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BackgroundAllogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT.Methods and findingsThe study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42-4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11-2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10-0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17-0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants.ConclusionsThe present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

Two novel alleles that appear to be generated from recombination between exons 2 and 3. [ABSTRACT FROM AUTHOR]

Background and objectives: Polymorphisms of the interleukin (IL)-17 proinflammatory cytokine family (IL17A and IL17F) have been associated with kidney chronic allograft failure (CAF). To date, the impact of heritable differences in IL17F genes and CAF among kidney transplant patients from North America has not been reported. The objective of the study was to assess the association of five distinct polymorphisms in the IL17F gene with histopathological changes in chronic kidney allograft failure. Methods: Two hundred eighteen kidney transplant recipients were enrolled. Surveillance biopsies were performed to evaluate 11 distinct histological markers and the combined grade of interstitial fibrosis and tubular atrophy, 6 to 12 months posttransplant. Using direct sequencing, the IL17F polymorphisms (-1507C/T rs1889570, -1165A/G rs1266828, -5046C/T rs7771511, -6328G/A rs766748, and -7488A/G rs763780) were genotyped in the 10 healthy volunteer samples followed by all kidney transplant recipients were genotyped for five IL17F gene polymorphisms using polymerase chain reaction and sequence-specific primers. The association was evaluated using both univariate and multivariate logistic regression analysis. Results: We observed weak associations of TC genotype of IL17F-1165 (rs1266828) and allele of IL17F -1507C (rs1889570) with glomerular sclerosis and interstitial fibrosis and tubular atrophy (p = 0.017 and p = 0.03) respectively. Allele C of IL-17 -1165C/T (rs1266828) was associated with better glomerular sclerosis (p = 0.004, odds ratio = 0.39) score. Conclusions: Our findings demonstrate that IL17F SNPs were not associated with CAF and support our prior published results that production of pro-inflammatory cytokines is not a strong predictor of CAF. [ABSTRACT FROM AUTHOR]

Introduction: Recipients of allogeneic HCT remain vulnerable to an increased risk of reactivation of otherwise latent viral infections due to an immune compromised state. Uncontrolled reactivation of Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) is one such major complication after T-cell depleted HCT. Recovering within weeks after transplantation and being first in line of defense against viral infections, natural killer (NK) cells are considered important in the immunopathogenesis of EBV complications. NK cell responses are regulated by activating and inhibitory cell surface receptors, central to which are the killer immunoglobulin-like receptors (KIR). Through these receptors, NK cells discriminate healthy cells from 'altered" self-cells by scaling the perturbations in HLA expression after viral transformation of the target cell. Here, we set out to determine whether and how KIR gene and motifs" content of HCT donors and/or recipients influences the development of PTLD after HCT. Methods: Hypothesizing that diverse NK cell receptor repertoires can titrate NK cell functional responses to EBV infections/reactivation and can potentially modify the risk of developing PTLD, we determined the KIR gene repertoires of 356 HLA-matched donor-recipient pairs of first allo-HCT and 50 healthy donors through Next Generation Sequencing (NGS) of the KIR locus on the Illumina MiSeq platform. PBMNCs from KIR typed healthy volunteers were stimulated with EBV-transformed target cells to enumerate NK cell response to EBV as a function of KIR gene content using a multicolor flow cytometry-based assay. Effect of KIR gene profile on development of PTLD was analyzed using binomial competing risks regression statistics. Distribution of NK cell functional response across various KIR characterized groups was analyzed using Mann-Whitney U statistics. Results: Donor telomeric A motifs (tAOl, KIR3DL1+ KIR2DS4+; KIR3DS1/2DS1+/-), strongly protected against PTLD (p = 0.0001) with at least one copy required for a significant protective effect. The number of EBV induced functional NK cell subsets were significantly higher in individuals with than without KIR genotypes containing tAOl motifs. There was no influence of recipients" KIR repertoire on the risk of developing PTLD. Conclusions: NK cell responsiveness, a function of KIR gene repertoire has a profound effect on the development of PTLD. Appropriately characterized KIR gene profile-based identification of HCT recipients at high risk of developing PTLD will enable closer monitoring of EBV DNAemia and facilitate prompt therapy. [ABSTRACT FROM AUTHOR]

Characterization of three novel HLA‐DPA1 alleles bearing null, synonymous, and non‐synonymous mutations. [ABSTRACT FROM AUTHOR]

The ability of COVID‐19 vaccination to induce anti‐HLA antibodies (Abs) formation in renal transplant candidates is not well studied. A 42‐year‐old man on a renal transplant waitlist, with no sensitization history, was tested for DSA before and after COVID‐19 vaccination. Patient has consistently tested negative for COVID‐19 virus. Eighteen days after receiving first dose of mRNA‐based vaccine, flow cytometry crossmatch (FCXM) was strongly positive with de novo donor‐specific Ab (dnDSA) against B57 and de novo non‐DSA against B58. Before vaccination, preliminary FCXM was negative with no anti‐HLA Abs. This event prompted the transplant team to cancel the surgery. COVID‐19 vaccination could be associated with anti‐HLA Abs formation in renal patients on waitlists that could affect future transplantability. [ABSTRACT FROM AUTHOR]

HLA‐DRB4*01:165N exhibits deletion of a nucleotide in exon 3, producing a premature stop codon. [ABSTRACT FROM AUTHOR]

Objective: The objective of our study was to determine levels of endothelial progenitor cells (EPCs) in preeclampsia and normotensive pregnant women.Study Design: Prospective cohort study of women with preeclampsia and normotensive pregnancies. EPCs were estimated by flow cytometry. Multiple linear regression was used to assess the association of EPCs with preeclampsia adjusting for maternal age, body mass index (BMI), gestation and ethnicity.Main Outcome Measure: Levels of EPCs in preeclampsia and normotensive pregnancies, with CD-34 and vascular endothelial (VE)-cadherin as markers of EPCs. VE-cadherin is an endothelial cell adhesion molecule used to delineate endothelial lineage of EPCs.Results: There were thirty women in the preeclampsia group and thirty-three in the normotensive group. The two groups were similar except for the BMI and blood pressures, which were higher in preeclampsia. On multiple linear regression, EPCs numbers were significantly higher by 29 (95% confidence interval 11.7-46.6, p = 0.001) in preeclampsia compared to the normotensive group. There was significant positive correlation between EPCs and systolic blood pressure in preeclampsia (Spearman correlation coefficient 0.39, p = 0.03).Conclusion: Although widely used in cardiovascular disease other than preeclampsia, this is the first study using VE-cadherin as a marker of endothelial lineage to define EPCs in preeclampsia. Our results suggest the higher number of EPCs in preeclampsia may be a response of the bone marrow to endothelial injury. [ABSTRACT FROM AUTHOR]