Decreased Risk of Graft Failure with Maternal Liver Transplantation in Patients with Biliary Atresia

The presence of maternal cells in offspring may promote tolerance to noninherited maternal antigens (NIMAs). Children with biliary atresia (BA) have increased maternal cells in their livers, which may impact tolerance. We hypothesized that patients with BA would have improved outcomes when receiving a maternal liver. We reviewed all pediatric liver transplants recorded in the SRTR database from 1996 to 2010 and compared BA and non-BA recipients of maternal livers with recipients of paternal livers for the incidences of graft failure and retransplantation. Rejection episodes after parental liver transplantation were examined for patients transplanted at our institution. BA patients receiving a maternal graft had lower rates of graft failure compared to those receiving a paternal graft (3.7% vs. 10.5%, p = 0.02) and, consequently, fewer episodes of retransplantation (2.7% vs. 7.5%, p = 0.04). These differences were not seen among non-BA patients or among BA patients who received female deceased donor grafts. In patients transplanted at our institution, paternal liver transplantation was associated with an increased incidence of refractory rejection compared to maternal liver transplantation only in BA. Our data support the concept that maternal cells in BA recipients promote tolerance to NIMAs and may be important in counseling BA patients who require liver transplantation (read more).

Three Patients with Full Facial Transplantation

Unlike conventional reconstruction, facial transplantation seeks to correct severe deformities in a single operation. We report on three patients who received full-face transplants at our institution in 2011 in operations that aimed for functional restoration by coaptation of all main available motor and sensory nerves. We enumerate the technical challenges and postoperative complications and their management, including single episodes of acute rejection in two patients. At 6 months of follow-up, all facial allografts were surviving, facial appearance and function were improved, and glucocorticoids were successfully withdrawn in all patients (read more)

Early Subclinical Rejection as a Risk Factor for Late Chronic Humoral Rejection

Background. Subclinical rejection and interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsies are associated with outcome. We study the relationship between histologic lesions in early protocol biopsies and histologic diagnoses in late biopsies for cause.
Materials and Methods. Renal transplants with a protocol biopsy performed within the first 6 months posttransplant between 1988 and 2006 were reviewed. Biopsies were evaluated according to Banff criteria, and C4d staining was available in biopsies for cause.
Results. Of the 517 renal transplants with a protocol biopsy, 109 had a subsequent biopsy for cause which showed the following histological diagnoses: chronic humoral rejection (CHR) (n=44), IF/TA (n=42), recurrence of the primary disease (n=11), de novo glomerulonephritis (n=7), T-cell-mediated rejection (n=4), and polyoma virus nephropathy (n=1). The proportion of retransplants (15.9% vs. 2.3%, P=0.058) and the prevalence of subclinical rejection were higher in patients with CHR than in patients with IF/TA (52.3% vs. 28.6%, P=0.0253). Demographic donor and recipient characteristics and clinical data at the time of protocol biopsy were not different between groups. Logistic regression analysis showed that subclinical rejection (relative risk, 2.52; 95% confidence interval, 1.1–6.3; P=0.047) but not retransplantation (relative risk, 6.7; 95% confidence interval, 0.8–58.8; P=0.085) was associated with CHR.
Conclusion. Subclinical rejection in early protocol biopsies is associated with late appearance of CHR (read more).

