Dimeric but not monomeric soluble CD40 prolongs allograft survival and generates regulatory T cells that inhibit CTL function
Dimeric but not monomeric soluble CD40 prolongs allograft survival and generates regulatory T cells that inhibit CTL function
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DOI：
10.1097/01.tp.0000181093.50141.6c
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发表时间：
2005-12-15
期刊：
影响因子：
6.2
通讯作者：
Uede, T
中科院分区：
文献类型：
--
作者：
Masunaga, T;Yamashita, K;Uede, T
背景我们以前报道过腺病毒介导的CD 40 Ig基因治疗（AdCD 40 Ig）诱导完全同种异体大鼠心脏移植物的长期接受，然而，其潜在机制尚未完全阐明。为了解决这一问题，我们比较了二聚体和单体可溶性CD40在体内延长同种异体移植物存活和在体外产生调节性T细胞的能力。比较了CD40 Ig（可溶性二聚体，含有Fc区）或CD40/Myc/His（可溶性单体，缺乏Fc区）治疗体外产生CD4（+）C25（+）调节性T细胞和预防大鼠心脏同种异体移植物（ACI至LEWIS）排斥反应的能力。通过抑制同种异体抗原特异性增殖和细胞毒性来确定产生的调节性T细胞的免疫调节能力。可溶性二聚体CD40 Ig不抑制CD4（+）T细胞增殖，但促进IL-2的产生和CD4（+）CD25（+）T细胞的产生，从而调节同种异体抗原特异性细胞毒性T淋巴细胞活性。AdCD40Ig或纯化的可溶性CD40Ig均能延长大鼠心脏移植物的存活时间。相反，尽管单体可溶性CD40/Myc/His以与CD40Ig相似的方式抑制IL-12的产生，但它并不增加IL-2的产生。此外，虽然CD40/Myc/His也能产生CD4（+）CD25（+）T细胞，但它们并没有表现出调节活性，并且给予可溶性CD40/Myc/His未能延长心脏移植物的存活。这些结果表明，除了阻断CD154-CD40相互作用之外，通过CD154的信号传导对于可溶性CD40 Ig的免疫调节作用也是重要的。总之，我们的研究结果提供了新的见解免疫调节机制的可溶性CD40结构。
Background. We previously reported that adenovirus mediated CD40Ig gene therapy (AdCD40Ig) induced long-term acceptance of fully allogeneic rat cardiac allografts, however, the underlying mechanism has not been fully clarified. To address this we have compared the ability of dimeric and monomeric soluble CD40 to prolong allograft survival in vivo and generate regulatory T cells in vitro.Methods. The ability of CD40Ig (soluble dimmer, containing an Fc region) or CD40/Myc/His (soluble monomer, lacking an Fc region) therapy to generate CD4(+)C25(+) regulatory T cells in vitro and to prevent rejection of rat cardiac allografts (ACI to LEWIS) was compared. Immunoregulatory capacity of regulatory T cells generated was determined by suppression of alloantigen specific proliferation and cytotoxicity.Results. Dimeric soluble CD40Ig did not inhibit CD4(+) T cell proliferation but rather promoted IL-2 production and the generation of CD4(+)CD25(+) T cells, which regulated alloantigen-specific cytotoxic T lymphocyte activity. Treatment with either AdCD40Ig or purified soluble CD40Ig prolonged the survival of rat cardiac allografts. In contrast, although monomeric soluble CD40/Myc/His suppressed IL-12 production in a similar manner to that achieved by CD40Ig, it did not augment IL-2 production. Moreover, while CD40/Myc/His also generated CD4(+)CD25(+) T cells, they did not exhibit regulatory activity and administration of soluble CD40/Myc/His failed to prolong cardiac allograft survival.Conclusions. These results suggest signaling through CD154 in addition to blocking of CD154-CD40 interaction is important for the immunomodulatory effects of soluble CD40Ig. Taken together, our results provide new insight into the mechanism of immunomodulation by soluble CD40 constructs.