Human Leukocyte Antigen Incompatibility Research Articles

Assessment of donor compatibility in human solid organ transplantation and evaluation of allogeneic responses using a novel humanized mouse model.

Abstract The end result of solid organ transplantation is dictated by selection of a well-matched donor, leading to allograft survival. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching results in poor graft acceptance, inflammation and rejection. The current evaluations for donor-recipient HLA incompatibility does not provide adequate information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a novel method for analysis of alloimmune responsiveness between donor and recipient in vivoby introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient’s personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing and mixed lymphocyte reaction (MLR) for assessment of allogeneic response was indistinguishable between 2 related donors of the recipient. Contrastingly in recipient’s humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with increased infiltration of cytotoxic GzmB +CD8 +T cells. Moreover, the same donor induced upregulation of genes involved in the allograft rejection identified by transcriptomic analysis of graft infiltrating CD45 +cells. Humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in transplantation. This approach can be used to evaluate alloresponses in cell based therapies as well. This study was supported by research funding from the Carlos and Marguerite Mason Trust, and by U.S. National Institutes of Health, National Cancer Institute Grant CA 172230

Comparative Study of the Impact of Human Leukocyte Antigens on Renal Transplant Survival in Andalusia and the United States

Renal transplantation is the treatment of choice for patients suffering from chronic renal disease, one of the leading causes of death worldwide. Among the biological barriers that may increase the risk of acute renal graft rejection is the presence of human leukocyte antigen (HLA) incompatibilities between donor and recipient. This work presents a comparative study of the influence of HLA incompatibilities on renal transplantation survival in the Andalusian (South of Spain) and United States (US) population. The main objective is to analyse the extent to which results about the influence of different factors on renal graft survival can be generalised to different populations. The Kaplan-Meier estimator and the Cox model have been used to identify and quantify the impact on the survival probability of HLA incompatibilities, both in isolation and in conjunction with other factors associated with the donor and recipient. According to the results obtained, HLA incompatibilities considered in isolation have negligible impact on renal survival in the Andalusian population and a moderate impact in the US population. Grouping by HLA score presents some similarities for both populations, while the sum of all HLA scores (aHLA) only has an impact on the US population. Finally, the graft survival probability of the two populations differs when aHLA is considered in conjunction with blood type. The results suggest that the disparities in the renal graft survival probability between the two populations under study are due not only to biological and transplantation-associated factors, but also to social-health factors and ethnic heterogeneity between populations.

Clinical significance of human leukocyte antigen incompatibility in allogeneic hematopoietic stem cell transplantation

The use of human leukocyte antigen (HLA)-incompatible transplantations, in addition to cord blood transplantation, is rapidly increasing due to the development and refinement of graft-versus-host disease prophylactic treatment with post-transplant cyclophosphamide or anti-thymocyte globulin. However, caution must be observed in interpretating the significance of HLA incompatibility because each transplant source differs, which affect the association between HLA compatibility and transplant outcome. In addition, the loci that should be evaluated, the level of matching (antigen/allele), the direction of incompatibility (graft-versus-host or host-versus-graft), and the combination of incompatible HLA alleles must be understood. Notably, the significance of HLA incompatibility changes with the development and improvement of GVHD prophylactic treatment. Factors that should be prioritized in donor selection should be evaluated in the future. This article outlines the significance of HLA incompatibility in each transplant source.

Role of therapeutic plasma exchange as a desensitization therapy in human leukocyte antigen incompatible renal transplant patients: A single-center experience