Induced Anti-Non Gal Antibodies in Human Xenograft Recipients

Anti-non gal antibodies are produced in xenograft recipients against multiple xenogeneic antigens. Studies in monkeys transplanted with pig organs lacking α-gal epitopes have suggested that anti-non gal antibodies mediate acute and chronic rejection of xenografts. This overview describes studies of these antibodies in patients who received xenografts and includes (1) an ovarian carcinoma patient receiving three intraperitoneal infusions of mouse fibroblasts in a gene therapy study, (2) orthopedic patients with torn anterior cruciate ligament replaced by a ligament made of pig patellar tendon, and (3) diabetic patients receiving fetal pig islet cell clusters xenograft together with a kidney allograft. Anti-non gal antibodies were found to be continuously produced as long as the xenograft was present in the recipient and were directed against a large number of pig proteins. Monitoring the immune response in the recipient of mouse fibroblasts indicated that the production of anti-non gal antibodies is much slower than that of the anti-Gal antibody, suggesting that they are generated by multiple B-cell clones, each initially comprising relatively few cells. Potent immunosuppression to prevent allograft rejection does not fully inhibit the production of anti-non gal antibodies. Much of this antibody response seems to be due to the differences in amino acid sequences between pig and human orthologous proteins as a result of evolutionary mutations. Overcoming the anti-non gal antibody barrier will require immunosuppressive agents that preferentially inhibit this immune response while maintaining protection against pathogens, or alternatively development of methods for induction of immune tolerance to xenogeneic pig antigens (read more).

Frequency of HLA-DP-specific antibodies and a possible new cross-reacting group

Callender CJ, Fernandez-Vina M, Leffell MS, Zachary AA

Clinical studies have demonstrated that HLA-DP-specific antibodies can be detrimental to a transplanted kidney. The number of patients affected is proportional to the frequency of DP antibodies. We determined the frequency of HLA-DP-specific antibodies en toto and in the absence of cross-reactive DR antibodies. Of 650 waitlisted renal patients, 271 (42%) were reactive with HLA-DP antigens in solid-phase immunoassays. Of these 271 sera, 58 (21%) were negative for reactivity with cross-reactive DR antigens, and 16 (5.9%) had no class II antibody other than DP. Eliminating sera containing DR cross-reactive antibodies reduced the frequency but not the overall strength of DP antibodies. Although most DP antibodies were not expected to yield a positive cytotoxicity crossmatch, 2 DP-specific antibodies yielded cytotoxic crossmatch tests with titers of >512. The occurrence of HLA-DP-specific antibody differed significantly between previously transplanted (62%) and nontransplanted (38%) patients, but no difference was observed among patients categorized by race or sex. One serum demonstrated strong cross-reactivity between DP and DRB1*01:03 in the absence of DR1 or DR11 reactivity. Sequence alignments were performed and a possible new cross-reactivity between DRB1*01:03 and DP2, DP9, DP10, DP13, DP16, and DP17 was defined. Two additional sera confirmed this cross-reactivity (read more)

Selling Bone Marrow

On December 1, 2011, in Flynn v. Holder, the U.S. Court of Appeals for the Ninth Circuit held that the ban on selling “bone marrow” that is part of the National Organ Transplant Act (NOTA) of 1984 does not encompass “peripheral blood stem cells” obtained through apheresis. This ruling means that the sale of blood stem cells for transplantation will now be permitted. The court based its holding solely on statutory interpretation of NOTA, not the plaintiffs' more radical claim that the prohibition on selling bone marrow violates the Equal Protection Clause of the U.S. Constitution, which prohibits the federal and state governments from denying any person the equal protection of the law. For those seeking to establish a constitutional right to buy and sell body parts in the United States, this case was a loss, but for those narrowly focused on blood stem cells obtained through apheresis, the decision legally sanctions a commercial market (read more).

Allo-HLA-reactive T cells inducing graft-versus-host disease are single peptide specific:

T-cell alloreactivity directed against non–self-HLA molecules has been assumed to be less peptide specific than conventional T-cell reactivity. A large variation in degree of peptide specificity has previously been reported, including single peptide specificity, polyspecificity, and peptide degeneracy. Peptide polyspecificity was illustrated using synthetic peptide-loaded target cells, but in the absence of confirmation against endogenously processed peptides this may represent low-avidity T-cell reactivity. Peptide degeneracy was concluded based on recognition of Ag-processing defective cells. In addition, because most investigated alloreactive T cells were in vitro activated and expanded, the previously determined specificities may have not been representative for alloreactivity in vivo. To study the biologically relevant peptide specificity and avidity of alloreactivity, we investigated the degree of peptide specificity of 50 different allo-HLA–reactive T-cell clones which were activated and expanded in vivo during GVHD. All but one of the alloreactive T-cell clones, including those reactive against Ag-processing defective T2 cells, recognized a single peptide allo-HLA complex, unique for each clone. Down-regulation of the expression of the recognized Ags using silencing shRNAs confirmed single peptide specificity. Based on these results, we conclude that biologically relevant alloreactivity selected during in vivo immune response is peptide specific (read more).

