Human Leukocyte Antigen Compatibility Research Articles

White blood cell inactivation after treatment with riboflavin and ultraviolet light

Functional white blood cells (WBCs) in blood components may be responsible for a number of adverse transfusion effects, including transfusion-associated graft-versus-host disease (TA-GVHD), alloimmunization, and alloimmune platelet (PLT) refractoriness. TA-GVHD occurs when functional lymphocytes are transfused into a patient who is unable to mount an immune response to the human leukocyte antigen (HLA) due to HLA compatibility or immunosuppression. Alloantibodies against HLA antigens on donor WBCs and PLTs are the major cause of refractoriness to PLT transfusions in patients receiving repeated blood transfusions. Attempts to reduce these undesirable effects have included leukoreduction filters and gamma irradiation. Studies have shown that exposure of PLT concentrates to riboflavin and light (Mirasol pathogen reduction technology [PRT], CaridianBCT Biotechnologies) causes irreparable modifications of nucleic acids that result in inactivation of a wide range of pathogens as well as inhibition of the immunologic responses mediated by WBCs present in PLT concentrates. This article summarizes these studies and also reports on additional findings from the Trial to Reduce Alloimmunization to Platelets (TRAP) and Mirasol Clinical Evaluation (MIRACLE) trials. Data from in vitro studies and this clinical trial suggest that PRT treatment may be as effective as gamma irradiation in preventing TA-GVHD and more effective than leukoreduction in preventing alloimmunization.

Impact of HLA Compatibility on Lung Transplant Survival and Evidence for an HLA Restriction Phenomenon: A Collaborative Transplant Study Report

Data concerning the impact of human leukocyte antigen (HLA) compatibility on lung transplant survival rates are limited. Using the Collaborative Transplant Study database, 5-year graft outcome according to HLA mismatch was examined in 8020 deceased donor lung transplants performed during 1989 to 2009. Graft survival rates showed a stepwise decrease as the combined number of HLA-A+B+DR mismatches increased from one to six (P<0.001). Surprisingly, the 28 grafts with 0 mismatches at all 3 loci had a 1-year survival rate of only 49.7%, significantly lower than for 1, 2, 3, 4, 5, or 6 mismatches (P=0.002, <0.001, <0.001, <0.001, 0.002, and 0.003, respectively). Multivariate regression analysis confirmed that, paradoxically, transplantation of grafts with zero HLA-A+B+DR mismatches was associated with a 19% increase in relative risk of failure. Donor lung preservation for up to 12 hr was not associated with inferior graft survival versus shorter preservation times (P=0.60). Our data show that a high number of HLA mismatches or zero mismatches impacts unfavorably on lung transplant survival.

Related cord blood banking for haematopoietic stem cell transplantation

The aims of this single centre study were to assess the feasibility of related cord blood collecting, the appropriateness of storage and the final suitability for transplantation. Since September 1994, 63 families were enrolled in this study. Families were eligible if they were caring for a patient with a disorder treatable by haematopoietic stem cell transplantation and were experiencing a pregnancy. A total of 72 cord blood units were collected and stored for 64 patients (both siblings and parents). We focussed on human leucocyte antigen (HLA) compatibility and cell content as critical requirements to unit's suitability for transplantation. HLA-typing was carried out for 34 donor-recipient couples and most units (72%) mismatched with the related patients. About 60% of collections had a minimum cell dose considered acceptable for transplantation. Only 21% of units had both compatibility degree and cell content suitable for transplantation. When applicable, information on the compatibility degree between the foetus and the patient should be obtained during pregnancy. Appropriateness of related cord blood banking for parents should be further investigated and cost-effective guidelines policies should be provided. Finally, as banking of related cord blood units is an important resource then, this public service should be supported and enhanced.

