A DNA-RFLP typing system that positively identifies serologically well-defined and ill-defined HLA-DR and DQ alleles, including DRw10

A single enzyme/multiple probe system of HLA-DR and DQ typing using restriction fragment-length polymorphism (RFLP) analysis is presented. TaqI-digested genomic DNAs are hybridized sequentially with short DR beta, DQ beta, and DQ alpha cDNA probes. The DR beta probe discriminates between the DR allelic specificities DR1 to DRw14, with the two exceptions of some DR3/DRw13 and some DR7/DRw9 combinations. We describe the positive identification of a DRw10-specific RFLP and demonstrate its segregation in families. The DQ beta probe defines an allelic system that identifies the alleles DQw1, DQw2, and DQw3. This permits the resolution of DR3/DRw13 and DR7/DRw9 alleles by defining the DR/DQ association caused by linkage disequilibrium. The DQ alpha probe defines another allelic series interrelated with, but independent from, the DQ beta series. Specific DQ beta/DQ alpha RFLP combinations correlate with known Dw splits of DR2, DRw6, and DR7. Combined use of the three probes permits the identification of HLA-DR, DQ, and certain Dw specificities and provides an effective and easily interpretable system for major histocompatibility complex class II allogenotyping.     

Long‐term outcomes and transmission rates in hepatitis C virus‐positive donor to hepatitis C virus‐negative kidney transplant recipients: Analysis of United States national data

The use of kidneys from hepatitis C virus (HCV)‐positive (D+) deceased donors for HCV‐negative recipients (R?) might increase the donor pool. We analyzed the national Organ Procurement and Transplant Network (OPTN) registry from 1994 to 2014 to compare the outcomes of HCV D+/R? (n = 421) to propensity‐matched HCV‐negative donor (D?)/R? kidney transplants, as well as with waitlisted patients who never received a transplant, in a 1:5 ratio (n = 2105, per matched group). Both 5‐year graft survival (44% vs 66%; P < .001) and patient survival (57% vs 79%; P < .001) were inferior for D+/R? group compared to D?/R?. Nevertheless, 5‐year patient survival from the time of wait listing was superior for D+/R? when compared to waitlisted controls (68% vs 43%; P < .001). Of the 126 D+/R? with available post‐transplant HCV testing, HCV seroconversion was confirmed in 62 (49%), likely donor‐derived. Five‐year outcomes were similar between D+/R? that seroconverted vs D+/R? that did not (n = 64). Our analysis shows inferior outcomes for D+/R? patients although detailed data on pretransplant risk factors was not available. Limited data suggest that HCV transmission occurred in half of HCV D+/R? patients, although this might not have been the primary factor contributing to the poor observed outcomes.     

Definition of High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Types Using Only Three Single Nucleotide Polymorphisms