Publication bias is present in blood and marrow transplantation: an analysis of abstracts at an international meeting
Publication bias is the preferential publication of research with positive results, and is a threat to the validity of medical literature. Preliminary evidence suggests that research in blood and marrow transplantation (BMT) lacks publication bias. We evaluated publication bias at an international conference, the 2006 Center for International Blood and Marrow Transplant Research (CIBMTR)/American Society for Blood and Marrow Transplantation (ASBMT) "tandem" meeting. All abstracts were categorized by type of research, funding status, number of centers, sample size, and direction of the results. Publication status was then determined for the abstracts by searching PubMed. Of 501 abstracts, 217 (43%) were later published as complete manuscripts. Abstracts with positive results were more likely to be published than those with negative or unstated results (P = .001). Furthermore, positive studies were published in journals with a mean impact factor of 6.92, whereas journals in which negative/unstated studies were published had an impact factor of only 4.30 (P = .02). We conclude that publication bias exists in the BMT literature. Full publication of research, regardless of direction of results, should be encouraged and the BMT community should be aware of the existence of publication bias (read more).

Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation:

Using a uniform detection method for donor-specific anti-HLA antibodies (DSAs), we sought to determine the effect of preformed DSAs on outcomes in double umbilical cord blood transplantation. DSAs were associated with an increased incidence of graft failure (5.5% vs 18.2% vs 57.1% for none, single, or dual DSA positivity; P = .0001), prolongation of the time to neutrophil engraftment (21 vs 29 days for none vs any DSA; P = .04), and excess 100-day mortality or relapse (23.6% vs 36.4% vs 71.4% for none, single, or dual DSA positivity; P = .01). The intensity of DSA reactivity was correlated with graft failure (median of mean fluorescent intensity 17 650 vs 1 850; P = .039). There was inferior long-term progression-free and overall survival when comparing patients with DSAs against both umbilical cord blood units to those without DSAs (3-year progression-free survival, 0% vs 33.5%, P = .004; 3-year overall survival 0% vs 45.0%, P = .04). We conclude that identification of preformed DSAs in umbilical cord blood recipients should be performed and that the use of umbilical cord blood units where preformed host DSAs exist should be avoided (read more).

Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia
Idiopathic aplastic anemia (AA) is a common cause of acquired BM failure. Although autoimmunity to hematopoietic progenitors is thought to be responsible for its pathogenesis, little is known about the molecular basis of this autoimmunity. Here we show that a substantial proportion of AA patients harbor clonal hematopoiesis characterized by the presence of acquired copy number-neutral loss of heterozygosity (CNN-LOH) of the 6p arms (6pLOH). The 6pLOH commonly involved the HLA locus, leading to loss of one HLA haplotype. Loss of HLA-A expression from multiple lineages of leukocytes was confirmed by flow cytometry in all 6pLOH(+) cases. Surprisingly, the missing HLA-alleles in 6pLOH(+) clones were conspicuously biased to particular alleles, including HLA-A*02:01, A*02:06, A*31:01, and B*40:02. A large-scale epidemiologic study on the HLA alleles of patients with various hematologic diseases revealed that the 4 HLA alleles were over-represented in the germline of AA patients. These findings indicate that the 6pLOH(+) hematopoiesis found in AA represents "escapes" hematopoiesis from the autoimmunity, which is mediated by cytotoxic T cells that target the relevant auto-antigens presented on hematopoietic progenitors through these class I HLAs. Our results provide a novel insight into the genetic basis of the pathogenesis of AA (read more).