Impact of human leukocyte antigen mismatching on outcomes of liver transplantation: A meta-analysis

To assess the effect of human leukocyte antigen (HLA) mismatching on liver graft outcome and acute rejection from a meta-analysis of available cohort studies. Articles in PubMed/MEDLINE, EMBASE and the Cochrane database from January 1970 to June 2009, including non-English literature identified in these databases, were searched. Only studies comparing HLA or sub-phenotype matching with mismatching were extracted. The percentage of graft survival was extracted by "Engauge Digitizer" from survival curves if the raw data were not displayed. A meta-analysis was performed when at least 3 studies provided data. Sixteen studies met the inclusion criteria. A lower number of HLA mismatches (0-2 vs 3-6) did reduce the incidence of acute rejection (relative risk: 0.77, P = 0.03). The degree of HLA mismatching (0-2 vs 3-6) had no significant effect on 1-year [hazard ratio (HR): 1.04, P = 0.68] and 5-year (HR: 1.09, P = 0.38) graft survival. In sub-phenotype analysis, the degree of HLA-A, B and DR mismatching (0 vs 1-2) had no significant effect on 1-year and 5-year graft survival, either. The HRs and P-values were 0.95, 0.71 (HLA-A, 1-year); 1.06, 0.60 (HLA-A, 5-year); 0.77, 0.16 (HLA-B, 1-year); 1.07, 0.56 (HLA-DR, 1-year); 1.18, 0.23 (HLA-DR, 5-year), respectively. The results of this systematic review imply that good HLA compatibility can reduce the incidence of acute rejection in spite of having no influence on graft outcomes. To obtain a short recovery time and minimize rejection post transplantation, HLA matching studies should be considered before the operation.

Low-Dose Total Body Irradiation and Fludarabine Conditioning for HLA Class I-Mismatched Donor Stem Cell Transplantation and Immunologic Recovery in Patients with Hematologic Malignancies: A Multicenter Trial

HLA-mismatched grafts are a viable alternative source for patients without HLA-matched donors receiving ablative hematopoietic cell transplantation (HCT), although their use in reduced intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT has been not well established. Here, we extended HCT to recipients of HLA class I-mismatched grafts to investigate whether NMA conditioning can establish stable donor engraftment. Fifty-nine patients were conditioned with fludarabine (Flu) 90 mg/m(2) and 2 Gy total body irradiation (TBI), followed by immunosuppression with cyclosporine (CsA) 5.0 mg/kg twice a day and mycophenolate mofetil (MMF) 15 mg/kg 3 times a day for transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs) from related (n = 5) or unrelated donors (n = 54) with 1 antigen +/- 1 allele HLA class I mismatch or 2 HLA class I allele mismatches. Sustained donor engraftment was observed in 95% of the evaluable patients. The incidence of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) was 69% and 41%, respectively. The cumulative probability of nonrelapse mortality (NRM) was 47% at 2 years. Two-year overall and progression-free survival (OS, PFS) was 29% and 28%, respectively. NMA conditioning with Flu and low-dose TBI, followed by HCT using HLA class I-mismatched donors leads to successful engraftment and long-term survival; however, the high incidence of aGVHD and NRM needs to be addressed by alternate GVHD prophylaxis regimens.

Maternal HLA Class I Compatibility in Patients With Biliary Atresia

Biliary atresia (BA) is an inflammatory cholangiopathy of unknown etiology. Maternal microchimerism has been identified in the livers of patients with BA. We analyzed the human leukocyte antigen (HLA) compatibility between 57 BA patient-mother pairs and 50 control-mother pairs. The HLA class I matching was significantly more frequent in BA pairs (odds ratio [OR]=2.46) than controls. Similar results were also found in child-to-mother HLA compatibility (OR=2.16). Our results indicate that patients with BA have an immunogenetic histocompatible relationship with their mothers, which may result in an increase in maternal microchimerism found in BA.

