Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
PLoS One. 2013 Jul 24;8(7):e69397. doi: 10.1371/journal.pone.0069397. Print 2013.
T cells play a major role in allograft rejection, which occurs after T cell activation by the engagement of several functional molecules to form an immune synapse with alloantigen presenting cells. In this study, the immune synapse was targeted using mAbs directed to the TCR beta-chain (TCRβ) and lymphocyte function-associated antigen-1 (LFA1) to induce long-term allograft survival. Evaluation of antigen-specific T cell responses was performed by adoptively transferring CFSE labeled transgenic OT-II cells into wild-type mice and providing OVA peptide by intravenous injection. Graft survival studies were performed in mice by transplanting BALB/c ear skins onto the flanks of C57BL/6 recipients. The anti-TCRβ plus anti-LFA1 mAb combination (but not either mAb alone) abrogated antigen-specific T cell responses invitro and invivo. Transient combination therapy with these agents resulted in significantly prolonged skin allograft survival in mice (51±10 days; p<0.01) when compared to treatment with either anti-TCRβ mAb (24±5 days) or anti-LFA1 mAb (19±3 days) alone or no treatment (10±1 days). When lymphoid tissues from these mice were analyzed at different times post-transplant, only those receiving the combination of anti-TCRβ and anti-LFA1 mAbs demonstrated long-lasting reductions in total T cell numbers, cellular and humoral anti-donor responses, and expression of CD3 on the surface of T cells. These results demonstrate that transient anti-TCRβ and anti-LFA1 mAb combination therapy abrogates antigen-reactive T cell responses with long-lasting effects that significantly prolong allograft survival.
T 细胞在同种异体移植物排斥中起主要作用，这种排斥发生在 T 细胞被几种功能性分子激活后，与同种抗原呈递细胞形成免疫突触。在这项研究中，使用针对 TCRβ链（TCRβ）和淋巴细胞功能相关抗原-1（LFA1）的 mAb 靶向免疫突触，以诱导长期同种异体移植物存活。通过将 CFSE 标记的转基因 OT-II 细胞过继转移到野生型小鼠中，并通过静脉注射提供 OVA 肽来评估抗原特异性 T 细胞反应。通过将 BALB/c 耳朵皮肤移植到 C57BL/6 受体的侧腹来在小鼠中进行移植物存活研究。抗 TCRβ加抗 LFA1 mAb 组合（而不是单独的任何一种 mAb）在体外和体内消除了抗原特异性 T 细胞反应。这些药物的短暂联合治疗导致小鼠皮肤同种异体移植物存活显著延长（51±10 天；p<0.01），与单独使用抗 TCRβ mAb（24±5 天）或抗 LFA1 mAb（19±3 天）或不治疗（10±1 天）相比。当在移植后不同时间分析这些小鼠的淋巴组织时，只有那些接受抗 TCRβ和抗 LFA1 mAb 组合的小鼠表现出总 T 细胞数量、细胞和体液抗供体反应以及 T 细胞表面 CD3 表达的持久减少。这些结果表明，短暂的抗 TCRβ和抗 LFA1 mAb 联合治疗消除了抗原反应性 T 细胞反应，具有显著延长移植物存活的持久影响。