Increased influx of myeloid dendritic cells during acute rejection is associated with interstitial fibrosis and tubular atrophy and predicts poor outcome
Kidney International 81, 64 (January (1) 2012)
Kim Zuidwijk, Johan W de Fijter, Marko J K Mallat, Michael Eikmans, Marian C van Groningen, Natascha N Goemaere, Ingeborg M Bajema & Cees van Kooten


Dendritic cells are key players in renal allograft rejection and have been identified as an intrinsic part of the kidney. Here we quantified and phenotyped the dendritic cell populations in well-defined biopsies of 102 patients with acute renal allograft rejection in comparison with 78 available pretransplant biopsies. There was a strong increase in BDCA-1⁺ and DC-SIGN⁺ myeloid, BDCA-2⁺ plasmacytoid, and DC-LAMP⁺ mature dendritic cells in rejection biopsies compared with the corresponding pretransplant tissue. Mature dendritic cells were mostly found in clusters of lymphoid infiltrate and showed a strong correlation with the Banff infiltrate score. The presence of both myeloid and plasmacytoid dendritic cell subsets in the kidney during acute rejection correlated with interstitial fibrosis and tubular atrophy. Importantly, the myeloid dendritic cell density at the time of acute rejection was an independent risk factor for loss of renal function after the first year. Thus, acute renal allograft rejection is characterized by an influx of myeloid and plasmacytoid dendritic cells, strongly associated with local damage in the graft. Hence, the density of myeloid dendritic cells during acute rejection could be an important risk factor for the long-term development of chronic changes and loss of graft function.

A longitudinal study of the course of asymptomatic antibody-mediated rejection in heart transplantation

Background: Growing evidence suggests worse cardiac allograft vasculopathy and mortality in patients with asymptomatic antibody-mediated rejection (AMR). Debate continues about whether therapeutic intervention is warranted to avoid adverse outcomes. In this study we examine the course of individual episodes of untreated asymptomatic AMR on follow-up endomyocardial biopsy (EMB).
Methods: The U.T.A.H. Cardiac Transplant Program database was queried for transplant recipients between 1985 and 2009 who survived beyond 1 year and had at least 1 episode of lone AMR with a follow-up EMB. All EMBs were screened for AMR by immunofluorescence and graded for severity. Data were analyzed based on time from transplant (early, ≤12 months; late, >12 months).
Results: Nine hundred fifty-eight patients with a total of 15,448 biopsies qualified for the study. Average age at transplant was 46.7 years; 13% of the patients were female. Within the first year post-transplant, asymptomatic AMR was diagnosed in 13.6% of biopsies compared with 5.2% beyond 1 year. AMR resolved in 65% (early) vs 75% (late) on follow-up EMB. More severe AMR was less likely to improve regardless of time from transplant. Furthermore, after an episode of AMR had resolved, the recurrence rate at 3, 6 and 12 months was 44%, 50.1% and 56.2%, respectively.
Conclusions: The incidence of AMR is higher in the first year post-transplant and the likelihood of resolution is less on follow-up EMB, especially when more severe. A small but significant number of cases became worse or did not change. These new findings may be helpful in planning future studies that test whether therapeutic interventions on asymptomatic AMR favorably impact outcomes (read more).

Some useful links on immunoinformatics

Some useful links on immunoinformatics :

Minimal Information about T Cell Assays (MIATA) project 

IMGT/HLA Database at European Bioinformatics Institute (EBI) contains the official sequences of the WHO Nomenclature Committee for Factors of the HLA System

dbMinor at Leiden University : the minor Histocompatibility Knowledge Database

AntigenDB (mirror) : 500 antigens from 44 important pathogenic species, including epitope search

Polymorphisms :

• Immuno Polymorphism Database (IPD) at EBI :
• KIR
• KIR ligand calculator (search for mismatches between KIR ligands)
• MHC (nomenclature in cattle, canines, felines, fish, non-human primates, rats, sheep, and swine)
• MHC motif viewer : display of the likely binding motif for all human class I proteins of the loci HLA A, B, C, and E and for MHC class I molecules from chimpanzee (Pan troglodytes), rhesus monkey (Macaca mulatta), and mouse (Mus musculus).
• Allele*Frequencies.net in worldwide population
• ALlele FREquency Database (ALFRED) at Yale University : gene frequency data on human populations supported by the U. S. National Science Foundation.