Evaluating risk of developing type 1 diabetes (T1D) depends on determining an individual’s HLA type, especially of the HLA DRB1 and DQB1 alleles. Individuals positive for HLA-DRB1*03 (DR3) or HLA-DRB1*04 (DR4) with DQB1*03:02 (DQ8) have the highest risk of developing T1D. Currently, HLA typing methods are relatively expensive and time consuming. We sought to determine the minimum number of single nucleotide polymorphisms (SNPs) that could rapidly define the HLA-DR types relevant to T1D, namely, DR3/4, DR3/3, DR4/4, DR3/X, DR4/X, and DRX/X (where X is neither DR3 nor DR4), and could distinguish the highest-risk DR4 type (DR4-DQ8) as well as the non-T1D–associated DR4-DQB1*03:01 type. We analyzed 19,035 SNPs of 10,579 subjects (7,405 from a discovery set and 3,174 from a validation set) from the Type 1 Diabetes Genetics Consortium and developed a novel machine learning method to select as few as three SNPs that could define the HLA-DR and HLA-DQ types accurately. The overall accuracy was 99.3%, area under curve was 0.997, true-positive rates were >0.99, and false-positive rates were <0.001. We confirmed the reliability of these SNPs by 10-fold cross-validation. Our approach predicts HLA-DR/DQ types relevant to T1D more accurately than existing methods and is rapid and cost-effective.Type 1 diabetes (T1D) is an autoimmune disease with both genetic and environmental components. More than 60 genes have been identified to affect the risk of T1D, with the HLA loci having the greatest impact on susceptibility (1,2). The association of T1D with alleles at HLA loci, especially the HLA class II genes DR and DQ, is well-validated (3). The DR-DQ types contributing the most risk are HLA-DRB1*03 (DR3), typically observed in haplotypic association with DQA1*05:01-DQB1*02:01 (DQ2), and HLA-DRB1*04 (DR4) in haplotypic association with DQA1*03-DQB1*03:02 (DQ8). The highest risk is seen in individuals who are heterozygous for these types. In contrast, HLA-DRB1*04 (DR4) in haplotypic association with DQA1*03-DQB1*03:01 (DQ7) is not associated with a high risk for T1D.HLA allele typing assists in determining risk for T1D and in studies to understand the pathogenesis of T1D. It is particularly useful in prevention and intervention trials that test potential preventative treatments in high-risk subjects (4). HLA typing also is required in genetic studies aimed at determining the molecular basis of T1D susceptibility, such as those performed by the Type 1 Diabetes Genetics Consortium (T1DGC) (5). However, the high cost of HLA genotyping not only is a major imposition on such large-scale programs but also is beyond the reach of small research groups. Several studies have recently undertaken prediction of HLA alleles using single nucleotide polymorphism (SNP) variation within the region (6–9). However, these methods did not focus on DR-DQ types, so the accuracy of prediction was not high even though a relatively large set of typed SNPs within the major histocompatibility complex (MHC) was used (e.g., 49 selected SNPs were used to impute HLA-B, HLA-DRB1, and HLA-DQB1 types in 9). Barker et al. (10) set the scene for rapid identification of HLA haplotypes relevant to T1D by finding two SNPs that could identify the HLA type with the highest risk for T1D, namely DR3/DR4 and DQ8. However, they only reported the predictive results for DR3/4 heterozygotes. Individuals homozygous for DR3 or DR4 also have an increased risk for developing T1D, but these and other DR types relevant to T1D were not distinguished by these SNPs (10).We therefore sought to find a minimal set of SNPs that could accurately annotate the six major DR type categories relevant for T1D risk: heterozygosity for DR3 and DR4 (denoted here as DR3/4); homozygosity for DR3 or DR4 (DR3/3 or DR4/4, respectively); carriage of a single DR3 type and a non-DR3, non-DR4 type (DR3/X); carriage of a single DR4 type and a non-DR3, non-DR4 type (DR4/X); and absence of both DR3 and DR4 (DRX/X). In addition, we reviewed the previously described SNPs for the DR3/DR4 and DQ8 types and sought to annotate the risk associated with different DR4 types: DR4-DQ8 (DQB1*03:02) and DR4-DQ7 (DQB1*03:01).     

Class II HLA Epitope Matching—A Strategy to Minimize De Novo Donor‐Specific Antibody Development and Improve Outcomes

De novo donor‐specific antibody (dnDSA) develops in 15–25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA‐DR/DQ/DP conformational epitopes for 286 donor–recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus‐specific epitope mismatches were more numerous in patients who developed HLA‐DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA‐DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA‐DR, 17 for HLA‐DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA‐DR and HLA‐DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA‐DR and 3 HLA‐DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA‐DR and DQ epitope matching outperforms traditional low‐resolution antigen‐based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long‐term graft outcome.     

