Zino Elisabetta, Vago Luca, Di Terlizzi Simona, Mazzi Benedetta, Zito Laura, Sironi Elisabetta, Rossini Silvano, Bonini Chiara, Ciceri Fabio, Roncarolo Maria Grazia, Bordignon Claudio, Fleischhauer Katharina
The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Milano, Italy.
Biol Blood Marrow Transplant. 2007 Sep;13(9):1031-40. doi: 10.1016/j.bbmt.2007.05.010. Epub 2007 Jul 20.
The majority of unrelated donor (UD) hematopoietic stem cell (HSC) transplants are performed across HLA-DP mismatches, which, if involving disparity in a host-versus-graft (HVG) direction for an alloreactive T cell epitope (TCE), have been shown by our group to be associated with poor clinical outcome in 2 cohorts of patients transplanted for hematopoietic malignancies and beta-thalassemia, respectively. Using site-directed mutagenesis of DPB1*0901, we show here that the TCE is abrogated by the presence of amino acids LFQG in positions 8-11 of the DP beta-chain. Based on this and on alloreactive T cell responsiveness, we have determined the presence or absence of the TCE for 72 DPB1 alleles reported in the ethnic groups representative of the worldwide UD registries, and predict that 67%-87% (mean 77%) of UD recipient pairs will not present a DPB1 TCE disparity in the HVG direction. We developed and validated in 112 healthy Italian blood donors an innovative approach of DPB1 epitope-specific typing (EST), based on 2 PCR reactions. Our data show that DPB1 TCE disparities may hamper the clinical success of a considerable number of transplants when DPB1 matching is not included into the donor selection criteria, and that a donor without DPB1 TCE disparities in the HVG direction can be found for the majority of patients. Moreover, the study describes the first protocol of targeted epitope-specific DPB1 donor-recipient matching for unrelated HSC transplantation. This protocol will facilitate large-scale retrospective clinical studies warranted to more precisely determine the clinical relevance of DPB1 TCE disparities in different transplant conditions.
大多数非血缘供者（UD）造血干细胞（HSC）移植是在HLA-DP错配的情况下进行的。如果这种错配涉及同种异体反应性T细胞表位（TCE）在宿主抗移植物（HVG）方向上的差异，我们的研究小组已表明，在分别接受造血系统恶性肿瘤和β地中海贫血移植的两组患者中，这与不良临床结局相关。通过对DPB1*0901进行定点诱变，我们在此表明，DPβ链第8-11位氨基酸LFQG的存在可消除该TCE。基于此以及同种异体反应性T细胞反应性，我们已确定了全球UD登记处代表的不同种族中报告的72个DPB1等位基因是否存在TCE，并预测67%-87%（平均77%）的UD受者对在HVG方向上不会出现DPB1 TCE差异。我们基于2个PCR反应，在112名健康的意大利献血者中开发并验证了一种创新的DPB1表位特异性分型（EST）方法。我们的数据表明，当供者选择标准中未纳入DPB1匹配时，DPB1 TCE差异可能会妨碍相当数量移植的临床成功，并且大多数患者都能找到在HVG方向上没有DPB1 TCE差异的供者。此外，该研究描述了首个针对非血缘HSC移植的靶向表位特异性DPB1供受者匹配方案。该方案将有助于开展大规模回顾性临床研究，以更精确地确定DPB1 TCE差异在不同移植条件下的临床相关性。