HLAMatchmaker by Rene' Duquesnoy : eplet mismatching calculators

MHC-binding epitope predictions :

• on payment immunogenicity screening :
• EpiVax, Inc. (on payment)
• Epibase^® by Lonza.
• Prediction Algorithm for Proteosomal Cleavages (PAProC)
• SYFPEITHI : epitope prediction by BioMedical Informatics (BMI) - Heidelberg (after the name of first natural MHC ligand directly msequenced, the nonapeptide SYFPEITHI eluted from H-2 K^d molecules of a mouse tumour line, P815, ortholog of human JAK1)
• Immune Epitope Database (IEDB) contains data related to antibody, T cell epitopes, and MHC binding data for humans, non-human primates, rodents, and other animal species
• NetMHCpan 2.4 server : database for quantitative predictions of peptide binding to any HLA-A and -B protein sequence.
• MHCPred 2.0
• RANKPEP at Harvard University
• Institute for Transfusion Medicine, Hannover Medical School, Germany :
• HistoCheck^ref (free registration required)
• PeptideCheck (free registration required)
• HaploCheck (free registration required)
• MHCO : An Ontology for Major Histocompatibility Complex Alleles and Molecules
• class I MHC-binding prediction :
• HLA-peptide binding prediction (human and murine) at BioInformatics & Molecular Analysis Section (BIMAS)
• SVMHC uses support vector machines and currently contains prediction for 26 MHC class I types from the MHCPEP database or alternatively 6 MHC class I types from the higher quality SYFPEITHI database^ref
• LpPep (for HLA-A2)^ref.
• NetMHC^{ref1, ref2, ref3}
• ProPred-I : the promiscuous human and murine MHC class-I binding peptide prediction server
• MAPPP  at Max-Planck-Institute for Infection  Biology : human and murine MHC-I binding prediction  using BIMAS or SYFPEITHI matrices
• class II MHC-binding prediction :
• EpiPredict
• MHC-Thread
• ProPred^ref
• Vaccinome's TEPITOPE

ABO Incompatible Kidney Transplantation—Current Status and Uncertainties: In the past, ABO blood group incompatibility was considered an absolute contraindication for kidney transplantation. Progress in defined desensitization practice and immunologic understanding has allowed increasingly successful ABO incompatible transplantation during recent years. This paper focused on the history, disserted outcomes, desensitization modalities and protocols, posttransplant immunologic surveillance, and antibody-mediated rejection in transplantation with an ABO incompatible kidney allograft. The mechanism underlying accommodation and antibody-mediated injury was also described (read more).

The renaissance of the trans-vivo delayed-type hypersensitivity (DTH) assay.

“Tip-Toeing” to an Assay for Transplantation Tolerance?

In 2000, Orosz and colleagues published a seminal paper using a trans-vivo delayed-type hypersensitivity (DTH) assay to investigate the immunological basis of human allograft acceptance (1). Donor-specific DTH responses, elicited by the indirect pathway of alloantigen presentation, were measured after injection of recipient peripheral blood mononuclear cells (PBMCs) and donor-cell lysate into the footpad of severe combined immunodeficient (SCID) mice. PBMCs from rejecting individuals triggered strong swelling reactions associated with humancell retention and mouse neutrophil recruitment whereas PBMCs from clinically tolerant recipients induced reduced or no DTH responses. PBMCs from tolerant recipients retained normal DTH responses to recall antigens such as tetanus/diphtheria toxoid or Epstein–Barr virus, but these responses were suppressed in a TGFb- and IL-10-dependent manner when donor and third-party antigens were co-injected. The demonstration that allograft acceptance was associated with reduced donor-specific DTH responses and also with increased linked-suppression provided evidence that immune regulation was an important mechanism for renal allograft acceptance in humans (read more)