Pre‐operative trans‐catheter arterial chemo‐embolization increases hepatic artery thrombosis after liver transplantation – a retrospective study

Little is known about nonsurgical risk factors for hepatic artery thrombosis (HAT ) after liver transplantation (LT ). We determined risk factors for HAT occurring within 90 days post‐LT and analysed the effect of HAT on graft and patient survival. Donor and recipient demographics, surgery‐related data and outcome in transplants complicated by thrombosis (HAT +) and their matched controls (HAT ?) were compared. Risk factors were assessed by univariate logistic regression. Median (IQR ) is given. A total of 25 HAT occurred among 1035 adult LT (1/1997–12/2014) and 50 controls were manually matched. Donor and recipient demographics were similar. Pre‐LT trans‐catheter arterial chemo‐embolization (TACE ) was more frequent in HAT + (HAT + 20% vs. HAT ? 4%, P = 0.037). HAT + had longer implantation [HAT + 88 min (76–108) vs. HAT ? 77 min (66–93), P = 0.028] and surgery times [HAT + 6.25 h (5.18–7.47) vs. HAT ? 5.25 h (4.33–6.5), P = 0.001]. Early graft dysfunction and sepsis were more frequent in HAT + and hospitalization longer. TACE had the greatest odds ratio in unadjusted analysis (OR : 6, 95% CI : 1.07–33.53, P = 0.03). All but seven grafts were lost after HAT (HAT + 72% vs. HAT ? 36%, P = 0.003); however, patient survival was unaffected (HAT + 79.8% vs. HAT ? 76%, P = 0.75). LT candidates undergoing TACE are at risk of developing HAT early after transplant.     

The impact of cytomegalovirus infection ≥1 year after primary renal transplantation

Browne BJ, Young J‐A, Dunn TB, Matas AJ. The impact of cytomegalovirus infection ≥1 yr after primary renal transplantation.
Clin Transplant 2010: 24: 572–579.
© 2010 John Wiley & Sons A/S. Abstract: We studied the impact of a first post‐transplant cytomegalovirus (CMV) infection greater than one year after primary kidney transplantation. Risk factors for developing late CMV were acute rejection and donor–recipient CMV status. Of those developing late CMV, 35% were donor (D) positive, recipient (R) negative; however, 23% were D+R+, 22% D?R+, and 15% D?R?. Late CMV was associated with significantly decreased patient and graft survival.     

Kidney transplantation from hepatitis C virus-positive donors into hepatitis C virus-positive recipients: a safe way to expand the donor pool?

INTRODUCTION: Because the disparity between the number of patients waiting for kidney transplants and the number of available cadaveric renal allografts continues to increase, there is a clear need to review the inclusion criteria for cadaveric donors. PATIENTS AND METHODS: From January 2001 to March 2004, 24 patients with end-stage renal disease and hepatitis C virus (HCV) seropositivity underwent a kidney transplantation. In 10 transplants in HCV-positive recipients, the donor was HCV-positive (D+/R+) and in 14 cases the donor (1 living donor) was HCV-negative (D-/R+). RESULTS: Two of 3 HCV-RNA-negative recipients who received a HCV-RNA+ kidney became HCV-RNA+ in the posttransplantation period. There was a low rate of acute rejection (8.3%). One D+/R+ patient experienced an acute vascular rejection, which finally resulted in graft loss, due to the resurgence of severe infectious disease. The serum creatinine levels at 6 months posttransplantation were similar in both groups. Acute liver dysfunction was observed in 1 patient. There was no death in the entire series. Graft survival was 92% and 90% for D+/R+ and D-/R+, respectively.     