ObjectiveDespite an increase in the rate of successful live donor renal transplantation done annually, the number of potential recipients with acceptable donors is relegated to the ever-expanding cadaver-donor waiting list due to sensitization to human leukocyte antigen (HLA) antibodies. If not sufficiently suppressed, these preformed HLA antibodies can trigger antimicrobial resistance (AMR) and early graft loss. To ameliorate this situation, various desensitization treatments are administered to provide a survival benefit to highly sensitized patients. MethodOne hundred and six patients in the time frame of January 2017 to March 2019 were included in the study group. The desensitization protocol included therapeutic plasma exchange and administration of low-dose intravenous immunoglobulin (100 mg/kg per therapeutic plasma exchange (TPE) session) to highly sensitized patients (treatment group) who subsequently underwent renal transplantation after negative pre-transplant Centers for Disease Control and Prevention Luminex crossmatch (CDC/LumXM). We compared graft survival rates between the group undergoing desensitization (treatment group) and matched control group of patients that underwent HLA-compatible transplantation. ResultsIn the treatment group, Kaplan-Meier analysis estimates an average rate of patient graft survival of 95.2% at 3 years post-transplant, as compared with the rate of 86.9% in the same time frame for the control-matched group (p < 0.05 for both comparisons). ConclusionDesensitization treatment with TPE before live donor renal transplantation in the case of patients with HLA sensitization provides better survival benefits along with monitoring for donor-specific antibodies (DSAs) and other infections, rather than waiting for a compatible organ donor. The data lays out evidence that desensitization treatments can assist overcome HLA incompatibility barriers in live donor renal transplantation.

Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation.

The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient’s personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient’s humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses.

Outcome of desensitization in human leukocyte antigen and ABO incompatible living donor kidney transplantation: Single center experience of first 200 incompatible transplants.

Although desensitization is well established, concerns about graft outcome, patient survival and rejection still exist. The present study aims at comparing outcomes of renal transplant recipients across simultaneous ABO and human leukocyte antigen (HLA) incompatibility barriers to those with ABO or HLA incompatibility alone. This was a retrospective study conducted from October 2015 to December 2018. All patients with a clinical diagnosis of chronic kidney disease, who were prospective HLA incompatible (HLAi) and/or ABO incompatible (ABOi) renal transplant recipients were included. A total of 400 cases including 36 ABOi transplants, 154 HLAi transplants, 10 simultaneously ABO and HLA incompatible transplants, and 200 ABO (ABOc) and HLA (HLAc) compatible kidney transplants from living donors were included. There were significantly more number of blood transfusions, previous transplants and pregnancies in HLAi transplant recipients relative to the ABOi or the control group. Mean number of therapeutic plasma exchange procedures per patient and mean plasma volume processed per procedure were slightly higher in the ABOi + HLAi category. The incidence of graft dysfunction due to suspected antibody-mediated rejection during first year was highest in the ABOi + HLAi group, followed by ABOc + HLAi and ABOi + HLAc, lowest in the ABOc + HLAc category. Mean time to first episode of graft dysfunction was significantly shorter with incompatible transplants. There were no kidney transplant recipient deaths in the study. Patient outcome and graft outcomes observed with incompatible transplants were not worse than those observed with compatible transplants.

Effect of the similarity of gut microbiota composition between donor and recipient on graft function after living donor kidney transplantation

Graft outcomes of unrelated donor kidney transplant are comparable with those of related donor kidney transplant despite their genetic distance. This study aimed to identify whether the similarity of donor–recipient gut microbiota composition affects early transplant outcomes. Stool samples from 67 pairs of kidney transplant recipients and donors were collected. Gut microbiota differences between donors and recipients were determined using weighted UniFrac distance. Among the donor–recipient pairs, 30 (44.8%) pairs were related, while 37 (55.2%) were unrelated. The unrelated pairs, especially spousal pairs, had similar microbial composition, and they more frequently shared their meals than related pairs did. The weighted UniFrac distance showed an inverse correlation with the 6-month allograft function (p = 0.034); the correlation was significant in the unrelated pairs (p = 0.003). In the unrelated pairs, the microbial distance showed an excellent accuracy in predicting the estimated glomerular filtration rate of < 60 mL/min/1.73 m2 at 6-months post-transplantation and was better than human leukocyte antigen incompatibility and rejection. The incidence of infection within 6 months post-transplantation increased in the recipients having dissimilar microbiota with donors compared to the other recipients. Thus, pre-transplantation microbial similarity in unrelated donors and recipients may be associated with 6-month allograft function.

Acute Rejection and Infectious Complications in ABO- and HLA-Incompatible Kidney Transplantations.

