Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation.

Immune reconstitution after allogeneic stem cell transplantation is a dynamic and complex process depending on the recipient and donor characteristics, on the modalities of transplantation, and on the occurrence of graft-versus-host disease. Multivariate methods widely used for gene expression profiling can simultaneously analyze the patterns of a great number of biological variables on a heterogeneous set of patients. Here we use these methods on flow cytometry assessment of up to 25 lymphocyte populations to analyze the global pattern of long-term immune reconstitution after transplantation. Immune patterns were most distinct from healthy controls at six months, and had not yet fully recovered as long as two years after transplant. The two principal determinants of variability were linked to the balance of B and CD8(+) T cells and of natural killer and B cells, respectively. Recipient's cytomegalovirus serostatus, cytomegalovirus replication, and chronic graft-versus-host disease were the main factors shaping the immune pattern one year after transplant. We identified a complex signature of under- and over-representation of immune populations dictated by recipient's cytomegalovirus seropositivity. Finally, we identified dimensions of variance in immune patterns as significant predictors of long-term non-relapse mortality, independently of chronic graft-versus-host disease.

Age-adjusted recipient pretransplantation telomere length and treatment-related mortality after hematopoietic stem cell transplantation.

Telomere attrition induces cell senescence and apoptosis. We hypothesized that age-adjusted pretransplantation telomere length might predict treatment-related mortality (TRM) after hematopoietic stem cell transplantation (HSCT). Between 2000 and 2005, 178 consecutive patients underwent HSCT from HLA-identical sibling donors after myeloablative conditioning regimens, mainly for hematologic malignancies (n = 153). Blood lymphocytes' telomere length was measured by real-time quantitative PCR before HSCT. Age-adjusted pretransplantation telomere lengths were analyzed for correlation with clinical outcomes. After age adjustment, patients' telomere-length distribution was similar among all 4 quartiles except for disease stage. There was no correlation between telomere length and engraftment, GVHD, or relapse. The overall survival was 62% at 5 years (95% confidence interval [CI], 54-70). After a median follow-up of 51 months (range, 1-121 months), 43 patients died because of TRM. The TRM rate inversely correlated with telomere length. TRM in patients in the first (lowest telomere length) quartile was significantly higher than in patients with longer telomeres (P = .017). In multivariate analysis, recipients' age (hazard ratio, 1.1; 95% CI, .0-1.1; P = .0001) and age-adjusted telomere length (hazard ratio, 0.4; 95% CI; 0.2-0.8; P = .01) were independently associated with TRM. In conclusion, age-adjusted recipients' telomere length is an independent biologic marker of TRM after HSCT.

Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.

Natural killer cells are the first lymphocyte subset to reconstitute, and play a major role in early immunity after allogeneic hematopoietic stem cell transplantation. Cells expressing the activating receptor NKG2C seem crucial in the resolution of cytomegalovirus episodes, even in the absence of T cells. We prospectively investigated natural killer-cell reconstitution in a cohort of 439 adult recipients who underwent non-T-cell-depleted allogeneic hematopoietic stem cell transplantation between 2005 and 2012. Freshly collected blood samples were analyzed 3, 6, 12 and 24 months after transplantation. Data were studied with respect to conditioning regimen, source of stem cells, underlying disease, occurrence of graft-versus-host disease, and profiles of cytomegalovirus reactivation. In multivariate analysis we found that the absolute numbers of CD56(bright) natural killer cells at month 3 were significantly higher after myeloablative conditioning than after reduced intensity conditioning. Acute graft-versus-host disease impaired reconstitution of total and CD56(dim) natural killer cells at month 3. In contrast, high natural killer cell count at month 3 was associated with a lower incidence of chronic graft-versus-host disease, independently of a previous episode of acute graft-versus-host disease and stem cell source. NKG2C(+)CD56(dim) and total natural killer cell counts at month 3 were lower in patients with reactivation of cytomegalovirus between month 0 and month 3, but expanded greatly afterwards. These cells were also less numerous in patients who experienced later cytomegalovirus reactivation between month 3 and month 6. Our results advocate a direct role of NKG2C-expressing natural killer cells in the early control of cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.

High prevalence of infectious events in thrombotic thrombocytopenic purpura and genetic relationship with toll-like receptor 9 polymorphisms: experience of the French Thrombotic Microangiopathies Reference Center.