HLAMatchmaker-based definition of structural human leukocyte antigen epitopes detected by alloantibodies

This review addresses the concept that human leukocyte antigen (HLA) antibody specificity should be determined to HLA epitopes rather than HLA antigens. HLAMatchmaker is a computer algorithm that considers small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes. This overview describes recent developments that have increased our understanding of structural epitope antigenicity, that is, reactivity with specific antibody and immunogenicity, that is, its ability to induce an antibody response. A determination of the repertoire of immunogenic epitopes is important for HLA compatibility testing and the identification of acceptable mismatches for sensitized patients.

Muscular Dystrophy Therapy by Nonautologous Mesenchymal Stem Cells: Muscle Regeneration Without Immunosuppression and Inflammation

The use of nonautologous stem cells isolated from healthy donors for stem-cell therapy is an attractive approach, because the stem cells can be culture expanded in advance, thoroughly tested, and formulated into off-the-shelf medicine. However, human leukocyte antigen compatibility and related immunosuppressive protocols can compromise therapeutic efficacy and cause unwanted side effects. Mesenchymal stem cells (MSCs) have been postulated to possess unique immune regulatory function. We explored the immunomodulatory property of human and porcine MSCs for the treatment of delta-sarcoglycan-deficient dystrophic hamster muscle without immunosuppression. Circulating and tissue markers of inflammation were analyzed. Muscle regeneration and stem-cell fate were characterized. Total white blood cell counts and leukocyte-distribution profiles were similar among the saline- and MSC-injected dystrophic hamsters 1 month posttreatment. Circulating levels of immunoglobulin A, vascular cell adhesion molecule-1, myeloperoxidase, and major cytokines involved in inflammatory response were not elevated by MSCs, nor were expression of the leukocyte common antigen CD45 and the cytokine transcriptional activator NF-kappaB in the injected muscle. Treated muscles exhibited increased cell-cycle activity and attenuated oxidative stress. Injected MSCs were found to be trapped in the musculature, contribute to both preexisting and new muscle fibers, and mediates capillary formation. Intramuscular injection of nonautologous MSCs can be safely used for the treatment of dystrophic muscle in immunocompetent hosts without inflaming the host immune system.

11: HLA Mismatches Influence Lung Transplant Recipient Survival, Bronchiolitis Obliterans, and Rejection – Implications for Donor Lung Allocation

Lung transplantation currently does not consider human leukocyte antigen (HLA) compatibility as a factor in matching donors and recipients. We previously reported that fewer individual Class I (HLA-A, B) and Class II (HLA-DR) antigen mismatches (MM) resulted in minor improvements in lung transplantation. In the current study, we evaluated whether the effects of total HLA MM, Class I MM and Class II MM were more important determinants of 1) recipient survival, 2) freedom from acute rejection (AR), and 3) the development of bronchiolitis obliterans (BO).

Analysis of maternal–offspring HLA compatibility, parent‐of‐origin and non‐inherited maternal effects for the classical HLA loci in type 1 diabetes

Type 1 diabetes (T1D) is a complex trait for which variation in the classical human leucocyte antigen (HLA) loci within the Major Histocompatibility Complex (MHC) significantly influences disease risk. To date, HLA class II DR-DQ genes confer the strongest known genetic effect in T1D. HLA loci may also influence T1D through additional inherited or non-inherited effects. Evidence for the role of increased maternal-offspring HLA compatibility, and both parent-of-origin (POO) and non-inherited maternal HLA (NIMA) effects in autoimmune disease has been previously established. The current study tested hypotheses that classical HLA loci influence T1D through these mechanisms, in addition to genetic transmission of particular risk alleles. The Type 1 Diabetes Genetics Consortium (T1DGC) cohort was of European descent and consisted of 2271 affected sib-pair families (total n = 11 023 individuals). Class I genes HLA-A, Cw and B, and class II genes HLA-DRB1, DQA1, DQB1, DPA1 and DPB1 were studied. The pedigree disequilibrium test was used to examine transmission of HLA alleles to individuals with T1D. Conditional logistic regression was used to model compatibility relationships between mother-offspring and father-offspring for all HLA loci. POO and NIMA effects were investigated by comparing frequencies of maternal and paternal transmitted and non-transmitted HLA alleles for each locus. Analyses were also stratified by gender of T1D-affected offspring. Strong associations were observed for all classical HLA loci except for DPA1, as expected. Compatibility differences between mother-offspring and father-offspring were not observed for any HLA loci. Furthermore, POO and NIMA HLA effects influencing T1D were not present. Maternal-offspring HLA compatibility, POO and NIMA effects for eight classical HLA loci were investigated. Results suggest that these HLA-related effects are unlikely to play a major role in the development of T1D.

