Frasca L, Tamir A, Jurcevic S, Marinari B, Monizio A, Sorrentino R, Carbonari M, Piccolella E, Lechler R I, Lombardi G
Department of Cell Development and Biology, La Sapienza University, Rome, Italy.
Transplantation. 2000 Aug 27;70(4):631-40. doi: 10.1097/00007890-200008270-00017.
It has been demonstrated that indirect recognition of allogeneic MHC molecules might play an important role in provoking graft rejection. Although direct recognition of allogeneic molecules on antigen presenting cells of the graft may induce a state of tolerance, the continuous presentation of processed alloantigens by specialized antigen presenting cells does not allow the same phenomenon to occur. Tolerance to interleukin-2 secreting T cells can be achieved in different ways, among these is the exposure to mutants of the wild type allopeptide. We have investigated whether peptide analogues of the allopeptide can induce tolerance in T cells with indirect allospecificity.
T cell clones with indirect anti-HLA-A2-specificity generated from a HLA-A2-DRB1*1502+ patient who chronically rejected a HLA-A2-expressing kidney allograft were used for this study. Nine peptide analogues of HLA-A2 (residues: 103-120) were produced with single amino acid substitutions at the putative T cell receptor for antigen contact positions. Their effect on the proliferation of a panel of T cell clones was evaluated.
Peptide analogues and wild type peptide had similar capacity to bind to the restriction molecule HLA-DRB1*1502. Co-presentation of the peptide analogues 111R/A, H, K and 114H/K, with the wild type peptide inhibited T cell responses, indicative of antagonism. In addition, one analogue 112G/S induced unresponsiveness in the T cells to subsequent culture with the wild type peptide.
The data presented here suggest that using reagents such as altered peptides may represent a strategy to prevent the activation of T cells with indirect alloreactivity and allograft rejection in vivo.
已证明对同种异体MHC分子的间接识别可能在引发移植排斥中起重要作用。尽管对移植物抗原呈递细胞上同种异体分子的直接识别可能诱导耐受状态，但专门的抗原呈递细胞持续呈递加工后的同种异体抗原并不会出现同样的现象。对分泌白细胞介素-2的T细胞的耐受可以通过不同方式实现，其中包括暴露于野生型别肽的突变体。我们研究了别肽的肽类似物是否能诱导具有间接同种异体特异性的T细胞产生耐受。
本研究使用了从一名长期排斥表达HLA-A2的肾移植的HLA-A2-DRB1*1502+患者产生的具有间接抗HLA-A2特异性的T细胞克隆。制备了9种HLA-A2（第103 - 120位氨基酸残基）的肽类似物，在假定的抗原接触位置的T细胞受体处进行了单个氨基酸替换。评估了它们对一组T细胞克隆增殖的影响。
肽类似物和野生型肽与限制性分子HLA-DRB1*1502结合的能力相似。肽类似物111R/A、H、K和114H/K与野生型肽共同呈递时抑制T细胞反应，表明存在拮抗作用。此外，一种类似物112G/S诱导T细胞对随后与野生型肽共培养无反应。
本文提供的数据表明，使用诸如改变肽之类的试剂可能是一种在体内预防具有间接同种异体反应性的T细胞活化和移植排斥的策略。