BACKGROUND: Infectious events have been reported as major environmental triggers of thrombotic thrombocytopenic purpura (TTP). We detail here the potential association between infections and TTP. STUDY DESIGN AND METHODS: We recruited randomly and prospectively a cohort of 280 consecutive TTP patients during a 9-year period. Features of infection were systematically recorded. RESULTS: Features consistent with an infectious event were observed in 114 patients (41%) at time of TTP diagnosis. Infectious agents were documented in 34 cases and were mainly Gram-negative bacilli. At time of diagnosis infected patients more frequently had fever (p < 0.001). Infections at diagnosis did not impact prognosis and outcome. Thirty-six percent of patients experienced an infectious event during hospitalization, which resulted in more exacerbation of TTP (p = 0.02). Infections were not overrepresented during treatment in patients who received steroids and/or rituximab. Further genetic analysis of toll-like receptor (TLR)-9 functionally relevant polymorphisms revealed that TLR-9 +2848 G and TLR-9 +1174 A genotypes were more frequent in TTP patients than in controls (p = 0.04 and p = 0.026, respectively) and more particularly in patients negative for the Class II human leukocyte antigen system susceptibility allele DRB1*11 (p = 0.001 and p = 0.002, respectively). Haplotypes estimation showed that 1174A-2848G haplotype was significantly more frequent in TTP (p = 0.004), suggesting a primary role for this haplotype variation in conferring a predisposition for acquired TTP. CONCLUSION: Infections should be considered as an aggravating factor during the course of TTP. Particular polymorphisms in TLR-9 gene may represent risk factors for TTP.

CD19+CD5+ B cells and B1-like cells following allogeneic hematopoietic stem cell transplantation.

We and others have previously reported the expansion of CD5(+)CD19(+) B cells after allogeneic hematopoietic stem cell transplantation. Recently, the equivalent of B1 cells in mice has been described in humans as CD20(+)CD27(+)CD43(+)CD70(-) B cells. In this article, we report that although 39% of CD5(+)CD19(+) cells were CD43(+) in controls, >75% of CD5(+)CD19(+) cells were CD43(+) in patients independent of the presence or absence of chronic graft-versus-host disease (GVHD) (P = .0001). CD5(+)CD19(+) B cell, CD5(+)CD43(+)CD19(+) B cell, and CD27(+)CD43(+) B cell counts were significantly lower in the patients with previous chronic GVHD, and this effect of GVHD was similar in both CD5(+) and CD5(-) within the CD27(+)CD43(+) B cell subset. Our results strongly suggest that the previously reported expansion of the CD5(+)CD19(+) population might be related to an expansion of the CD27(+)CD43(+) B cell subset and that CD27(+)CD43(+) B cell reconstitution is impaired in patients with chronic GVHD.

NK-cell education is shaped by donor HLA genotype after unrelated allogeneic hematopoietic stem cell transplantation.

The rules governing natural killer (NK)-cell education in the allogeneic environment created by unrelated hematopoietic stem-cell transplantation (HSCT) are still largely elusive, especially in an unrelated donor setting. NK-cell inhibitory receptors for self-human leukocyte antigen (HLA) play a central role in the acquisition or maintenance of NK-cell functional competence. Therefore, the responsiveness of different NK-cell subsets was assessed as a function of their expression or absence of expression of self-HLA-specific inhibitory receptors, in a large cohort (n = 60) of unrelated HSCT recipients. A fully effective NK-cell education process was achieved within the first year after allogeneic HSCT and lasted for at least 3 years thereafter. In addition, HLA-mismatched HSCT led to a stable education pattern that was determined by the donor's HLA ligands. These data suggest that the NK cell's education partner could be of hematopoietic rather than extrahematopoietic origin. This donor-ligand-driven NK-cell education model would suggest a sustained graft-versus-leukemia effect after HLA-mismatched HSCT.

Kidney graft dysfunction in simultaneous pancreas-kidney recipients after pancreas failure: analysis of early and late protocol biopsies.

