yuan, XL;Salama, AD;Sayegh, MH
CD 134-CD 134配体（CD 134 L）共刺激通路已被证明是T和B细胞活化的关键;然而，其在调节同种异体应答中的作用尚未探索。此外，它与其他人的互动。共刺激途径和免疫抑制剂尚不清楚。我们研究了阻断CD 134-CD 134 L通路对完全MHC不匹配的大鼠心脏和皮肤移植模型中同种异体排斥反应的影响。与未经治疗的受体相比，单独使用CD 134 L阻断剂并不能延长移植物的存活时间，与供体特异性输血、环孢素或雷帕霉素联合使用，在延长移植物存活时间方面不如B7阻断剂有效。然而，与B7阻断剂联合使用，所有受者均实现了长期同种异体移植物存活（>200天）。此外，这在降低产生IFN-γ的同种异体反应性淋巴细胞的频率和抑制活化/效应淋巴细胞的产生方面具有协同作用。最令人印象深刻的是，这种组合防止排斥反应的致敏模型，过继转移致敏淋巴细胞到无胸腺心脏移植受体。与未治疗的受体（平均存活时间（MST）：5.3 +/- 0.5天）相比，抗CD 134 L mAb单独使用可适度延长同种异体移植物存活时间（MST：14 +/- 2.8天），CTLA 4 Ig也是如此（MST：21.5 +/- 1.7天），但所有移植物均在24天内发生排斥反应。重要的是，联合阻断进一步显著延长了同种异体移植物存活（MST：75.3 +/- 12.7天），并阻止了扩张。和/或致敏/效应同种异体反应性T细胞的持续存在。我们的数据表明，CD 134-CD 134 L是同种异体反应，特别是回忆/致敏反应的关键途径，并与CD 28-B7协同介导同种异体排斥反应期间的T细胞效应器反应。了解这些不同途径之间的协作机制对于开发新的策略以促进移植物长期存活是重要的。
The CD134-CD134 ligand (CD134L) costimulatory pathway has been shown to be critical for both T and B cell activation; however, its role in regulating the alloinumme response remains unexplored. Furthermore, its interactions with other. costimulatory pathways and immunosuppressive agents are unclear. We investigated the effect of CD134-CD134L pathway blockade on allograft rejection in fully MHC-mismatched rat cardiac and skin transplantation models. CD134L blockade alone did not prolong graft survival compared with that of untreated recipients, and in combination with donor-specific transfusion, cyclosporine, or rapamycin, was less effective than B7 blockade in prolonging allograft survival. However, in combination with B7 blockade, long-term allograft survival was achieved in all recipients (>200 days). Moreover, this was synergistic in reducing the frequency of IFN-gamma-producing alloreactive lymphocytes and inhibiting the generation of activated/effector lymphocytes. Most impressively, this combination prevented rejection in a presensitized model using adoptive transfer of primed lymphocytes into athymic heart transplant recipients. In comparison to untreated recipients (mean survival time (MST): 5.3 +/- 0.5 days), anti-CD134L mAb alone modestly prolonged allograft survival (MST: 14 +/- 2.8 days) as did CTLA4Ig (MST: 21.5 +/- 1.7 days), but all grafts were rejected within 24 days. Importantly, combined blockade further and significantly prolonged allograft survival (MST: 75.3 +/- 12.7, days) and prevented the expansion. and/or persistence of primed/effector alloreactive T cells. Our data suggest that CD134-CD134L is a critical pathway in alloinumme responses, especially recall/primed responses, and is synergistic with CD28-B7 in mediating T cell effector responses during allograft rejection. Understanding the mechanisms of collaboration between these different pathways is important for the development of novel strategies to promote long-term allograft survival.