Allocation of Deceased Donor Kidneys in São Paulo, Brazil: Effect of Human Leukocyte Antigen Compatibility on Graft Survival

In Brazil, organ transplantation has been regulated by a federal law since 1997. This law was created to guarantee equal access to treatment on a national scale. Deceased donor organ procurement and sharing are centralized and controlled by the Health Department of each state of the nation, following a regional allocation policy. In São Paulo, time on the waiting list was the main criterion adopted to allocate deceased donor kidneys up to January 1, 2002. After that, HLA mismatches (MM) were the main criterion. The aim of this study was to investigate the impact of HLA compatibility on graft survival among 3312 consecutive kidney recipients. The 2-year kidney graft survival rates were compared among recipients transplanted based on the waiting time policy and based on HLA MM. Better results were observed in the HLA MM group (78.1% vs 64.9%; P < .0001). Regarding kidney allocation based on HLA MM, recipients transplanted with 0 HLA-A, -B, or -DR MM showed significantly better 5-year survival rates than those with 1–2 or 3–4 or 5–6 HLA-A, -B, or -DR MM (70.36% vs 64.71% vs 58.07% vs 55.64%; P < .050). We concluded that HLA compatibility is a feasible criterion to allocate deceased donor kidneys in Brazil.

Contribution of HLA Incompatibility on Clinical Outcomes of CBT in Patients with MDS Including Secondary AML in Japan: Multivariate Analysis Using Competing Risk Regression Model

[Study purpose] We have reported that overall results of cord blood transplantation (CBT) were inferior to those of bone marrow transplantation (BMT) from unrelated donor in myelodysplastic syndrome (MDS) including transformed acute myelogenous leukemia (AML/MDS) (ASH 2007). Poor engraftment and higher incidence of relapse in CBT patients were serious problems. We now show here the impact of conditioning regimen and GVHD prophylaxis method on clinical outcomes of CBT, and then show the results when we looked for the appropriate graft selection in terms of human leukocyte antigen (HLA) compatibility and cell dose.[Patients and Methods] Clinical data of 333 patients with MDS including AML/MDS who received unrelated CBT without prior transplant history between 1998 and 2006 in Japan were collected by the Japan Cord Blood Bank Network (JCBBN). The median period of follow-up for survivors (n=148) after transplants was 13 (range, 1–99) months. We analyzed the hematopoietic recovery, incidences of acute and chronic graft-versus-host disease (GVHD), risks of transplant-related mortality (TRM) and relapse, and disease-free survival (DFS) using competing risk regression models.[Results] Both myeloablative conditioning regimen including 8Gy or more dose of total body irradiation (TBI) and GVHD prophylaxis as calcineurin inhibitor (cyclosporin or taclorimus) plus methotrexate (MTX) significantly (p<0.05) contributed to the lower risks of relapse and TRM and better DFS in univariate analysis. In multivariate analysis, TBI including regimen contributed the better engraftment of platelet (p=0.009) and lower risk of relapse (p=0.011). Calcineurin inhibitor plus MTX method was associated with the lower risks of grades III+IV acute GVHD (p=0.006) and TRM (p=0.002). Next, we analyzed 116 patients who used TBI including regimen and calcineurin inhibitor plus MTX combination and looked for significant graft factors for better clinical outcomes of CBT. In multivariate analysis, one antigen or more of HLA disparity by high resolution typing in either GVHD or rejection direction was significantly associated with lower risk of relapse (p<0.001). On the other hand, there was no event in HLA matched recipients by high resolution typing (n=5) and thus HLA compatibility seemed to be implicated in low risk of TRM. Finally, 2 antigens mismatch by low resolution typing affected better DFS result in multivariate analysis (p=0.01). Those advantages in HLA mismatched cord blood recipients might be induced by allo-reactivity against MDS. In contrast to HLA disparity, cell numbers of nucleated cells, of CD34 positive cells and of CFU-GM at the cryopreservation did not affect to the results in our analysis probably because of the selection bias as bellow: As the cell dose is a top priority of graft selection in most centers and majority (87%) of patients was adult (>15 years old), grafts had relatively high quantity with narrow range, which the median numbers of nucleated cells, CD34 positive cells and CFU-GM were 2.57 (74% patients in 2.0–3.5 dose range) ×107/kg, 0.85 (76% in 0.5–2.0 dose range) ×105/kg and 25.4 (77% in 10–50 dose range) ×103/kg, respectively.[Conclusion] Myeloablative conditioning regimen with TBI and calcineurin inhibitors plus MTX for GVHD prophylaxis in CBT might be promising for MDS patients and HLA disparity possibly contributed on lower risk of relapse and better DFS in this setting.

