Predicting an HLA-DPB1 expression marker based on standard DPB1 genotyping: Linkage analysis of over 32,000 samples

The risk of acute graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation is increased with donor-recipient HLA-DPB1 allele mismatching. The single-nucleotide polymorphism (SNP) rs9277534 within the 3′ untranslated region (UTR) correlates with HLA-DPB1 allotype expression and serves as a marker for permissive HLA-DPB1 mismatches. Since rs9277534 is not routinely typed, we analyzed 32,681 samples of mostly European ancestry to investigate if the rs9277534 allele can be reliably imputed from standard DPB1 genotyping. We confirmed the previously-defined linkages between rs9277534 and 18 DPB1 alleles and established additional linkages for 46 DPB1 alleles. Based on these linkages, the rs9277534 allele could be predicted for 99.6% of the samples based on DPB1 genotypes (99.99% concordance). We demonstrate that 100% prediction accuracy could be achieved if the prediction utilized exon 3 sequence information. DPB1 genotyping based on exon 2 data alone allows no unambiguous rs9277534 allele prediction but was estimated to maintain 99% accuracy for samples of European descent. We conclude that DPB1 genotyping is sufficient to infer the DPB1 expression marker rs9277534 with high accuracy. This information could be used to select donors with permissive HLA-DPB1 mismatches without directly screening for rs9277534.     

Use of gene-modified regulatory T-cells to control autoimmune and alloimmune pathology: Is now the right time?

Adoptive immunotherapy using genetically targeted T-cells has recently begun to achieve impressive clinical impact in selected tumor types. Furthermore, long-term follow-up studies indicate thus far that integrating viral vectors do not elicit clinically evident genotoxicity in T-cells, unlike hematopoietic stem cells. The optimism engendered by this clinical experience provides a platform for consideration of the extended use of this technology in other disease types. One area of particular interest entails the harnessing of regulatory T-cells (Tregs) in order to down-regulate unwanted immune responses. Increasing evidence supports the efficacy of this approach in pre-clinical models of autoimmune disease and allograft rejection. Nonetheless, questions remain about optimal host cell, transgene cargo, phenotypic stability of engineered cells in vivo and potential for toxicity. Here, we review the evidence that genetically engineered Tregs can effectively dampen pathogenic immune responses and critically evaluate the prospects for clinical development of this approach.     

L‐Selectin Is Dispensable for T Regulatory Cell Function Postallogeneic Bone Marrow Transplantation

In murine models, the adoptive transfer of CD4⁺/CD25⁺ regulatory T cells (T_regs) inhibited graft‐versus‐host disease (GvHD). Previous work has indicated a critical role for the adhesion molecule L‐selectin (CD62L) in the function of T_regs in preventing GvHD. Here we examined the capacity of naive wild‐type (WT), CD62L^?/? and ex vivo expanded CD62L^Lo T_regs to inhibit acute GvHD. Surprisingly, we found that CD62L^?/? T_regs were potent suppressors of GvHD, whereas CD62L^Lo T_regs were unable to inhibit disease despite being functionally competent to suppress allo T cell responses in vitro. Concomitant with improved outcomes, WT and CD62L^?/? T_regs significantly reduced liver pathology and systemic pro‐inflammatory cytokine production, although CD62L^?/? T_regs were less effective in reducing lung pathology. While accumulation of CD62L^?/? T_regs in GvHD target organs was equivalent to WT T_regs, CD62L^?/? T_regs did not migrate as well as WT T_regs to peripheral lymph nodes (PLNs) over the first 2 weeks posttransplantation. This work demonstrated that CD62L was dispensable for T_reg‐mediated protection from GvHD.     

Antibodies to 60, 65 and 70 kDa heat shock proteins in pediatric allogeneic stem cell transplant recipients

Allogeneic SCT remains the only means of cure for many patients with various malignant disorders as well as non-malignant diseases. Infection together with severe aGvHD may result in a significant incidence of transplant-related morbidity and mortality. Current evidence suggests that hSPS represent major immunodominant antigens in many pathogens and therefore might play an important role in the pathogenesis of GvHD. We investigated the levels of total Ig, IgG and IgM isotype antibodies to rh-hsp60, recombinant Mycobacterium bovis hsp65 and stress-inducible rh-hsp70 in sera of pediatric patients undergoing SCT by using ELISA. We studied whether humoral immune responses to hSPS follow transplant-related complications, bacterial and fungal infection. Anti-hsp antibodies were detected in patients' sera before conditioning, over the course of conditioning and all the time post-transplant. We found no correlation between anti-hsp antibodies and the occurrence and severity of GvHD and/or other transplant-related complications like graft failure, hemorrhagic cystitis and capillary leakage syndrome. However, elevated anti-hsp antibodies involving IgM and IgG isotypes were found to be associated with bacterial and fungal infection depending on etiological agents. We demonstrated de novo humoral response to hSPS in a cohort of patients with actual infection caused by Klebsiella pneumoniae (anti-hsp60, anti-hsp65 and anti-hsp70), Pseudomonas aeruginosa (anti-hsp60, anti-hsp70) and Aspergillus fumigatus (anti-hsp65). We conclude that anti-hsp antibodies might be produced after SCT in relation to infection depending on etiological agents; however, transplant-related complications by themselves had a little impact.     

HLA-B44 subtyping in the Catalan population using reference strand mediated conformation analysis. Implications for the selection of unrelated bone marrow donors

Cytotoxic T lymphocytes (CTLs) reactive against the disparity between HLA-B*4402 and HLA-B*4403 have been reported after unrelated donor bone marrow transplantation. These CTLs have been associated with acute graft-versus-host disease and graft rejection. This study describes the HLA-B44-subtyping in the Catalan population using reference-strand mediated conformation analysis. It has been performed on 297 unrelated HLA-B44+ cord blood units from the Barcelona Cord Blood Bank (Barcelona, Spain). We have found a predominance of HLA-B*4403 (66.04%) over HLA-B*4402 (33.02%), whereas the predominant HLA-B44 allele in Northern Europe and the United States is HLA-B*4402. This inverted proportion between HLA-B44 subtypes in Mediterranean populations compared with other Caucasian populations suggests that HLA-B44 subtyping should be performed when an HLA-B44+ unrelated donor marrow is identified.     

Mucosal-associated invariant T cells for cancer immunotherapy

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