BackgroundPatients receiving ABO-incompatible (ABOi) or human leukocyte antigen (HLA)-incompatible (HLAi) kidney transplantation (KT) require potent immunosuppression and are thus at a higher risk of infectious complications. We evaluated the clinical outcomes of KT stratified by ABO and HLA incompatibilities and identified the factors associated with the clinical outcomes.Material/MethodsRecipients who underwent living-related KT between 2012 and 2017 were included and classified into 4 groups: ABO-compatible and HLA-compatible (ABOc/HLAc), HLA-incompatible (ABOc/HLAi), ABO-incompatible (ABOi/HLAc), and ABO-incompatible and HLA-incompatible (ABOi/HLAi). Cox proportional hazards regression analyses were carried out to evaluate the risk factors of acute rejection. Out of the 1732 patients who underwent KT, 1190, 131, 358, and 53 were in the ABOc/HLAc, ABOi/HLAc, ABOc/HLAi, and ABOi/HLAi groups, respectively.ResultsThe ABO/HLAi group showed the lowest 5-year graft survival rate (91.7%). Death-censored graft survival was not significantly different among the groups. The mortality rate from infections was significantly higher in the ABOi/HLAi group (7.5%) than the other groups. Antibody-mediated rejection-free graft survival was the lowest in the ABOi/HLAi group, with significant differences compared with the ABOi/HLAc group (P=0.02) and the ABOc/HLAi group (P=0.03). ABOi/HLAi (hazard ratio [HR], 2.63; 95% confidence interval [CI], 1.04–6.65; P<0.01) and combined infection (HR, 1.91; 95% CI, 1.45–2.51; P<0.01) were significant risk factors for acute rejection.ConclusionsPatients with both ABO and HLA incompatibilities showed inferior rates of overall patient and graft survival due to infectious complications. Infection was a prominent risk factor of acute rejection following KT after adjusting for possible confounders including ABO and HLA incompatibility.

Impact of HLA compatibility in recipients of kidneys from expanded criteria donors: A Collaborative Transplant Study Report.

Due to a widespread organ shortage, the use of expanded criteria donors (ECDs) in kidney transplantation has increased persistently, reaching approximately 40% in recent years. Whether human leucocyte antigen (HLA) matching between donor and recipient should be part of allocation algorithms in transplantation of ECD kidneys, and especially of ECD kidneys from ≥70-year-old donors, is still in question. To this end, 135,529 kidney transplantations performed between 2000 and 2017 and reported to the Collaborative Transplant Study were analysed and the impact of HLA-A+B+DR mismatches on death-censored graft and patient survival as well as on rejection episodes was investigated. Results were stratified according to donor status (standard criteria donor (SCD) versus ECD) and age of ECD. HLA incompatibility increased the five-year death-censored graft failure risk similarly strong in recipients of ECD and SCD transplants (hazard ratio (HR) per HLA mismatch 1.078 and 1.075, respectively; p<.001 for both). Its impact on rejection treatments during the first post-transplant year was also significant but slightly weaker for recipients of ECD transplants (risk ratio (RR) per HLA mismatch 1.10 for ECD transplants and 1.13 for SCD transplants; p<.001 for both). Mortality increased gradually from zero to six HLA mismatches in recipients of SCD transplants, whereas for ECD transplants a significant increase was notable only from zero to more than zero mismatches. A significant but slightly less pronounced impact of HLA incompatibility on graft failure was observed in transplants from ≥70- compared with <70-year-old ECDs (HR per mismatch 1.047 and 1.093; p=.009 and<0.001, respectively). The influence of HLA mismatches on rejection treatments was the same for both ECD age groups (RR=1.10, p<.001 and p=.004, respectively). Our data indicate that HLA matching should be part of allocation algorithms not only in transplantation of kidneys from SCDs but also from ECDs.

Regional Report on Organ Transplantation in Trinidad and Tobago.

Regional Report on Organ Transplantation in Trinidad and Tobago.

A case report of ABO and human leukocyte antigen incompatible renal transplant – Being immunologically smart

Blood group and human leukocyte antigen (HLA) incompatibility are major immunological barriers in renal transplantation. Desensitization and subsequent transplantation improve the longevity and quality of life of these patients when compared to being on a waitlist. For best outcomes, a complete repertoire of immunological workup and an in-depth understanding of these tests are important for choosing the most suitable donor against whom the recipient is least sensitized. We present an interesting case of a sensitized patient who had the option of undergoing renal transplant with either a blood group incompatible mother or a compatible aunt as the prospective donor. Despite the blood group incompatibility, the mother was chosen as the donor in view of the lower strength of anti-HLA antibodies against her. The patient had a successful posttransplant outcome with good graft function at 1 year follow-up. Careful donor selection after detailed immunological workup is important while transplanting sensitized recipients. HLA incompatibility rather than blood group incompatibility should be the deciding factor in such cases.

