Jürgen Sauter

PURPOSE: For patients with hematologic malignancies, relapse is the leading cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Frequently, relapses are explained by immune evasion through alterations of human leukocyte antigens (HLAs), but determinants and clinical consequences remain poorly defined. METHODS: We analyzed 533 relapses of hematologic cancers after allo-HCT from different donor types, conducted at 27 centers worldwide. Genomic loss of mismatched HLA (HLA loss) was assessed using a newly developed next-generation sequencing pipeline. Clinical and immunogenetic factors associated with HLA loss were evaluated. Using HLA data from approximately 5 million individuals, a web-based tool to infer HLA incompatibility phasing was developed. RESULTS: HLA loss occurred in 15.6% of relapses, with significant variation according to donor type (28.7% haploidentical family, 7.2% unrelated adult, 2.7% cord blood, P < .0001). The distribution of HLA mismatches across the patient's haplotypes, predicted through the phasing tool, was strongly associated with HLA loss, with an incidence of 27.6% when HLA mismatches were in the same haplotype, compared with 5.4% if present on different haplotypes ( P < .0001). HLA loss affected postrelapse outcomes, abrogating the efficacy of original donor lymphocyte infusions, with significant survival advantage by second allo-HCT from a different donor. CONCLUSION: The likelihood of HLA loss varies significantly according to the number and positioning of HLA mismatches between patient and donor. A newly developed phasing tool enables reliable prediction of its risk, supporting informed donor selection. Routine assessment of HLA loss at relapse is warranted, as it critically affects the success of immunologic salvage therapies.

Standardised data representation is fundamental to the integrity, interoperability and reproducibility of immunogenetics and histocompatibility testing. While well‐established standards such as the genotype list (GL) String, histoimmunogenetics markup language (HML) and minimum information for reporting next‐generation sequence genotyping exist for encoding HLA genotyping results, no equivalent syntax currently exists for describing phenotype‐ or antigen‐level information that underlies antibody testing and immunological risk assessment. We introduce the phenotype list (PL) String grammar and the phenotype list string code (PLSC) syntax, structured, machine‐readable grammars designed to represent antigen‐ and protein‐level data across three contexts: (1) the HLA phenotype composition of assay reagents, (2) test results derived from those reagents and (3) clinical interpretations of HLA antibody specificities. PL String extends the hierarchical logic of the GL String grammar, while adapting a subset of GL String delimiters and rules to describe ambiguity, heterodimeric relationships and phenotypic composition. PL String incorporates explicit namespace definitions (e.g., World Health Organization HLA Nomenclature Committee for Factors of the HLA System, Organ Procurement and Transplantation Network, Eurotransplant and NMDP) to ensure traceability and compatibility with existing regulatory and operational frameworks. By harmonising how HLA phenotypic and antibody data are encoded, PL Strings enable automated data exchange between laboratories, registries and information systems, reducing transcription errors and improving computational interpretation. This new grammar establishes a foundation for interoperable representation of serologic and functional HLA data, facilitating reproducible research and enhancing clinical decision support in transplantation and immunogenetics. Technical specifications for PL Strings and PLSCs are available at plstring.org .

HIV cure is exceptionally rare, with only six cases documented among the estimated 88 million individuals who have acquired HIV since the onset of the epidemic ^1–6 . Successful cures, including that of the pioneering individual known as the Berlin patient, are limited to those who received allogeneic stem cell transplants (allo-SCTs) for haematological cancers. HIV resistance from stem cell donors with the rare homozygous CCR5Δ32 mutation was long considered the main mechanism for HIV remission without antiretroviral therapy. However, recent reports have highlighted CCR5-independent mechanisms as important contributors to HIV cure ^6–8 . Here we provide new evidence for this conceptual shift, whereby long, treatment-free HIV remission was achieved after allo-SCT with functionally active CCR5. A man with heterozygous CCR5 wild-type/Δ32 living with HIV received allo-SCT from a HLA-matched unrelated heterozygous CCR5 wild-type/Δ32 donor as treatment for acute myeloid leukaemia. Three years after allo-SCT, the patient discontinued antiretroviral therapy. So far, HIV remission has been sustained for more than 6 years with undetectable plasma HIV RNA. Reservoir analysis revealed intact proviral HIV before transplantation, but no replication-competent virus in blood or intestinal tissues after allo-SCT. Declining or absent HIV-specific antibody and T cell responses support the absence of viral activity. High antibody-dependent cellular cytotoxicity activity at the time of transplantation may have contributed to HIV reservoir clearance. These results demonstrate that CCR5Δ32-mediated HIV resistance is not essential for durable remission, which underscores the importance of effective viral reservoir reductions in HIV cure strategies.

Donor age is one factor to optimize allogeneic hematopoietic cell transplantation (alloHCT). Therefore, we investigated whether young unrelated donors (UD) provide a benefit for older patients with myeloid malignancies compared to HLA-identical sibling donors (MSD). We performed a retrospective registry study on patients ≥50 years who received a first alloHCT between 2010 and 2020. We compared event-free survival (EFS) of patients who were transplanted from MSD aged ≥50 years versus UD aged ≤35 years who were HLA-compatible for HLA-A, -B, -C, and -DRB1. In total, we analyzed data from 3460 patients. With multivariable adjustment EFS (HR 0.86, p = 0.003), OS (HR 0.82, p < 0.001), and risk of relapse (HR 0.84, p = 0.018) were significantly better for HLA-compatible UD compared to MSD. No survival advantage was found, when UD with unfavorable sex or CMV constellation were compared to MSD with favorable constellations. In a meta-analysis on 9905 patients with myeloid malignancies, including ours, we found reduced risk of relapse (pooled HR 0.78, p = 0.006) and better EFS (pooled HR 0.89, p < 0.001) for young matched UD versus MSD. To select young HLA-compatible UD over older MSD may reduce relapse risk and improve survival for older patients with myeloid malignancies.