Preformed antibodies detected by cytotoxic assay or multibead array decrease liver allograft survival: Role of human leukocyte antigen compatibility

The significance of human leukocyte antigen (HLA) compatibility and preformed antibodies in liver transplantation remains unclear. The objectives of this study were to evaluate, in a single-center cohort comprising 896 liver transplants, whether the degree of donor-recipient compatibility and preformed antibodies modified graft survival. Univariate Kaplan-Meier analysis demonstrated that donor-recipient HLA compatibility had a marginal impact on allograft survival. As for compatibility at individual antigen loci, 2 mismatches at HLA-A conferred a survival advantage in retransplanted allografts (P = 0.011). HLA-B and HLA-DR loci did not play a significant role in outcome in any pathology. The concordance of results on preformed antibodies detected by complement-dependent cytotoxicity (CDC) and a multiple bead assay (Luminex xMAP) showed a strong correlation between both techniques (P < 0.0001). Both CDC-detected and Luminex-detected antibodies were associated with shorter graft survival within the first year post-transplant (P = 0.01 and P = 0.016, respectively). Positive CDC T crossmatches and Luminex-detected HLA class II antibodies played a significant role in decreasing graft survival (P = 0.043 and P = 0.0019 at 1 year, respectively, and P = 0.005 and P = 0.038 at 5 years, respectively). A correlation was also observed between the presence of preformed Luminex-detected class II or Luminex I and II antibodies and allograft rejection (P = 0.001 and P = 0.042, respectively). In conclusion, although HLA typing is not a prerequisite for transplantation, screening of HLA antibodies with Luminex techniques and CDC crossmatch may be useful in the detection of at-risk patients that could benefit from increased surveillance and tailored therapy following transplantation.

Association of treatment with 15‐deoxyspergualin and BK virus nephropathy in kidney allograft recipients