BACKGROUND: Kidney graft survival in simultaneous pancreas-kidney (SPK) recipients is known to decrease after pancreas graft failure. METHODS: Sixty-three consecutive SPK recipients were retrospectively reviewed. Kidney graft function and proteinuria were evaluated at three months after the transplantation and at last follow-up. Histopathologic findings of protocol biopsies performed three months and one yr after transplantation were analyzed. RESULTS: Twelve patients lost the pancreas graft. Donors' characteristics were similar in patients with or without pancreas failure. After a median follow-up of 36 months, mean eGFR with a functional pancreas was 69.5 mL/min/1.73 m² vs. 56.3 mL/min/1.73 m² (p = 0.01) after pancreas loss. Patients who lost pancreas had a median proteinuria of 0.28 g vs. 0.13 g per 24 h (p = 0.02). Analysis of three-month protocol biopsies revealed more frequent isolated glomerulitis after pancreas failure (p = 0.0001), without peritubular capillaritis or C4d deposition. No donor-specific anti-HLA antibodies were detectable in these patients. Chronic tubulointerstitial changes were more frequent in patients with pancreas loss. There was no evidence of diabetic nephropathy recurrence. CONCLUSION: SPK recipients develop an early kidney graft dysfunction after pancreas failure. Histopathologic findings revealed frequent glomerulitis without antibody-mediated rejection and early chronic changes.

Polymorphisms in the immunoregulatory genes are associated with hematopoietic recovery and increased susceptibility to bacterial infections in patients with thalassaemia major undergoing matched related hematopoietic stem cell transplantation.

In this study, the impact of polymorphisms in the genes of proinflammatory (IL-ß, TNF-α, IL-6, IFN-γ), anti-inflammatory (transforming growth factor [TGF]-ß, IL-10, IL-Ra), and other immunoregulatory factors (FcγRIIa, NOS3) along with the conventional risk factors on the rate of hematopoietic recovery and first episodes of bacterial, viral, or invasive fungal infections in 102 patients with ß-thalassaemia major who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with relatively uniform protocols at our center from June 1995 to June 2004 with a minimum follow-up of at least 2 years were studied retrospectively for 180 days after hematopoietic stem cell transplantation (HSCT). Our data show that (1) donor IL-1RN∗2/2 (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.17-5.09; P = .018) and FCγRIIA +4481G/G genotypes (HR, 3.1; 95% CI, 1.56-6.31; P = .001) increased the incidence of bacterial infection; (2) fungal infection was increased in recipients with whose donors had IFN-γ +874T/T genotype (HR, 3.8; 95% CI, 1.08-13.62; P = .037); (3) time to neutrophil recovery was shorter in splenectomized patients (HR, 3.1; 95% CI, 1.70-5.64; P < .001), donors without IL-10 -1082A, -819T, and -592A haplotype (HR, 1.6; 95% CI, 1.02-2.39; P = .039), and recipients with IFN-γ +874A/A genotype (HR, 1.6; 95% CI, 1.05-2.56; P = .029); and (4) time to platelet recovery was shorter in patients with IL-10 -1082A/A genotype (HR, 1.8; 95% CI, 1.14-2.68; P = .010) and with donors having TNF-α -308G/G genotypes (HR, 1.8; 95% CI, 1.06-2.93; P = .028). These data suggest that outcome after allogeneic stem cell transplantation could be affected by many factors. The mechanisms by which they bring about such impact needs further evaluation.

Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation.

Long-term T-cell reconstitution after hematopoietic stem cell transplantation (HSCT) is dependent on patient thymic function and affected by graft-versus-host disease (GVHD). To assess the impact of acute GVHD (aGVHD) on thymic function, we followed a cohort of 93 patients who received HSCT from a human histocompatibility leukocyte antigen-identical sibling, mainly for hematologic malignancies. Thymic output was measured by signal-joint T-cell receptor excision circles (sjTREC) real-time polymerase chain reaction. Absolute sjTREC number was lower at 6 months in patients with aGVHD (P = .014), associated with lower absolute counts of naive CD4 T cells at 6 and 12 months (P = .04 and .02), and persistent abnormalities in T-cell repertoire diversity. Age and aGVHD affected thymic function independently in multivariate analysis. In patients less than 25 years of age, thymic function recovered almost totally at 1 year. As a marker of thymocyte proliferation, we quantified the betaTREC generated during the T-cell receptor beta-chain recombination, in a group of 20 age-matched patients. Mean betaTREC level was reduced at 6 months in patients with aGVHD, indicating an impact on early thymic differentiation rather than on intrathymic proliferation. These data show that aGVHD or its treatment has a transient impact on thymic function in younger patients in the first months after HSCT.