Renal Transplant Outcomes in Spousal and Living-Related Donors in Malaysia

Studies have shown that a compatible human leukocyte antigen (HLA) match can confer a favourable effect on graft outcomes. We examined the outcomes of HLA matching in renal transplant donors in Malaysia. A total of 140 patients who had compatible ABO blood type with negative T-cell lymphocytotoxicity crossmatch were included in the study and 25% of them were spousal transplant donors. No remarkable differences in acute rejection rate, graft survival, patient survival and serum creatinine level were observed between the spousal and living-related donor groups. The spousal donor group had a higher degree of HLA mismatch than the living-related donor group. HLA-A mismatch was associated with increased rejection risk at 6 months (odds ratio [OR], 2.75; P = 0.04), 1 year (OR, 2.54; P = 0.03) and 3 years (OR, 3.69; P = 0.001). It was also observed in the deleterious effects of HLA-B and HLA-DQ loci when the number of antigen mismatches increased. The risk was 7 times higher in patients with ≥1 mismatch at HLA-A, HLA-B and HLA-DR loci than those who did not have a mismatch at these loci at 6 months (P = 0.01), 1 year (P = 0.03) and 3 years (P = 0.003). A good match for HLA-A, HLA-B, HLA-DR and HLA-DQ can prevent acute rejection risk in renal transplant patients. Consequently, spousal donor transplants could be a safe intervention in renal patients.

International cooperation for kidney exchange success

Kidney exchange programs (KEPs) have been developed in different countries to overcome incompatibilities between living kidney donors and their intended recipients.1,2 The effectiveness of existing KEPs is limited due to the number of donor-recipient pairs registered, particularly in small countries, and the accumulation of difficult to match recipients (eg, hypersensitized and blood group 0).3 The first successful European binational cooperation to increase the size and might add genetic heterogeneity of the donor pool was carried out between Austria and Czech-Republic in 2016.4 Furthermore, a European Network for Collaboration on KEPs, under the scope of a COST action, has started to share best practices, enhance discussions, and set the basis for future international collaborations.2 We report the first transnational kidney exchange procedure carried out in the framework of an international cooperation managed and overseen by the National Transplant Organizations of Italy, Portugal, and Spain. These countries started their KEPs in 2006, 2010, and 2009, respectively.2 Authorities and centers developed a common protocol and rules in 2017. A minimum annual activity of 10 living kidney transplants and human leukocyte antigen laboratory accreditation by the European Foundation of Immunogenetics were required for centers to participate. Challenges posed by different native languages, sharing schemes (eg, in Portugal, unspecified donor chains and registration of compatible pairs are not allowed), procedures (eg, anonymity between pairs is not required in Italy), and coordination of logistics were addressed and overcome. Communication was performed in English, only incompatible pairs were registered in the international program, anonymity was set as a mandatory requirement, and an ad hoc check-list for the coordination of the process was established. The Spanish KEP software, which contains a registry of pairs and a matching algorithm, was modified to accommodate the needs of the international scheme. The Organización Nacional de Trasplantes coordinated the initiative. The main elements of the project are summarized in Table 1.TABLE 1.: Matching algorithm and operating protocolIn May 2018, a matching run was undertaken between 14 hospitals (10 Spanish, 3 Italian, and 1 Portuguese) that registered 110 incompatible pairs (79 Spanish, 17 Portuguese, and 14 Italian) due to human leukocyte antigen incompatibility in 101 cases, unmatched in their KEPs. Of the individuals registered, 71 patients and 54 donors were blood type O. Regarding sensitization, the number of patients with calculated panel reactive antibodies ≥ 80% was 78 (71%). A two-way exchange was identified between one pair at Fundación Puigvert in Barcelona, Spain, and one at Ospedale Cisanello in Pisa, Italy. Clinical data were shared and negative cell-based crossmatches were confirmed. The date of the crossed-transplants and logistical issues were agreed upon. The procedures took place in July 2018. Once recovered, kidneys were shipped between centers by private flight. Cold-ischemia time was <8 hours. A week later, recipients and donors were discharged without complications and good renal function. Anonymity was maintained at every moment. Kidney exchanges between countries with different languages, regulations, and daily practice are feasible. Refinements of this approach and the participation of other countries2 will fortunately enhance opportunities of transplantation for patients in need.