HLA DQ region gene polymorphism associated with primary IgA nephropathy

IgA nephropathy (IgAN) has been associated with HLA-DR4. We have recently described two non-allelic Taq I DQ beta gene-associated fragments sized 2.0 kb (T2) and 6.0 kb (T6), which strongly associate with DR4. T2 represents a polymorphism of the DQ beta gene and has been redesignated DQw8 (10th International HLA Workshop). The origin of the T6 fragment has not been determined, but probably represents a polymorphism of either the DQ beta or DX beta gene. When present together T2 and T6 define a subgroup of DR4 subjects at high risk of developing autoimmune disease. We have, therefore, studied DQ beta gene polymorphisms in IgAN. The DR antigen distribution was similar in IgAN and normal controls. The T2+/T6+ phenotype was present in 49% patients with IgAN compared to 15% of controls [P less than 0.0001, chi 2 = 32.8, Cramer's V = 0.41; relative risk = 5.5 (range, 2.8-11.0)]. Seventy-two percent of DR4+ IgAN patients and 29% of DR4+ controls were T2+/T6+ (P = 0.007, chi 2 = 17.0). These findings confirm the hypothesis that disease susceptibility genes are important in IgAN, and suggest that the putative gene(s) are located within or near to the DQ subregion. Moreover, similar DQ beta gene associations have been found in IDDM and pemphigus vulgaris, pointing to a common immunogenetic mechanism predisposing to several autoimmune diseases.     

Long-term follow-up of Czech children with D+ hemolytic-uremic syndrome

Fifty-seven children (f/m=31/26) who survived diarrhea (D) + hemolytic uremic syndrome (HUS) were evaluated. The examinations were performed 1–27 years (median 7 years) from the onset of the acute disease. Patients aged 2.3–27 years (median 10 years) were allocated to three groups: Recovery (R, complete recovery), Residual renal symptoms (RRS, hematuria and/or proteinuria and/or hypertension with glomerular filtration rate (GFR) >80 ml/min/1.73 m², or moderate renal insufficiency with slightly decreased GFR to 60–80 ml/min/1.73 m² with or without residual renal symptoms), and Chronic renal insufficiency/failure (CRI/F, dialysis, transplantation – GFR <60 ml/min/ 1.73 m²). Results from 18 patients who survived more than 10 years after HUS demonstrated a high prevalence of renal damage. Only 6/18 patients were in group R, 7/18 patients were in group RRS and 5/18 patients were in group CRI/F. An early onset of HUS (36 patients between 0 and 2 years) was associated with a better prognosis when compared with late onset (21 patients aged more than 2 years), P=0.009. Serology typing of Human leukocyte antigens (HLA) classes I and II in 64 patients revealed a significantly higher frequency of DR9 antigen (P=0.0037) and a lower frequency of DQ1 antigen (P=0.009) in D+HUS patients compared with healthy Czech blood donors. Conclusion: Our study demonstrates a high prevalence of late renal damage in Czech patients surviving after D+HUS. The HLA typing in our group revealed a significantly higher rate of HLA DR9 haplotypes in D+HUS patients. Received: 4 January 2001 / Revised: 9 October 2001 / Accepted: 2 January 2002     

A prospective longitudinal analysis of cytomegalovirus (CMV)‐specific CD4+ and CD8+ T cells in kidney allograft recipients at risk of CMV infection

Cytomegalovirus (CMV)‐specific cellular immunity is essential in controlling CMV infection after transplantation. We investigated whether CMV‐specific T cell levels predict CMV DNAemia after kidney transplantation. Using cytokine‐flow cytometry, we enumerated interferon‐γ producing CMV‐specific CD4+ and CD8+ T cells at serial time points among CMV‐mismatched (D+/R?) and seropositive (R+) kidney recipients who received 3 months of valganciclovir prophylaxis. Among 44 patients, eight (18%) developed CMV DNAemia at a mean (±SD) time of 151 (±33) days after transplantation, including two (5%) with CMV syndrome and three (7%) with tissue‐invasive CMV disease. Cox proportional hazards regression analysis showed that CMV mismatch (D+/R?) status (HR: 13, 95% CI: 1.6–106.4; P = 0.02) and diabetes mellitus (HR: 5.6; 95%CI: 1.1–27.9; P = 0.03) were significantly associated with CMV DNAemia. In contrast, the percentage or change‐over‐time in CMV‐specific CD4+ [pp65 (P = 0.45), or CMV lysate (P = 0.22)] and CD8+ [pp65 (P = 0.43), or IE‐1 (P = 0.37)] T cells were not significantly associated with CMV DNAemia. CMV‐specific T cell assays have limited clinical utility among CMV R+ kidney recipients who received valganciclovir prophylaxis. On the other hand, the clinical utility of CMV‐specific T cell assays will need to be assessed in a larger cohort of CMV D+/R? kidney recipients who remain at high‐risk of delayed‐onset CMV disease.     

