Manuel Muro

The Murcia Region unrelated donor (URD) registry was established in 1992 as part of the Spanish Bone Marrow Donor Registry (REDMO). This study aimed to comprehensively characterize the long-term evolution of URD recruitment, human leukocyte antigen (HLA) genetic diversity, allele and haplotype frequencies, and the spectrum of novel HLA alleles detected over the 34 years from 1992 to 2025. Recruitment trends, URD demographic characteristics, HLA allele and haplotype frequencies, and newly detected HLA alleles were analyzed retrospectively. HLA typing was performed using serological methods (1992–1996); PCR-SSO, PCR-SSP, and PCR-SSO Luminex (1997–2018); sequence-based typing (SBT, 2018–2021); and next-generation sequencing (NGS, 2021–2025). NGS was used to analyze a subset of 650 URDs to determine high-resolution HLA allele frequencies, Hardy–Weinberg equilibrium, expected heterozygosity, and extended HLA haplotypes. Newly detected HLA alleles were further characterized by the affected HLA locus and the localization of sequence variants within exons, introns, and the 3′-untranslated region (3′UTR). Between 1992 and 2025, 33.271 URDs were recruited, of whom 27.107 remained active in REDMO at the time of analysis. URD recruitment increased substantially following the implementation of the Spanish National Bone Marrow Plan in 2012 and reached a historical high in 2017. Additional recruitment peaks were associated with major regional public awareness campaigns. High-resolution HLA analysis of the NGS cohort demonstrated extensive immunogenetic diversity across all analyzed HLA loci, with a mean expected heterozygosity of 0.914. Ten frequent extended HLA haplotypes were identified, the most prevalent being HLA-A*29:02-C*16:01-B*44:03-DRB1*07:01-DQB1*02:02. Thirty-nine novel HLA alleles were characterized, exhibiting heterogeneous distributions among HLA loci and across coding and non-coding genomic regions. Exonic variants were predominantly detected in HLA-C, whereas intronic variants were mainly observed in HLA-C, HLA-DQB1, and HLA-A. This study integrates 34 years of URD recruitment with high-resolution immunogenetic characterization of the Murcia Region URD registry, providing new insights into the evolution of donor recruitment, HLA diversity, and the discovery of novel HLA alleles. The implementation of NGS enabled precise molecular characterization of HLA diversity and substantially expanded the detection and characterization of novel HLA alleles. Together, these findings provide a robust immunogenetic framework for the Murcia URD population, supporting donor recruitment strategies, optimization of URD searches, registry management, and future research in population genetics and hematopoietic stem cell transplantation.

Problems: Pregnancy is a sensitizing event for human leukocyte antigen (HLA) alleles, as the fetus, acting as a semi‐allograft, expresses maternal and paternal haplotypes in a codominant manner. Consequently, the mother may develop anti‐HLA antibodies directed against the paternal haplotype. However, unlike in organ transplantation, this sensitization is not usually associated with fetal rejection in multiparous women, raising a central question in reproductive immunology: How is maternal‐fetal tolerance achieved and maintained? Method of Study: This review examines the influence of the HLA system on the immunological mechanisms underlying maternal–fetal tolerance. Results: Accumulating evidence suggests that this phenomenon results from a complex network of cellular and molecular interactions. The roles of non‐classical HLA molecules, particularly HLA‐G, the modulation of NK activity via KIR receptors, and the expansion of regulatory T cells, which contribute to the maintenance of systemic immunological tolerance, are highlighted. In parallel, the relevance of anti‐HLA antibodies and polymorphisms in HLA regulatory regions in susceptibility to gestational complications has been investigated. Conclusion: It considers how insights from reproductive immunology may inform related fields such as transplantation and oncology.

HLA‐DPA1*01:248 and ‐DPA1*02:01:41, two novel HLA‐DPA1 alleles detected by next generation sequencing.

HLA‐B*51:448 , a novel HLA class I allele detected by next‐generation sequencing.

Today, there have been spectacular advances in surgical techniques, organ preservation for transplantation, optimal and efficient donor and recipient selection, more efficient diagnosis of transplant complications, and major progress in pharmacological immunosuppression procedures. In this regard, survival rates after transplantation of various organs have been gaining ground, particularly in the case of lung transplants, whose average survival rate is lower than other types of transplants. In this regard, it is important to detect acute and subclinical clinical rejection, as well as chronic allograft rejection. This is especially important in heart and lung transplants. In the latter type of transplant, and due to the chronic dysfunction of the lung allograft, it is key to detect rejection early and promptly, as it can affect up to half of the transplant patient population. Therefore, effective diagnostic tools are needed to visualize the level of allograft damage using genomic methods such as those that measure donor-derived cell-free DNA (dd-cfDNA). The plasma concentration of dd-cfDNA increases after graft injury or infection. Our team has experience quantifying this parameter in allograft injury progression, and our experience and comparison with the published literature will be presented in the following sections, discussing validated and non-validated results.

Two novel HLA‐C alleles, HLA‐C*06:02:01:107 and HLA‐C*07:01:01:148 , detected by next‐generation sequencing.

Three new HLA‐A intronic variants, HLA‐A*02:05:01:25, HLA‐A*29:02:01:42 and HLA‐A*32:01:01:46 , detected by next‐generation sequencing.

HLA‐C*05:311 , a novel HLA class I allele detected by next‐generation sequencing.

B cells have attracted increasing interest in the field of organ transplantation due to their newly discovered immunoregulatory properties in alloimmune responses. Traditionally, B cells have been primarily associated with adaptive immunity to foreign substances and alloreactive immune response to allografts, differentiating into antibody-producing plasma cells or memory cells upon antigen recognition and T cell collaboration. However, the existence of B cells with regulatory functions (Bregs) in humans has been widely confirmed, highlighting the presence of this subset, which has immunosuppressive properties and which might contribute to allograft tolerance, within the B cell compartment in humans and mice. In this mini review, we summarize all the information available in the published reports about the role of regulatory B cells in solid organ transplantation.