Phenotype Frequencies of Autosomal Minor Histocompatibility Antigens Display Significant Differences among Populations

Minor histocompatibility (H) antigens are allogeneic target molecules having significant roles in alloimmune responses after human leukocyte antigen–matched solid organ and stem cell transplantation (SCT). Minor H antigens are instrumental in the processes of transplant rejection, graft-versus-host disease, and in the curative graft-versus-tumor effect of SCT. The latter characteristic enabled the current application of selected minor H antigens in clinical immunotherapeutic SCT protocols. No information exists on the global phenotypic distribution of the currently identified minor H antigens. Therefore, an estimation of their overall impact in human leukocyte antigen–matched solid organ and SCT in the major ethnic populations is still lacking. For the first time, a worldwide phenotype frequency analysis of ten autosomal minor H antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major ethnic populations. Significant differences in minor H antigen frequencies were observed between the ethnic populations, some of which appeared to be geographically correlated

HLA-specific B cells: II. Application to transplantation

BACKGROUND. Differences in the antibody response to allogeneic transplantation exist between groups defined by race or gender. These differences may reflect differences in immune competency and/or exposure to alloantigens. We have investigated the frequencies and phenotypes of HLA-specific B cells to address those possibilities. METHODS. HLA-specific B cells were identified by staining with HLA tetramers (tet) as described previously and the distribution of CD27 and CD38 among those cells were measured in groups defined by various parameters. Possible correlation between frequencies of HLA-specific B cells and production of HLA-specific antibody after transplantation was also investigated. RESULTS. We found no correlation between the frequencies of CD27+tet+ (33%-44% vs. 34%-36%) or CD38+tet+ (57%-65% vs. 59%-66%) B cells and a previous mismatch for the HLA antigen of the tetramer. However, there was an increase in CD38+tet+ B cells among patients making antibody to the tetramer antigen (67%-72% vs. 53%-56%). Blacks had lower frequencies of CD27+ B cells than did whites (11.8% vs. 28.9%, P=0.003), but had greater increases of these cells among tet+ cells than did whites. There was a higher frequency of tet+ B cells among patients who developed new antibody to the HLA antigen (3.9%-8.6%) of the tetramer after transplantation than among those who did not (1.1%-3.7%). CONCLUSIONS. The phenotype of HLA-specific B cells reflects current or historic sensitization to HLA and may reflect inherent differences between groups defined by race and/or gender. The frequencies of HLA-specific B cells may predict patients at risk for production of donor-specific antibody after transplantation. © 2007 Lippincott Williams & Wilkins, Inc

Partially Mismatched Transplantation and Human Leukocyte Antigen Donor-Specific Antibodies

AbstractThe presence of donor human leukocyte antigen (HLA)-specific antibodies (DSA) increases engraftment failure risk in partially HLA-mismatched, or HLA-haploidentical, allogeneic marrow (alloBMT) transplantation. As pre-existing sensitization to HLA antigens is not well characterized among candidates for HLA-haploidentical alloBMT, we retrospectively evaluated both the incidence and relative strength of DSA in this patient population. Based on correlations of solid-phase antibody assays on the Luminex (Luminex, Austin, TX) platform with actual crossmatch tests, DSA were characterized as weak for results that were consistent with negative flow cytometric crossmatch results or as moderate-to-strong for results consistent with positive flow cytometric or cytotoxicity crossmatches. We evaluated 296 alloBMT candidates; 111 (37.5%) were female. DSA were detected in 43 (14.5%) candidates, mostly among female candidates (42.9% female versus 12.5% male). Moderate-to-strong DSA strength was more frequently encountered when directed against haploidentical donors as compared with mismatched unrelated donors. DSA were most commonly detected in female patients directed against their children. Because the presence of DSA has been considered prohibitive for HLA-mismatched alloBMT, we additionally report a desensitization methodology used to reduce DSA to negative or weak levels, ie, levels well below those detectable in a flow cytometric crossmatch. Nine patients without other available donors underwent desensitization. Eight who reduced their DSA to negative or weak levels proceeded to alloBMT and achieved full donor engraftment. These data support routine DSA evaluation in all patients considered for mismatched alloBMT; however, for patients with no other viable options, desensitization to weak or negative DSA levels may afford the opportunity for successful transplantation

Complex HLA-DR and -DQ Interactions Confer Risk of Narcolepsy-Cataplexy in Three Ethnic Groups

Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles—DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)—were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of λ statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy

Clinical results from transplanting incompatible live kidney donor/recipient pairs using kidney paired donation

Context: First proposed 2 decades ago, live kidney paired donation (KPD) was considered a promising new approach to addressing the shortage of organs for transplantation. Ethical, administrative, and logistical barriers initially proved formidable and prevented the implementation of KPD programs in the United States. Objective: To determine the feasibility and effectiveness of KPD for the management of patients with incompatible donors. Design, Setting, and Patients: Prospective series of paired donations matched and transplanted from a pool of blood type or crossmatch incompatible donors and recipients with end-stage renal disease (6 conventional and 4 unconventional KPD transplants) at a US tertiary referral center (between June 2001 and November 2004) with expertise in performing transplants in patients with high immunologic risk. Intervention: Kidney paired donation and live donor renal transplantation. Main Outcome Measures: Patient survival, graft survival, serum creatinine levels, rejection episodes. Results: A total of 22 patients received transplants through 10 paired donations including 2 triple exchanges at Johns Hopkins Hospital. At a median follow-up of 13 months (range, 1-42 months), the patient survival rate was 100% and the graft survival rate was 95.5%. Twenty-one of the 22 patients have functioning grafts with a median 6-month serum creatinine level of 1.2 mg/dL (range, 0.8-1.8 mg/dL) (106.1 mu;mol/L [range, 70.7-159.1 mu;mol/L]). There were no instances of antibody-mediated rejection despite the inclusion of 5 patients who were highly sensitized to HLA antigens due to previous exposure to foreign tissue. Four patients developed acute cellular rejection (18%). Conclusions: This series of patients who received transplants from a single-center KPD pool provides evidence that recipients with incompatible live donors, even those with rare blood type combinations or high degrees of HLA antigen sensitization, can receive transplants through KPD with graft survival rates that appear to be equivalent to directed, compatible live donor transplants. If these results can be generalized, broader availability of KPD to the estimated 6000 patients with incompatible donors could result in a large expansion of the donor pool. ©2005 American Medical Association. All rights reserved