BK virus nephropathy (BKVN) has been proposed as an important cause of allograft dysfunction and loss in kidney allograft recipient over the last decade. Intense immunosuppression and tubular injury have been shown to promote the replication of polyomavirus. 15-deoxyspergualin (DSG), an effective immunosuppressive agent, is used as a rescue drug for acute rejection in clinical renal transplantation in Japan. To determine whether DSG is a risk factor for BKVN and outline the relationship among BKVN, DSG, and other risk factors, we analyzed 88 patients who received living-related renal transplantation between January 1999 and April 2003. A total of 114 biopsy specimens from 88 living-related kidney transplantation recipients (performed between January 1999 to April 2003) were retrospectively analyzed. Patients received immunosuppression therapy based on calcineurin inhibitors and corticosteroid [tacrolimus (TAC) 33 and cyclosporin (CyA) 55]. Additionally, mycophenolate mofeteil (MMF) was used in 21 patients; DSG was used in seven patients; and anti-CD3 monoclonal antibody was used in 16 patients. We analyzed the degree of donor/recipient human leucocyte antigen (HLA) compatibility assessed by the number of HLA-A, -B, and -DR-mismatched antigens in 88 patients. The diagnosis of BKVN was made by the light microscopic examination and a positive immunohistochemical staining of anti-40 antibody in biopsy specimens. Patients were divided into two groups of group A (mild histological change) and group B (moderate or severe histological change) to determine the risk factors in different histological staging. The clinical course of two typical patients in different histological stage is described briefly to outline the risk factors of BKVN. We identified seven cases of BKVN (8.0%) from 88 transplanted patients. Significantly higher incidence of combination regimen consisting of TAC and MMF in BKVN group was noticed compared with non-BKVN group (57.1% vs. 9.9%; p = 0.003). BKVN was associated with a significantly higher incidence of DSG administration compared with non-BKVN group (57.1% vs. 3.7%; p </= 0.001). No difference was found in HLA mismatch between BKVN and non-BKVN group. Additionally, a significantly higher incidence of acute rejection episode prior to BKVN diagnosis was found in group B compared with group A (100% vs. 0%; p = 0.002), and the same statistical difference was shown in the number of anti-rejection therapy between group B and group A (100% vs. 0%; p = 0.002). We recognized a significant difference between group B and group A in terms of the combine regimen therapy of TAC with MMF (p = 0.002) and no difference in graft loss rate (p = 0.092), even though it was 50% in group B and was 0% in group A. In this study, our data indicated excessive intense immunosuppression with TAC-MMF is related to the development of BKVN. In addition, we found that anti-rejection therapy, especially with DSG, may accelerate the development of BKVN.

14th International HLA and Immunogenetics Workshop: Report on the structural basis of HLA compatibility

Under auspices of the 14th International Human Leukocyte Antigen (HLA) and Immunogenetics Workshop, multilaboratory collaborative studies were organized addressing the following projects: (1) identification of structurally defined class I and class II HLA epitopes by human monoclonal antibodies, (2) assessment of the relative immunogenicity of structurally defined donor HLA mismatches in kidney transplantation, and (3) evaluation of the usefulness of structurally based HLA matching in platelet transfusion support of alloimmunized thrombocytopenic patients. This progress report describes a preliminary HLAMatchmaker-based data analysis in each project. The findings support the clinical usefulness of structural HLA matching.

Human leukocyte antigen and adult living-donor liver transplantation outcomes: An analysis of the organ procurement and transplantation network database

Human leukocyte antigen (HLA) compatibility has no clinically significant impact in cadaveric liver transplantation. Less is known regarding living-donor liver transplantation (LDLT). Our prior analysis of the Organ Procurement and Transplantation Network (OPTN) database suggested a higher graft failure rate in patients who underwent LDLT from donors with close HLA match. We further investigated the effect of HLA-A, -B, and -DR matching on 5-yr graft survival in adult LDLT by analyzing OPTN data regarding adult LDLT performed between 1998 and 2005. We evaluated associations between 5-yr graft survival and total, locus-specific, and haplotype match levels. Separate analyses were conducted for recipients with autoimmune (fulminant autoimmune hepatitis, cirrhosis secondary to autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) or nonautoimmune liver disease. Multivariable Cox proportional hazard models were used to evaluate interactions and adjust for potential confounders. Among 631 patients with available donor/recipient HLA data, the degree of HLA match had no significant effect on 5-yr graft survival, even when analyzed separately in recipients with autoimmune vs. nonautoimmune liver disease. To be able to include all 1,838 adult LDLTs, we considered a first-degree related donor as substitute for a close HLA match. We found no difference in graft survival in related vs. unrelated pairs. In conclusion, our results show no detrimental impact of close HLA matching on graft survival in adult LDLT, including in recipients with underlying autoimmune liver disease.