KIR3DS1 is an activating natural killer (NK) cell receptor gene– present in 10-40% of humans– and is associated with extended AIDS-free survival. Although its ligand HLA-F has been identified, the underlying protective mechanism in HIV-1 is not yet understood. We sought to uncover the role of the KIR3DS1/HLA-F axis through investigating HLA-F surface and transcriptional changes during acute and chronic HIV-1 infection. HLA-F⁺ CD4 T cells were detected in people living with HIV (PLHIV) without antiretroviral treatment (N=102) and frequencies correlated with viremia but not with CD4 T cell count. Single-cell transcriptome analyses of PLHIV following acute HIV-1 acquisition revealed increased HLA-F mRNA levels in CD4 T cells associated with innate signaling signatures. In vitro, HLA-F mRNA was upregulated in both HIV-1–infected and bystander CD4 T cells. Functional studies demonstrated that bystander-activated CD4 T cells were reduced in the presence of NK cells during HIV-1 infection, and depleting NK cells increased the frequency of HLA-F⁺ CD4 T cells. Genotyping of our cohort revealed that KIR3DS1⁺ PLHIV exhibited significantly lower frequencies of HLA-F⁺ CD4 T cells. Taken together, these results establish HLA-F as a novel marker of innate T cell activation that is linked to HIV-1 viremia and suggest an immunoregulatory role of NK cells in controlling HIV-1-mediated inflammation by killing activated bystander CD4 T cells.

Despite over 41 million registered potential volunteer stem cell donors worldwide, many patients in need of a transplant do not find an HLA‐matched unrelated donor or cord blood units, with the respective odds differing significantly between various populations. In this study, we analysed data of 2205 unsuccessful real‐life donor searches sent to the DKMS Registry to identify populations in which further donor recruitment would be associated with particularly large patient benefits. For that purpose, we estimated haplotype frequencies of 67 donor populations at various sample sizes and entered them into two different mathematical models. These models assessed patient benefits from population‐specific donor recruitment, operationalised by the number of originally unsuccessful searches that may become successful due to new donors. Consistently, across the different mathematical models and sample sizes, we obtained several countries from East and Southeast Asia (Thailand, Vietnam, China, and the Philippines) and the population of Asians in the USA as countries/populations where donor recruitment activities would be particularly beneficial for patients. We also identified various countries in Southeast and Central Europe as possible target regions for donor recruitment with above‐average patient benefits. The results presented are registry‐specific in the sense that they were obtained by optimising unsuccessful searches that had been sent to the DKMS Registry. Therefore, it would be desirable to apply the presented methods to a global data set that includes all unsuccessful stem cell donor searches worldwide and uses population‐specific haplotype frequencies based on all donors available in the WMDA Search & Match Service.

A fundamental endeavor of the International Histocompatibility and Immunogenetics Workshop (IHIW) was assembling a collection of DNA samples homozygous through the MHC genomic region. This collection proved invaluable for assay development in the histocompatibility and immunogenetics field, for generating the human reference genome, and furthered our understanding of MHC diversity. Defined by their HLA‐A, ‐B, ‐C and ‐DRB1 alleles, the combined frequency of the haplotypes from these individuals is ∼20% in Europe. Thus, a significant proportion of MHC haplotypes, both common and rare throughout the world, and including many associated with disease, are not yet represented. In this workshop component, we are collecting the next generation of MHC‐homozygous samples, to expand, diversify and modernize this critical community resource that has been foundational to the field. We asked laboratories worldwide to identify samples homozygous through all HLA class I and/or HLA class II genes, or through whole‐genome SNP genotyping or sequencing, to have extensive homozygosity tracts within the MHC region. The focus is non‐Europeans or those having HLA haplotypes less common in Europeans. Through this effort, we have obtained samples from 537 individuals representing 294 distinct haplotypes, as determined by their HLA class I and II alleles, and an additional 50 haplotypes distinct in HLA class I or II alleles. Although we have expanded the diversity, many populations remain underrepresented, particularly from Africa, and we encourage further participation. The data will serve as a resource for investigators seeking to characterise variation across the MHC genomic region for disease and population studies. [Correction added on [24 July 2024], after first online publication: the Abstract was inadvertently remove and has been reinstated in this version.]

MICA is a stress-induced ligand of the NKG2D receptor that stimulates NK and T cell responses and was identified as a key determinant of anti-tumor immunity. The MICA gene is located inside the MHC complex and is in strong linkage disequilibrium with HLA-B. While an HLA-B*48-linked MICA deletion-haplotype was previously described in Asian populations, little is known about other MICA copy number variations. Here, we report the genotyping of more than two million individuals revealing high frequencies of MICA duplications (1%) and MICA deletions (0.4%). Their prevalence differs between ethnic groups and can rise to 2.8% (Croatia) and 9.2% (Mexico), respectively. Targeted sequencing of more than 70 samples indicates that these copy number variations originate from independent nonallelic homologous recombination events between segmental duplications upstream of MICA and MICB. Overall, our data warrant further investigation of disease associations and consideration of MICA copy number data in oncological study protocols.