Assessment of human leukocyte antigen immunogenicity: current methods, challenges and opportunities.

Purpose of reviewDonor–recipient human leukocyte antigen (HLA) matching improves outcomes after solid-organ transplantation, but current assessment of HLA incompatibility is inadequate as it does not consider the relative immunogenicity of individual HLA mismatches. In this article, we review existing strategies for assessing HLA immunogenicity and discuss current challenges and future opportunities in this field.Recent findingsCurrent HLA immunogenicity algorithms focus primarily on the humoral component of the alloimmune response and aim to determine a measure of ‘dissimilarity’ between donor and recipient HLA. This can be achieved by deriving information from comparison of donor and recipient HLA at the amino acid sequence, structural and/or the physicochemical level, accounting for both B-cell and T-cell pathways of alloreactivity. Substantial evidence now supports the superiority of this molecular definition of HLA incompatibility, over conventional enumeration of HLA antigenic differences, for assessing the risk of humoral alloimmunity and for predicting graft outcomes after transplantation.SummarySignificant progress has been made in developing computational HLA immunogenicity algorithms that offer exciting opportunities for a more rational approach to determining the degree of donor–recipient HLA incompatibility and to defining HLA-related immunological risk. A number of challenges now need to be overcome to enable their implementation into clinical practice.

Outcomes after Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes: A Center for International Blood and Marrow Transplant Registry (CIBMTR®) Study

Background:Although, widespread application of innovative sequencing technologies is rapidly unraveling the molecular underpinnings driving the pathogenesis of myelodysplastic syndromes (MDS), allogeneic hematopoietic cell transplantation (HCT) remains the only therapeutic modality that has demonstrated curative potential. However, a significant proportion of patients lack a human leukocyte antigen (HLA)-matched sibling or unrelated donor, and alternative donor sources are needed to extend HCT to patients that are otherwise suitable. There have been few published series solely dedicated to describing the outcomes of adult patients who have undergone umbilical cord blood transplantation (UCBT) for MDS.Methods:We identified 176 adult MDS patients who underwent UCBT, at 59 centers, between 2004 and 2013 from the CIBMTR database. The primary endpoints were the estimated incidences of graft-vs-host-disease (GVHD), relapse, transplant-related mortality (TRM), disease free survival (DFS), and overall survival (OS). Multivariate models were built to assess the ability of the revised International Prognostic Scoring System (IPSS-R) to predict post-HCT outcome.Results:Median age at the time of transplant was 56 (18-73) with 32%, 27%, 34% having a comorbidity score (HCT-CI) of 0, 1-2, or ≥ 3, respectively. The median time from diagnosis to transplant was 9 (< 1-147) months; 23% of patients did not receive pre-HCT chemotherapy; 72% has a marrow blast count ≤ 5%. IPSS-R scores are shown in Table 1. Myeloablative and reduced-intensity/non-myeloablative conditioning was used in 35% and 65%, respectively; 43% incorporating ATG/alemtuzumab. Double units were used in 80%; median total nucleated cell dose (TNC) of 4 × 107 /kg (< 1-29); considering the unit with the higher number of HLA incompatibilities with the recipient, 60% had ≥ 2 mismatches. The 100-day probability of grade 2-4 acute GVHD was 38%. The 3-year probabilities of chronic GVHD, relapse, TRM, DFS, and OS was 28%, 32%, 40%, 28%, and 31%, respectively. In multivariate analysis using marginal Cox model to adjust for center effect, increasing IPSS-R score at the time of HCT was associated with inferior post-HCT TRM, DFS, and OS (Table 2). IPSS-R was associated with neither GVHD nor relapse. HCT-CI was associated with TRM (P = .001), DFS (P = .02), and OS (P = .001), and conditioning intensity was associated with relapse (P < .001). A higher proportion of myeloablative HCTs were done for those with high-risk disease by IPSS-R, but the interaction between conditioning intensity and IPSS-R for relapse was not significant.Conclusions:Treatment decisions and clinical trial design can be informed by providing a descriptive analysis of UCBT for MDS that incorporates a large number of patients from multiple centers. In this analysis, TRM was significantly associated with HCT-CI scores. Interestingly, IPSS-R, a model that specifically quantifies disease risk, at the time of HCT did not predict for post-HCT relapse, but did for TRM.Table 1Pre-HCT risk scoresIPSS-R prior to transplantVery low18 (10)Low41 (23)Intermediate33 (19)High34 (19)Very high22 (13)Missing28 (16)Table 2Multivariate analysis*TRMIPSS-RNRR95% CI Lower Limit95% CI Upper LimitP -valueOverallP -valueVery low/Low641.006Intermediate34.68.341.35.30High/Very high541.761.122.75.01Missing282.05.934.52.08DFSIPSS-RNRR95% CI Lower Limit95% CI Upper LimitP -valueOverallP -valueVery low/Low641.02Intermediate34.83.501.37.50High/Very high541.391.021.91.04Missing281.63.952.81.08OSIPSS-RNRR95% CI Lower Limit95% CI Upper LimitP -valueOverallP -valueVery low/Low651.008Intermediate35.88.511.50.60High/Very high551.551.122.14.01Missing281.72.913.26.09* When adjusting for center effect and HCT-CI DisclosuresNo relevant conflicts of interest to declare.