MICA-129 genotype, soluble MICA, and anti-MICA antibodies as biomarkers of chronic graft-versus-host disease.

The MHC class I-related chain A (MICA) molecules exist as membrane-bound and soluble isoforms and are encoded by a polymorphic gene. Their genetic and phenotype characteristics have been studied in various pathologic settings but not in the context of hematopoietic stem cell transplantation (HSCT). Here, we evaluated whether MICA-related features namely MICA-129 gene polymorphism, serum levels of soluble MICA (sMICA) and anti-MICA antibodies (MICA Abs) before and after HSCT could influence the incidence of chronic graft-versus-host disease (cGVHD) and relapse of their disease in 211 HLA-identical sibling pairs and in a subset of 116 recipients, respectively. Although the MICA-129 val/val genotype and elevated sMICA serum levels after HSCT are independently associated with the incidence of cGVHD (P = .002 and .001) regardless of history of acute GVHD, the presence of MICA Abs before transplantation confers protection against cGVHD (P = .04). There is an inverse relationship between MICA Abs and sMICA, suggesting an antibody-based neutralization of deleterious effects of sMICA. Similarly, these genetic and phenotype characteristics of MICA influence the incidence of relapse. Altogether, these data suggest that the studied MICA genotype and phenotype specificities could be used as relevant biomarkers for cGVHD monitoring.

Long-term immune deficiency after allogeneic stem cell transplantation: B-cell deficiency is associated with late infections.

Immune reconstitution was analyzed in 140 consecutive patients who were 2-year disease-free and who underwent myeloablative allogeneic transplantation. A CD4 and CD8 defect was observed involving naive, terminally differentiated, memory and competent cells and above limits values for activated subsets. Natural killer cells normalize at six months while we observed expansion of CD19(+)/CD5(+) B cells after three months and a persisting defect of memory B cells. Chronic graft-versus-host disease did not influence significantly those parameters for CD8 subsets while the naïve and competent CD4 subsets were strongly affected. But the most profound impact of chronic graft-versus-host disease was on B-cell subsets, especially on the memory B population. The cumulative incidence of late severe infections was low (14% at four years). Using Cox's models, only low B-cell counts at 12 (P=0.02) and 24 (P=0.001) months were associated with the hazard of developing late infection, in particular if patients did not develop chronic graft-versus-host disease.

An unusual CD56(bright) CD16(low) NK cell subset dominates the early posttransplant period following HLA-matched hematopoietic stem cell transplantation.

The expansion of the cytokine-producing CD56(bright) NK cell subset is a main feature of lymphocyte reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT). We investigated phenotypes and functions of CD56(bright) and CD56(dim) NK subsets from 43 HLA-matched non-T cell-depleted HSCT donor-recipient pairs. The early expansion of CD56(bright) NK cells gradually declined in the posttransplant period but still persisted for at least 1 year and was characterized by the emergence of an unusual CD56(bright)CD16(low) subset with an intermediate maturation profile. The activating receptors NKG2D and NKp46, but also the inhibitory receptor NKG2A, were overexpressed compared with donor CD56(bright) populations. Recipient CD56(bright) NK cells produced higher amounts of IFN-gamma than did their respective donors and were competent for degranulation. Intracellular perforin content was increased in CD56(bright) NK cells as well as in T cells compared with donors. IL-15, the levels of which were increased in the posttransplant period, is a major candidate to mediate these changes. IL-15 serum levels and intracellular T cell perforin were significantly higher in recipients with acute graft-vs-host disease. Altogether, CD56(bright) NK cells postallogeneic HSCT exhibit peculiar phenotypic and functional properties. Functional interactions between this subset and T cells may be important in shaping the immune response after HSCT.

Donor KIR3DL1/3DS1 gene and recipient Bw4 KIR ligand as prognostic markers for outcome in unrelated hematopoietic stem cell transplantation.