The impact of direct‐acting antiviral agents on liver and kidney transplant costs and outcomes

Direct‐acting antiviral medications (DAAs) have revolutionized care for hepatitis C positive (HCV+) liver (LT) and kidney (KT) transplant recipients. Scientific Registry of Transplant Recipients registry data were integrated with national pharmaceutical claims (2007‐2016) to identify HCV treatments before January 2014 (pre‐DAA) and after (post‐DAA), stratified by donor (D) and recipient (R) serostatus and payer. Pre‐DAA, 18% of HCV+ LT recipients were treated within 3 years and without differences by donor serostatus or payer. Post‐DAA, only 6% of D‐/R+ recipients, 19.8% of D+/R+ recipients with public insurance, and 11.3% with private insurance were treated within 3 years (P < .0001). LT recipients treated for HCV pre‐DAA experienced higher rates of graft loss (adjusted hazard ratio [aHR] _1.341.85_2.10, P < .0001) and death (aHR _1.471.68_1.91, P < .0001). Post‐DAA, HCV treatment was not associated with death (aHR _0.340.67_1.32, P = .25) or graft failure (aHR _0.320.64_1.26, P = .20) in D+R+ LT recipients. Treatment increased in D+R+ KT recipients (5.5% pre‐DAA vs 12.9% post‐DAA), but did not differ by payer status. DAAs reduced the risk of death after D+/R+ KT by 57% (_0.190.43_0.95, P = .04) and graft loss by 46% (_0.270.54_1.07, P = .08). HCV treatment with DAAs appears to improve HCV+ LT and KT outcomes; however, access to these medications appears limited in both LT and KT recipients.     

Clinical Outcome of Kidney Transplant Patients on the Allograft Function,Loss, Effects of HLA-DQB1-DSA+, and Graft Survival

IntroductionMatching for HLA-DQB1 molecules and anti-DQ donor-specific antibodies (DSAs) has been less studied to allocate transplants from deceased donors in developed countries. The aim of this study was to evaluate the clinical outcome of 519 kidney transplant recipients on the allograft function, loss, and survival and with emphasis on effects of HLA-DQB1-DSA⁺ at minimum of 10 years’ follow-up.MethodsFive hundred nineteen kidney transplant patients were allocated into 3 groups (G) by immunologic profiles, namely, G1 (SPI-SAB HLA-DQ negative [DQ⁻]), G2 (SPI-SAB HLA-DQ positive DSA negative [DQ⁺/DSA⁻]), and G3 (SPI-SAB HLA-DQ DSA positive [DQ⁺ DSA⁺]), and the outcomes were reported until 10 years after transplantation.ResultsThe proportion of rejection episodes was higher in G3 (25.0% and 26.32%, respectively) than in G1 (8.63% and 6.82%, respectively) and G2 (10.0% and 0%, respectively; P = .047 and P = .014, respectively). In G3, 3 patients lost their grafts by antibody-mediated rejection. Patients who received kidneys from deceased donors (G3) showed worse graft survival rates than those from G1 donors (P = .001). Patients from G3 had a 2.18-fold higher risk of graft loss than patients from G1 (P = .028).ConclusionAllograft function was worse in G3 than in G2 or G1, and graft losses were more frequent by T-cell-mediated rejection in G1, and graft losses by antibody-mediated rejection were similar in G1 and G3 due to HLA class I (A1, 11 and B 8, 52) and HLA class II by DR7 and DQ 2, 5, 9 DSA, respectively. Allograft survival decreased in patients with HLA-DQB1 DSA. The risk of graft loss was 1.75-fold that in patients who received transplants from living donors.     