Impact of Human Leukocyte Antigen Compatibility on Engraftment in Adult Patients Receiving Reduced-Intensity Umbilical Cord Blood Transplantation Using Calcineurin Inhibitor Alone for GVHD Prophylaxis.

Despite the fact that the majority of cord blood grafts were human leukocyte antigen (HLA) disparate at one to two antigens, acute graft-versus-host disease (GVHD) was less severe after cord blood transplantation (CBT) compared to unrelated bone marrow transplantation. On the other hand, engraftment failure is a serious problem after CBT. We retrospectively analyzed the influence of HLA compatibility on engraftment after reduced-intensity umbilical cord blood transplantation (RI-CBT). We analyzed the clinical outcome of patients who underwent first RI-CBT at Toranomon hospital between January 2002 and December 2005. Those who had died within 28 days from the day of transplant were excluded from these analyses. All 156 patients had hematological malignancies including 41 with AML, 21 with ALL, 6 with CML, 19 with MDS, 31 with malignant lymphoma, 14 with adult T-cell leukemia/lymphoma, 6 with other diseases. Median age was 54 years (range, 17–79 years). All of them were considered to be inappropriate for conventional stem cell transplantation due to the lack of an HLA-identical related donor, age >50 years old and/or organ dysfunction. The preparative regimens were mainly composed of fludarabine 125 mg/m2, melphalan 80 mg/m2, and 4 Gy total body irradiation. GVHD prophylaxis was composed of cyclosporine or tacrolimus alone. Eight, 46, 98 and 4 patients received 6 of 6, 5 of 6, 4 of 6 and 3 of 6 HLA antigen matched cord blood in graft-versus-host (GVH) direction. Primary engraftment failure was diagnosed in 18 patients (11.5%). Median time to engraftment was 19 days (range, 11–55 days) for the total patient group. In GVH direction, the cumulative incidence of engraftment at day 100 were 94.4% in 5 to 6 of 6 antigen matched cord blood and 85.3% in 3 to 4 of 6 antigen matched cord blood (p=0.001). Median time to engraftment was 17 days (range, 11–36 days) in 5 to 6 antigen matched cord blood and 20 days (range, 11–55 days) in 3 to 4 antigen matched cord blood. In host-versus-graft direction, the cumulative incidence of engraftment at day 100 were 90.9% in 5 to 6 antigen matched cord blood and 87.5% in 3 to 4 antigen matched cord blood (p=0.5895). Median time to engraftment was 18.5 days (range, 11–55 days) in 5 to 6 antigen matched cord blood and 19 days (range, 11–49 days) in 3 to 4 antigen matched cord blood. In univariate analysis, both total cell dose (>3 x 107/kg) and CD34 positive cell dose (>1 x105/kg) were significantly associated with the engraftment (p=0.0009 and p=0.0005). Age, gender, risk, GVHD prophylaxis, blood type mismatch and early immune reaction were not associated with the engraftment kinetics. Multivariate analysis revealed 5 to 6 antigen mismatch in GVH direction was a significant independent factor for engraftment (p=0.0073), as well as CD34 positive cell dose. In conclusion, HLA disparities in GVH direction are associated with engraftment in adult patients receiving reduced-intensity umbilical cord blood transplantation using calcineurin inhibitor alone for GVHD prophylaxis.

Impact of high-resolution matching in allogeneic unrelated donor stem cell transplantation in Switzerland