Given their antileukemic activity, natural killer (NK) cells can alter the outcome of hematopoietic stem cell transplantation (HSCT). The physiologic functions of NK cells are regulated by the interaction of killer immunoglobulin-like receptors (KIR) with specific HLA class I ligands. In the literature, different models based on HLA class I and/or KIR donor (D)/recipient (R) gene disparities are considered as predictors of NK cell alloreactivity. In this retrospective and multicentric French study, we analyzed the clinical impact of the different NK-alloreactivity models in 264 patients who underwent T repleted unrelated HSCT. First, we did not observe that the "KIR ligand-ligand" model had a significant clinical impact on unrelated HSCT outcome, whereas the "missing KIR ligand" model had a significant but limited effect on unrelated HSCT, because only the absence of C1 ligand in patients with myelogenous diseases was associated with a decreased overall survival (OS) (hazard ratio=2.17, P=.005). The "KIR receptor-receptor" and the "KIR receptor-ligand" models seemed the most capable of predicting NK alloreactivity because they had a significant impact on acute graft-versus-host disease (aGVHD) occurrence, OS, and relapse incidence in D/R unrelated pairs. In particular, KIR3DL1 gene mismatches in the GVH direction (D(+)R(-)) and the D KIR3DL1(+)/3DS1(+) and R Bw4(-) combination were respectively correlated with the lowest OS in HLA identical pairs (HR=1.99, P =.02) and the highest incidence of relapse in HLA nonidentical D/R unrelated pairs (HR=4.72, P =.03). Overall, our results suggest a detrimental effect of KIR3DL1(+)/3DS1(+) donor NK cells transplanted into HLA-Bw4(-) patients in the absence of an educational process via KIR3DL1/HLA-Bw4 interactions.

The PTPN22 R620W polymorphism is associated with severe bacterial infections after human leukocyte antigen geno-identical haematopoietic stem-cell transplantations.

PTPN22 is a negative regulator of T-cell activation. The C1858T PTPN22 polymorphism has been associated with autoimmune diseases. The role of PTPN22 in immune response and autoimmune diseases suggested that PTPN22 polymorphism could impact outcome of allogeneic hematopoietic stem-cell transplantations that is impaired by immunological and infectious complications. One hundred ninety-two patients who received a non-T-depleted bone marrow transplant from a human leukocyte antigen-identical sibling donor were included in this study. Donor PTPN22 C1858Tpolymorphism was not associated with severe acute graft-versus-host disease, relapse, survival, cytomegalovirus, and fungal infections, but significant with severe bacterial infections (24% for donor CC vs. 0% for donor CT+TT genotypes, P=0.003). The association was confirmed by a multivariate analysis (P=0.036, hazard ratio=2.28, 95% confidence interval=1.06-4.90). This could improve the genetic risk assessment of severe bacterial infections in allogeneic hematopoietic stem-cell transplantations.

HLA-E*0101 allele in homozygous state favors severe bacterial infections in sickle cell anemia.

Severe bacterial infections are the major causes of morbidity and mortality in sickle cell anemia (SCA) but are poorly explained. The distribution of a bi-allelic polymorphism (Arg107Gly) of human leukocyte antigen-E (HLA-E) locus was investigated in 144 SCA patients, most of whom originated from from sub-Saharan Africa. Among them, 73 presented with at least one severe bacterial infection, whereas 71 did not. The HLA-E*0101/E*0101 genotype was more frequent among the group with infections than their counterparts (47% vs 21%; p corrected = 0.003). This genetic association is of relevance, given the emerging evidence for the involvement of HLA-E molecules in host response to pathogens.

Clinical profile, biological markers, and comorbidity index as predictors of transplant-related mortality after allo-HSCT.

Various pretransplant patient and disease characteristics are associated with treatment-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, TRM cannot yet be satisfactorily predicted. We prospectively investigated the aggregate impact of pretransplant clinical variables (period, donor/recipient age, gender, cytomegalovirus status, disease risk, stem cell source, and HLA matching), comorbidity index scores (Hematopoietic Cell Transplantation Comorbidity Index), and biological markers (telomere length, ferritin, and C-reactive protein) on TRM in single-center patients receiving a first allo-HSCT. From 2006 to 2012, all variables were available for 178 patients. In multivariate analysis, only mismatched unrelated donor (hazard ratio [HR], 2.79; 95% confidence interval [CI], 1.19-6.58; P = .019) and shorter age-adjusted recipient telomere length (HR, 2.17; 95% CI, 1.03-4.57; P = .041) were independently associated with TRM. Pre-allo-HSCT age-adjusted telomere length thus appears to be a useful new predictor of TRM in the setting of HSCT.

Prediction of CD4(+) T cell epitopes restricted to HLA-DP4 molecules.