Approach to managing platelet refractory patients

The diagnosis of platelet refractoriness is made when at least on two sequential occasions, a 10‐min to 1‐h post‐transfusion, the CCI is less than 5 × 109/l, using ABO‐identical fresh platelets of less than 72 h old. In practice, an increase in the patient's platelet counts of &lt;10 × 109/l after the transfusion can be used. Refractoriness to platelet transfusion can be due to non‐immune and immune causes. Non‐immune causes include sepsis and disseminated intravascular coagulation. Twenty percent of cases have a combination of both immune and non‐immune causes. Immune causes include alloimmunization to human leukocyte antigen (HLA) and/or human platelet antigens(HPA). The pattern of refractoriness and clinical condition may assist in determining the cause. Patients who are likely to receive multiple platelet transfusion should have their post transfusion platelet count estimated. If refractoriness is suspected, HLA typing and antibody investigation should be done. While waiting for the test result and the supply of HLA matched platelets, ABO compatible platelets may be given. Doubling the dose or giving more frequent transfusion maybe necessary in non‐immune cases. Where patient's HLA type is known, an identical or closely identical platelet can be given. Another approach is by giving platelet from donors lacking HLA antigens that correspond to the recipient's alloantibodies. Crossmatched platelets can be given in the absence of typed HLA platelets. Approximately 20–25% cases may be due to platelet‐specific antibodies, and undetected HLA incompatibility, in which case, the patient can be given antigen negative platelet.

Gene expression changes in HLA mismatched mixed lymphocyte cultures reveal genes associated with allorecognition.

Human leucocyte antigen (HLA) compatibility is the main factor determining the occurrence of graft‐vs‐host disease (GVHD) in patients. It has also been shown that minor histocompatibility antigen differences as well as genetic polymorphisms that are not sequenced by standard methodology for HLA typing can play a role. We used mixed lymphocyte cultures (MLCs) as a functional cellular test and investigated gene expression changes driven by HLA incompatibility in an effort to better understand the mechanisms involved in the disease. Gene expression profile of HLA matched and HLA mismatched MLC identified differentially regulated genes and pathways. We found that a great number of genes related to immune function were differentially regulated; these genes were also found to be associated with GVHD and graft rejection. The majority of differentially regulated genes were interferon‐gamma (IFNγ)‐inducible genes and IFNγ neutralisation in MLCs abrogated their induction. The microRNA‐155, a recently identified target for acute GVHD (aGVHD), was also found to be significantly induced in HLA mismatched MLC but not in the matched setting and its induction was not diminished by blocking IFNγ. In this proof‐of‐principle study we show gene expression changes in mismatched MLC that represent alloreactive responses, correlate with markers involved in GVHD and can potentially be useful in the study of the biological processes involved in this disease.