It is currently unknown what degree of human leukocyte antigen (HLA)-mismatching is acceptable in unrelated donor hematopoietic stem cell transplantation (UD-HSCT). Mismatches at some loci may be more permissive than others. We have analyzed the effect of high-resolution HLA-matching on outcome of all 214 consecutive recipients of UD-HSCT carried out in Switzerland. All typing was by the Swiss reference laboratory. Donor-recipient pairs were HLA-10/10 matched (n=130) or mismatched for either HLA-A/-B/-DRB1/multiple loci (n=33; (HLA-A/-B=10); (-DRB1=8); (multiple=15)); HLA-C (n=29) or HLA-DQ/-DRB3 (n=22; (DQ=16); (-DRB1=6)). The median follow-up was 32 months. Survival probabilities (+/-95% confidence interval) at 3 years were 57 (+/-10)% for recipients of HLA 10/10-matched transplants, 53 (+/-22)% for recipients of HLA-DQ/-DRB3-mismatched transplants, 44 (+/-20)% for recipients of HLA-C-mismatched transplants and 0% for recipients of transplants mismatched at HLA-A/-B/-DRB1/multiple loci (P<0.0001). In multivariate analyses, HLA compatibility was the variable most significantly associated with survival and treatment-related mortality. We found important differences in survival in recipients of UD-HSCT with best results for transplants from 10/10 matched donors. Single mismatches at HLA-DQ/-DRB3 were well tolerated, mismatches at HLA-C had intermediate results and mismatches at HLA-A/-B/-DRB1/multiple loci resulted in poor survival.

HLAMatchmaker-driven analysis of responses to HLA-typed platelet transfusions in alloimmunized thrombocytopenic patients

This study describes a novel application of HLAMatchmaker to determine platelet compatibility in 16 alloimmunized patients with aplastic anemia refractory to random donor platelet transfusions. HLAMatchmaker is a software algorithm that predicts HLA compatibility by identifying immunogenic epitopes represented by amino acid triplets in antibody-accessible regions of human leukocyte antigen (HLA) molecules and determines the number of triplet mismatches (TMMs) and highly immunogenic triplet mismatches (HIMMs). Corrected count increments (CCIs) and molecular HLA typing were available for 523 transfusions. Conventional compatibility assessment based on cross-reactive group (CREG) determination was not predictive of transfusion outcome. Low HIMMs and TMMs numbers were associated with a higher likelihood of satisfactory (CCIs > or = 8) compared with unsatisfactory (CCIs < 8) outcomes (median HIMMs = 4 vs 6, p2 value < .001; median TMMs = 11 vs 13, p2 value < .001). Although receiver operator characteristic curves revealed that HIMMs or TMMs number are not powerful predictors of individual transfusion outcome, a threshold of at least 3 HIMMs or at least 9 TMMs appeared to be associated with successful transfusions. Triplet-matched transfusions were successful, regardless of CREG matching. Our data validate HLAMatchmaker for platelet transfusions and demonstrate its potential to refine and expand donor selection for HLA-alloimmunized patients.

The effect of HLA class I (A and B) and class II (DR) compatibility on liver transplantation outcomes: An analysis of the OPTN database

The purpose of this study was to explore the relationship between human leukocyte antigen (HLA) compatibility and liver transplantation outcomes by analyzing the effect of HLA compatibility on 5-year graft survival. We analyzed first liver transplants between 1987 and 2002 in the Organ Procurement and Transplantation Network (OPTN) database, where A, B, or DR loci data were available. Graft failure was defined as retransplantation or death from transplant-related cause. We evaluated associations between total and locus-specific match levels and 5-year graft survival. Multivariable Cox proportional-hazard models were used to evaluate statistical interactions and adjust for the effect of potential confounders. Among 29,675 first-time transplants, the overall degree of HLA match had no effect on 5-year graft survival, even after controlling for potential confounders. Univariate and multivariable analyses showed that the 0 HLA antigen mismatch cohort of patients had higher 5-year graft failure rates than the other 6 antigen mismatch groups. However, this occurred in a small group with a disproportionately large number of live donors and split-liver recipients. When these recipients were excluded from the analysis, the effect was no longer seen. Finally, multivariable, locus-specific analyses showed no association between 5-year graft survival and degree of match/mismatch and the A, B, or DR loci. In conclusion, this careful examination of the OPTN database, with respect to HLA match or mismatch and liver graft survival, reaffirms that HLA matching has no clinically significant impact on this outcome.