We have set up a method to predict peptide binding to HLA-DP4 molecules. These HLA II molecules are the most frequent worldwide and hence are an interesting target for epitope-based vaccines. The prediction is based on quantitative matrices built with binding data for peptides substituted at anchoring positions for HLA-DP4. A set of 98 peptides of various origins was used to compare the prediction with binding activity. At different prediction thresholds, the positive predictive value and the sensitivity of the prediction ranged from 50% to 80%, demonstrating its efficiency. This prediction method can be applied to the entire genomes of pathogens and large peptide sequences derived from tumor antigens.

Homozygous status for HLA-E*0103 confers protection from acute graft-versus-host disease and transplant-related mortality in HLA-matched sibling hematopoietic stem cell transplantation.

BACKGROUND: The posttransplant period following hematopoietic stem cell transplantation (HSCT) is potentially high risk for developing survival-compromising complications, many of which are known to be under the control of immunogenetic factors. Given the dual role of human leukocyte antigen (HLA)-E molecules in innate and adaptive immune processes, we analyzed the impact of HLA-E polymorphism in genoidentical HSCT setting. METHODS: We analyzed 187 HLA-genoidentical sibling pairs for HLA-E polymorphism. To explore its potential association with the incidence of acute and chronic graft versus host disease (aGVHD, cGVHD), severe infections, risk for transplant-related mortality (TRM), and overall survival, HLA-E locus was genotyped by a polymerase chain-reaction-sequence-specific primer (PCR-SSP) strategy. RESULTS: Multivariate analysis, taking into account the patient-, donor- and transplant-related factors, showed that the incidence of aGVHD and TRM at day 180 were low when the genotype was HLA-E*0103/E*0103, either in the donor or in the recipient, the pairs being identical for HLA-E alleles (hazard ratio [HR]=0.71, P=0.009; and HR=0.42, P=0.04, respectively). We also found a trend towards association between E*0103 homozygosity and improved survival (P=0.05). There was no association between HLA-E polymorphism and incidence of severe infections. CONCLUSIONS: These data suggest that the homozygous state for HLA-E*0103 allele behaves as a protective genetic factor against aGVHD and TRM and likely contributes to improved survival in HLA-genoidentical bone marrow transplantation.

Thrombotic Thrombocytopenic Purpura in Black People: Impact of Ethnicity on Survival and Genetic Risk Factors.

Black people are at increased risk of thrombotic thrombocytopenic purpura (TTP). Whether clinical presentation of TTP in Black patients has specific features is unknown. We assessed here differences in TTP presentation and outcome between Black and White patients. Clinical presentation was comparable between both ethnic groups. However, prognosis differed with a lower death rate in Black patients than in White patients (2.7% versus 11.6%, respectively, P = .04). Ethnicity, increasing age and neurologic involvement were retained as risk factors for death in a multivariable model (P < .05 all). Sixty-day overall survival estimated by the Kaplan-Meier curves and compared with the Log-Rank test confirmed that Black patients had a better survival than White patients (P = .03). Salvage therapies were similarly performed between both groups, suggesting that disease severity was comparable. The comparison of HLA-DRB1*11, -DRB1*04 and -DQB1*03 allele frequencies between Black patients and healthy Black individuals revealed no significant difference. However, the protective allele against TTP, HLA-DRB1*04, was dramatically decreased in Black individuals in comparison with White individuals. Black people with TTP may have a better survival than White patients despite a comparable disease severity. A low natural frequency of HLA-DRB1*04 in Black ethnicity may account for the greater risk of TTP in this population.

Association of HLA-E polymorphism with severe bacterial infection and early transplant-related mortality in matched unrelated bone marrow transplantation.

Despite prophylactic measures, susceptibility to severe infections in patients who had undergone bone marrow transplantation (BMT) is quite variable. To evaluate the potential role of human leukocyte antigen (HLA)-E polymorphism on the incidence of early infections, we analyzed 77 unrelated-donor (UD) BMT pairs identically matched for classical HLA class I and class II alleles. Multivariate analysis taking into account the patient-, donor- and transplant-related factors showed that bacterial infections and transplant-related mortality (TRM) at day 180 were high when the donor genotype was HLA-E*0101/E*0101 (hazard ratio [HR]=2.20; P=0.03 and HR=2.12, P=0.048, respectively), suggesting that homozygous state for HLA-E*0101 allele is a risk factor for early severe bacterial infections and TRM in UD-BMT.