Current trends in platelet transfusions practice: The role of ABO-RhD and human leukocyte antigen incompatibility.

Platelet transfusions have contributed to the revolutionary modern treatment of hypoproliferative thrombocytopenia. Despite the long-term application of platelet transfusion in therapeutics, all aspects of their optimal use (i.e., in cases of ABO and/or Rh (D incompatibility) have not been definitively determined yet. We reviewed the available data on transfusion practices and outcome in ABO and RhD incompatibility and platelet refractoriness due to anti-human leukocyte antigen (HLA) antibodies. Transfusion of platelets with major ABO-incompatibility is related to reduced posttransfusion platelet (PLT) count increments, compared to ABO-identical and minor, but still are equally effective in preventing clinical bleeding. ABO-minor incompatible transfusions pose the risk of an acute hemolytic reaction of the recipient that is not always related to high anti-A, B donor titers. ABO-identical PLT transfusion seems to be the most effective and safest therapeutic strategy. Exclusive ABO-identical platelet transfusion policy could be feasible, but alternative approaches could facilitate platelet inventory management. Transfusion of platelets from RhD positive donors to RhD negative patients is considered to be effective and safe though is associated with low rate of anti-D alloimmunization due to contaminating red blood cells. The prevention of D alloimmunization is recommended only for women of childbearing age. HLA alloimmunization is a major cause of platelet refractoriness. Managing patients with refractoriness with cross-matched or HLA-matched platelets is the current practice although data are still lacking for the efficacy of this practice in terms of clinical outcome. Leukoreduction contributes to the reduction of both HLA and anti-D alloimmunization.

Ceppellini Lecture 2012: Collateral damage from HLA mismatching in kidney transplantation

Inclusion of human leukocyte antigen (HLA) matching in donor kidney allocation schemes has been based solely on its association with graft survival. Other long-term effects associated with HLA incompatibility are largely unexplored. Data from deceased donor kidney transplants reported to the Collaborative Transplant Study have been analyzed to assess the relation between HLA mismatching and clinical events to 3 years post-transplant, and an overview of these analyses is presented. A significant correlation was observed between the number of mismatches and the need for anti-rejection therapy during the first year post-transplant, which was maintained for HLA-DR and HLA-A + B mismatching separately and at years 2 and 3 post-transplant. The number of HLA-DR mismatches and the number of HLA-A + B mismatches as well as rejection treatment showed significant associations with the dose of maintenance steroids. The cumulative incidences of death with a functioning graft from infection or cardiovascular causes, but not from cancer, were also significantly associated with HLA mismatching. The number of HLA-DR mismatches showed a significant association with the incidence of non-Hodgkin lymphoma and hip fractures. These findings show that the adverse consequences of HLA mismatching on kidney transplants extend beyond an effect on graft survival, and include an increased risk of death with a functioning graft, non-Hodgkin lymphoma and hip fracture.

Strategies for Expanding the UK Pool of Potential Intestinal Transplant Donors

The pool of suitable donors and listed recipients for intestinal transplantation is small, resulting in difficulties in donor-to-recipient matching and significant mortality on the waiting list. This study aims to help define the pool of potential donors for intestinal transplantation and propose methods for an increased utilization of donor bowels in the United Kingdom. Data on bowel offering from 657 donors after brain stem death (DBD) and on 46 patients on the active intestinal transplant list over 12 months from 14 April 2011 were obtained from the UK Transplant Registry. Family consent for bowel donation was lower than for the other transplantable organs. Only 57% of bowels from DBD donors with consent and meeting the bowel offering criteria were offered for transplantation. A lack of suitable recipients was the most common reason cited for not offering. Only 10% of offered bowels were accepted and transplanted by centers. Donor size discrepancy and human leukocyte antigen incompatibility were common reasons for declining offers of the bowel. There was a scarcity of young and small donors compared with the number of young and small patients requiring a transplant. Two patients who were on the active list during the time period died. An increased awareness of bowel donation is needed to improve the low offering rate of bowels from DBD donors. A more robust UK bowel allocation system and a formalized European-wide intestinal donor organ sharing program should lead to an increased utilization of available donor bowels and a lower waiting list mortality rate.