Co-expression of HLA DR3 and DQ8 results in the development of spontaneous insulitis and loss of tolerance to GAD65 in transgenic mice

Specific HLA DQ and DR alleles have been associated with susceptibility to type 1 diabetes. HLA DQ8 and DQ2 have been shown to strongly predispose to disease and to be in linkage disequilibrium with at-risk DR4 and DR3 alleles, respectively. Inheritance of a mixed DR3/DR4 haplotype confers the greatest risk. A double transgenic mouse expressing both DR3 and DQ8 was generated to investigate potential major histocompatibility complex class II interactions. The DR3/DQ8 transgenic mice developed a spontaneous loss of tolerance to GAD65, in which the T-cell response to GAD65 was restricted by HLA DR. Although the mice also showed spontaneous insulitis, they did not progress to overt diabetes. Mice expressing either transgene (DQ8 or DR3) alone showed mild infiltration of their islets, which disappeared when DQ8 or DR3 was co-expressed with a resistant DR2 allele or the neutral DQ6 allele. Therefore, in a fashion analogous to human diabetes, the murine model demonstrated a requirement for a combination of at-risk DR and DQ allotypes for the initiation of spontaneous autoimmunity.     

Épitope partagé des allèles HLA–DRB1 et sex-ratio chez des patients italiens atteints de polyarthrite rhumatoïde

Objective. – To investigate the association between the HLA–DRB1 alleles sharing the epitope (Q/R)(K/R)RAA and rheumatoid arthritis (RA) in a large sample of Italian patients (N =264) recruited from a single centre over the last 5 years.Methods. – Patients’ classification according to the ACR criteria. DNA typing of HLA–DRB1 alleles by conventional polymerase chain reaction sequence specific oligonucleotide probing techniques.Results. – Low-resolution DRB1 “generic” typing showed a significantly higher frequency of DR4+ RA patients as compared to normal controls. Both DR1 and DR10 specificities were over-represented in our patients, but neither reached the statistically significant P level of 0.05 after Bonferroni’s correction. However, direct search of Q(K/R)RAA epitopes, which are present in most DR4+ and DRl+ samples, demonstrated that these motifs were found at increased frequencies in RA patients. Stratification according to gender did not show differences in the proportion of disease-associated HLA alleles.Conclusions. – Our study confirms the association of HLA–DR4, and –DR1 alleles, and more generally speaking of the shared epitopes Q(K/R)RAA, with disease susceptibility in italian patients.     

Long-term outcomes of cytomegalovirus infection and disease after lung or heart–lung transplantation with a delayed ganciclovir regimen

Abstract: Background: Information is limited on long‐term outcomes after preemptive use of ganciclovir to control cytomegalovirus (CMV) infection in lung transplantation. Methods: We studied 78 lung recipients who received antithymocyte globulin induction from 1994 to 2000. All patients received six months of oral acyclovir (800 mg TID). This was interrupted three wk post transplantation for a two‐wk course of IV ganciclovir. Additional courses of ganciclovir were administered based on serial virological monitoring. CMV‐mismatched patients (R?D+) also received four doses of CMV immunoglobulin between weeks 2 and 8. Results: The one yr cumulative risk of CMV disease was 2% (1/61) in CMV seropositive (R+) patients, but was 37% (6/17) in R?D+ patients (p < 0.0001). Over 4.3 yr of follow‐up, patients with CMV infection developed more chronic graft dysfunction caused by bronchiolitis obliterans or bronchiolitis obliterans syndrome than patients without CMV infection (p = 0.012). This effect was also apparent in the subgroup of R+ recipients (p = 0.043). Acute rejection and overall survival were not associated with CMV infection. Conclusions: The use of prophylactic acyclovir and short preemptive courses of ganciclovir effectively controlled CMV disease in R+ patients, but was a relative failure in R?D+ patients. CMV infection was significantly associated with chronic graft dysfunction, even in R+ recipients who had good control of CMV symptoms.     

