Anti-TCRβ mAb induces long-term allograft survival by reducing antigen-reactive T cells and sparing regulatory T cells.
Anti-TCRβ mAb induces long-term allograft survival by reducing antigen-reactive T cells and sparing regulatory T cells.
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DOI：
10.1111/j.1600-6143.2012.04006.x
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Stepkowski SM
中科院分区：
文献类型：
--
作者：
Miyahara Y;Khattar M;Schroder PM;Mierzejewska B;Deng R;Han R;Hancock WW;Chen W;Stepkowski SM
TCR特异性抗体可以调节TCR与抗原- mhc复合物的结合，进而调节体内t细胞对同种抗原的反应。本研究发现，体内注射针对小鼠TCRβ (H57-597)、TCRα或CD3的单克隆抗体可迅速减少正常小鼠CD4+和CD8+ t细胞的数量，但H57-597单克隆抗体最有效地增加了CD4+Foxp3+ Treg细胞的频率。当给小鼠注射SEB超抗原和H57-597单抗时，SEB反应性Vβ8+ t细胞完全消失，而SEB非反应性Vβ2+ t细胞不受影响。更重要的是，短暂的H57-597单抗治疗在阻止t细胞对同种抗原的反应方面具有持久的效果，并且在11名受者中有10名产生了长期的同种异体心脏移植存活（100天）。虽然Treg细胞参与维持供体特异性移植物的长期存活，但随着时间的推移，t细胞会恢复稳态，并保留对第三方同种异体移植物的免疫力。此外，短暂的H57-597单抗治疗显著延长了naïve受体的同种异体皮肤移植和皮肤致敏受体的同种异体心脏移植的存活时间。因此，H57-597单抗对TCRβ链的短暂调节显示出有效的、持久的治疗效果，以控制异体免疫反应。
TCR specific antibodies may modulate the TCR engagement with antigen-MHC complexes, and in turn regulate in vivo T-cell responses to allo-antigens. Herein, we found that in vivo administration of mAbs specific for mouse TCRβ (H57-597), TCRα, or CD3 promptly reduced the number of CD4+ and CD8+ T-cells in normal mice, but H57-597 mAb most potently increased the frequency of CD4+Foxp3+ Treg cells. When mice were injected with staphylococcal enterotoxin B (SEB) superantigen and H57-597 mAb, the expansion of SEB-reactive Vβ8+ T-cells was completely abrogated while SEB-non-reactive Vβ2+ T-cells remained unaffected. More importantly, transient H57-597 mAb treatment exerted long-lasting effect in preventing T-cell responses to allo-antigens, and produced long-term cardiac allograft survival (>100 days) in 10 out of 11 recipients. While Treg cells were involved in maintaining donor-specific long-term graft survival, T-cell homeostasis recovered over time and immunity was retained against third party allografts. Moreover, transient H57-597 mAb treatment significantly prolonged survival of skin allografts in naïve recipients as well as heart allografts in skin-sensitized recipients. Thus, transient modulation of the TCRβ chain by H57-597 mAb exhibits potent, long-lasting therapeutic effects to control allo-immune responses.
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