Maiers Martin, Sullivan Stephen, McClain Christopher, Leonhard-Melief Christina, Turner Marc L, Turner David
CIBMTR (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, USA.
iPSirius, Paris, France; Lindville Bio, Edinburgh, UK; Global Alliance for iPSC Therapies, Jack Copland Centre, Heriot-Watt Research Park, Edinburgh, UK.
Cytotherapy. 2025 Mar;27(3):300-306. doi: 10.1016/j.jcyt.2024.11.001. Epub 2024 Nov 15.
Several countries have either developed or are developing national induced pluripotent stem cell (iPSC) banks of cell lines derived from donors with HLA homozygous genotypes (two identical haplotypes) prevalent in their local populations to provide immune matched tissues and cells to support regenerative medicine therapies. This 'haplobank' approach relies on knowledge of the HLA genotypes of the population to identify the most beneficial haplotypes for patient coverage, and ultimately identify donors or cord blood units carrying two copies of the target haplotype.
A potentially more efficient alternative to a national bank approach is to assess the haplotypes required to provide global patient coverage and to produce a single, global haplobank. Toward that end, we have developed an algorithm to prioritize HLA haplotypes that optimize coverage across the global population.
We analyzed data from eighteen countries participating in the Global Alliance for iPS Therapy (GAiT). A representative pool of HLA genotypes, reflecting the HLA of patients, was derived by sampling from each country's WMDA hematopoietic stem cell donor registry, or surrogate population. An algorithm was created based on HLA-A, -B and -DRB1 haplotype homozygous types with population HLA matching coverage defined by the absence of Host versus Graft (HvG) mismatches at these loci. HLA matching coverage was determined by iteratively selecting HLA haplotypes that provide the largest coverage against patient HLA genotypes sampled from the same population, excluding genotypes compatible with previous iterations.
The top 10 haplotypes for each of the 18 countries were identified with patient coverage ranging from 19.5% in Brazil to 63.8% in Japan, with a mean coverage of 33.3%. In a 'global' model, utilizing the 180 most frequent haplotypes across all 18 populations (equivalent to 10 lines per country), the patient coverage ranged from 54.6% in India to 81.7% in Sweden, with a mean of 68.4%. Our findings demonstrate that global collaboration could more than double the potential for patient HLA matching coverage.
Interrogation of unrelated hematopoietic stem cell donor registry and cord blood bank HLA data demonstrated that HLA-A, -B, and -DRB1 homozygous donors for the top 180 global haplotypes are widely available. These results show that a globally coordinated strategy for haplobanking would reduce redundancy and allow more patients to be treated with the same investment.
一些国家已经建立或正在建立国家诱导多能干细胞（iPSC）库，这些库中的细胞系来源于当地人群中常见的具有HLA纯合基因型（两个相同单倍型）的供体，以提供免疫匹配的组织和细胞来支持再生医学疗法。这种“单倍型库”方法依赖于对人群HLA基因型的了解，以确定对患者覆盖最有益的单倍型，并最终确定携带目标单倍型两份拷贝的供体或脐带血单位。
一种可能比国家库方法更有效的替代方法是评估提供全球患者覆盖所需的单倍型，并建立一个单一的全球单倍型库。为此，我们开发了一种算法，对优化全球人群覆盖的HLA单倍型进行优先级排序。
我们分析了参与全球诱导多能干细胞治疗联盟（GAiT）的18个国家的数据。通过从每个国家的世界骨髓捐献者协会（WMDA）造血干细胞供体登记处或替代人群中抽样，得出了一组反映患者HLA的代表性HLA基因型。基于HLA-A、-B和-DRB1单倍型纯合类型创建了一种算法，人群HLA匹配覆盖率由这些位点不存在宿主与移植物（HvG）错配来定义。通过迭代选择对从同一人群中抽样的患者HLA基因型提供最大覆盖的HLA单倍型来确定HLA匹配覆盖率，排除与先前迭代兼容的基因型。
确定了18个国家中每个国家的前10个单倍型，患者覆盖率从巴西的19.5%到日本的63.8%不等，平均覆盖率为33.3%。在一个“全球”模型中，利用所有18个人群中最常见的180个单倍型（相当于每个国家10个细胞系），患者覆盖率从印度的54.6%到瑞典的81.7%不等，平均为68.4%。我们的研究结果表明，全球合作可以使患者HLA匹配覆盖的潜力增加一倍以上。
对无关造血干细胞供体登记处和脐带血库HLA数据的审查表明，全球前180个单倍型的HLA-A、-B和-DRB1纯合供体广泛可用。这些结果表明，全球协调的单倍型库策略将减少冗余，并允许以相同的投资治疗更多患者。