HLA-DQ beta sequence polymorphism and genetic susceptibility to IDDM

The analysis of HLA-DQ beta nucleotide sequence polymorphism in insulin-dependent diabetes mellitus (IDDM) patients and control subjects suggests a role for the DQ beta-chain in genetic susceptibility. Sequence determination and oligonucleotide hybridization was carried out on enzymatically amplified DNA from various HLA-DR-typed individuals, including the rare class of DR2+ patients. In the analysis of DQ beta variation in DR4, DRw6, and DR2 haplotypes, a correlation was observed between the presence of the negatively charged residue Asp at position 57 and low susceptibility and the presence of an Ala (DR4), Val (DRw6), or Ser (DR2) and higher susceptibility. However, important exceptions to this pattern have been identified in the analysis of heterozygous DR1/4 IDDM patients. In these individuals, susceptibility appears to correlate with specific DR beta l alleles (Dw4) on the DR4 haplotype, rather than with the DQ beta allele (DQB3.2) that contains Ala at position 57. The DQ beta alleles found in some Chinese IDDM patients also proved discordant with the position-57 correlations. Thus, although there is a general correlation between the residue at position 57 of the DQ beta-chain and IDDM susceptibility, these data do not support the notion that Asp 57 confers complete resistance or protection to IDDM. In general, these results suggest that IDDM susceptibility is conferred by specific combinations of DQ beta and DR beta sequences.     

Early steroid withdrawal in HIV-infected kidney transplant recipients: Utilization and outcomes

Kidney transplant (KT) outcomes for HIV-infected (HIV+) persons are excellent, yet acute rejection (AR) is common and optimal immunosuppressive regimens remain unclear. Early steroid withdrawal (ESW) is associated with AR in other populations, but its utilization and impact are unknown in HIV+ KT. Using SRTR, we identified 1225 HIV+ KT recipients between January 1, 2000, and December 31, 2017, without AR, graft failure, or mortality during KT admission, and compared those with ESW with those with steroid continuation (SC). We quantified associations between ESW and AR using multivariable logistic regression and interval-censored survival analysis, as well as with graft failure and mortality using Cox regression, adjusting for donor, recipient, and immunologic factors. ESW utilization was 20.4%, with more zero HLA mismatch (8% vs 4%), living donors (26% vs 20%), and lymphodepleting induction (64% vs 46%) compared to the SC group. ESW utilization varied widely across 129 centers, with less use at high- versus moderate-volume centers (6% vs 21%, P < .001). AR was more common with ESW by 1 year (18.4% vs 12.3%; aOR: _1.081.61_2.41, P = .04) and over the study period (aHR: _1.021.39_1.90, P = .03), without difference in death-censored graft failure (aHR _0.600.91_1.36, P = .33) or mortality (aHR: _0.751.15_1.77, P = .45). To reduce AR after HIV+ KT, tailoring of ESW utilization is reasonable.     

"Extended" A1, B8, DR3 haplotype shows remarkable linkage disequilibrium but is similar to nonextended haplotypes in terms of diabetes risk

To evaluate potential differential diabetes risk of DR3 haplotypes we have evaluated class I alleles as well as two microsatellites previously associated with differential risk associated with DR3 haplotypes. We found that over one-third of patient DR3 chromosomes consisted of an extended DR3 haplotype, from DQ2 to D6S2223 (DQ2, DR3, D6S273-143, MIC-A5.1, HLA-B8, HLA-Cw7, HLA-A1, and D6S2223-177) with an identical extended haplotype in controls. The extended haplotype was present more frequently (35.1% of autoimmune-associated DR3 haplotypes, 39.4% of control DR3 haplotypes) than other haplotypes (no other haplotype >5% of DR3 haplotypes) and remarkably conserved, but it was not transmitted from parents to affected children more frequently than nonconserved DR3-bearing haplotypes. This suggests that if all alleles are truly identical for the major A1, B8, DR3 haplotype (between A1 and DR3), with different alleles on nonconserved haplotypes without differential diabetes risk, then in this region of the genome DR3-DQ2 may be the primary polymorphisms of common haplotypes contributing to diabetes risk.     

The influence of histocompatibility on graft rejection and graft survival within a single center population of heart transplant recipients.

BACKGROUND: We report a consecutive single center series of 261 patients who received first orthotopic heart transplants from 1986 to 1997. The 1- and 5-year graft survivals were 78 and 68%. The influence of histocompatibility was investigated by comparing graft survival and numbers of treated rejection episodes with HLA-A, -B, and -DR mismatches over different time periods. FINDINGS: Recipients with six mismatches for HLA-A+-B+-DR combined (13.4%) had reduced survival at 7 years (47%) when compared with other recipients (64%). In the first year of transplant, recipients with four HLA-A+-B mismatches had significantly reduced actuarial graft survival (P=0.03) with the greatest influence apparent at 6 months [0-3 mismatches (n=193) 85% versus 4 mismatches (n=68) 69%; P=0.005, OR=2.1]. For 182 recipients with functioning hearts at 1 year, the number of rejection episodes treated within this time was strongly influenced by HLA-DR mismatch [0 DR mismatch (n=15) mean 1.2 rejection episodes versus 1 DR mismatch (n=76) mean 2.7 rejection episodes versus 2 DR mismatches (n=91) mean 3.8 rejection episodes: P=0.0002]. Of these 182 transplants, recipients who had more than four treated rejection episodes during the first year had a significantly reduced 7- year survival [<5 rejection episodes (n=133) 85% versus more than four rejection episodes (n=49) 66%; P=0.02, OR=3.4], as did those with two HLA-DR mismatches [0+1 mismatch (n=91) 87% versus 2 mismatches (n=91) 70%; P<0.05, OR=2.4]. INTERPRETATION: We show that graft loss in the first 6 months of transplant is significantly influenced by four HLA-A+-B mismatches. HLA-DR mismatch significantly increases the number of rejection episodes within the first year, without influencing graft survival. After 12 months both >4 rejection episodes in the first year and two HLA-DR mismatches are markers for late graft loss. We postulate that immunological graft loss in the first 6 months is dominated by the direct allorecognition pathway driven by HLA-DR mismatch. This mechanism is later lost or suppressed. Our data highlight HLA-DR mismatch as a marker for late graft loss and we show an advantage to avoiding transplanting hearts with six HLA-A+-B+-DR mismatches and to minimizing HLA-DR mismatches whenever possible.     

Allosensitization after transplant failure: the role of graft nephrectomy and immunosuppression – a retrospective study

There are conflicting data about the role of transplant nephrectomy and immunosuppression withdrawal on the development of allosensitization and the impact on re‐transplantation. We divided 109 first graft recipients into two groups according to whether they underwent nephrectomy (NX+, n = 61) or their graft was left in situ (NX?, n = 48). Sera were assessed for HLA‐A/B/Cw/DR/DQ antibodies at the time of NX/transplant failure and after 3, 6, 12, 24 months. The NX+ group showed a higher rate of donor specific antibody (DSA) and non‐DSA human leukocyte antigen (HLA) antibody production at all the time points. Multivariable analysis showed that nephrectomy was a strong, independent risk factor for the development of DSAs after 12 and 24 months (P = 0.005 and 0.008). In the NX? group, low tacrolimus levels correlated with DSA formation (AUC 0.817, P = 0.002; best cut‐off level 2.9 ng/ml). Analysis with a standardized pool of UK donors showed a more difficult grade of HLA matchability following nephrectomy compared with the NX? group. Nephrectomy is followed by the long‐term production of DSA and non‐DSA HLA antibodies and negatively impacts on the chances of finding a HLA‐compatible kidney. Tacrolimus levels ≥3 ng/ml are protective against the development of allosensitization and could facilitate re‐transplantation in the NX? group.