Recurrence of Type 1 Diabetes After Simultaneous Pancreas–Kidney Transplantation in the Absence of GAD and IA-2 Autoantibodies:

We report herein the patterns of type 1 diabetes recurrence in a simultaneous pancreas–kidney transplant (SPK) recipient, in the absence of rejection. A 38-year-old female underwent SPK for end-stage nephropathy secondary to type 1 diabetes. Fasting blood glucose, HbA1c, fructosamine, C-peptide and autoantibodies (GAD-65, IA-2) were monitored throughout follow-up. At 3.5 years post-SPK, HbA1c and fructosamine increased sharply, indicating loss of perfect metabolic control, despite C-peptide levels in the normal-high range. Exogenous insulin was restarted 4 months later. C-peptide levels abruptly fell and became undetectable at 5.5 years. Autoantibody levels, which were undetectable at the time of SPK, never converted to positivity. Pancreas retranspantation was performed at 6 years. The failed pancreas graft had a normal macroscopic appearance. On histology, there were no signs of cellular or humoral rejection in the kidney or pancreas. A selective peri-islet lymphocytic infiltrate was observed, together with near-total destruction of β cells. At 2.5 years post retransplantation, pancreatic graft function is perfect. This observation indicates unequivocally that pancreas graft can be lost to recurrence of type 1 diabetes in the absence of rejection. GAD-65 and IA-2 autoantibodies are not reliable markers of autoimmunity recurrence.

Advances in Direct T-Cell Alloreactivity: Function, Avidity, Biophysics and Structure

Although T-cell-based adaptive immunity plays a crucial role in protection against infectious pathogens and uncontrolled outgrowth of malignant cells, a large portion of these T cells are also capable of responding to allogeneic HLA molecules, violating the paradigm of self-major histocompatibility complex (MHC) restriction. Recent studies have provided insights into the mechanisms by which these T cells recognize allogeneic targets. The role of antiviral T cells in direct alloreactivity through peptide-dependent molecular mimicry and alternate peptide-MHC docking modes has emerged as major models for the human alloresponse. Here, we review in depth recent advances in this field and discuss how molecular interactions between T cells and HLA molecules drive the activation of these effector cells and its potential implications for alloreactivity in human transplantation (read more).

Not very related to transplantation, but a useful insight on how vaccination can trigger anti-HLA antibodies....

Alloantibodies against MHC Class I: A Novel Mechanism of Neonatal Pancytopenia Linked to Vaccination

da Journal of Immunology

Fetal/neonatal alloimmune thrombocytopenia is a frequent disease in humans where alloantibodies against platelet Ags lead to platelet destruction and hemorrhage. Although a role in the disease for Abs against MHC has been suspected, this has not been formally demonstrated. Since 2007, a hemorrhagic syndrome due to thrombocytopenia and designated as bovine neonatal pancytopenia (BNP) has been recognized in calves in several European countries. An inactivated antiviral vaccine is strongly suspected to be involved in this syndrome because of its highly frequent use in the dams of affected calves. In this study, we show that BNP is an alloimmune disease, as we reproduced the signs by transferring serum Abs from vaccinated BNP dams into healthy neonatal calves. Ab specificity was strongly associated with the presence of allogeneic MHC class I Abs in the dams. MHC class I staining was also observed on Madin–Darby bovine kidney cells, a cell line related to the one used to produce the vaccine Ag. Our report emphatically demonstrates that alloimmunization against MHC class I is associated with a substantial risk of developing cytopenia-associated syndromes in neonates when a cell line of the same species is used to produce an inactivated vaccine injected into the mother (read more).

Paired kidney transplantation

A slideset presented at the Donor's Surgeon meeting held in Naples, Italy, on Nov 30-Dec 2 2011.
Download here (Microsoft PowerPoint 2007 or higher required).

EpHLA: An innovative and user-friendly software automating the HLAMatchmaker algorithm for antibody analysis

The global challenge for solid organ transplantation programs is to distribute organs to the highly sensitized recipients. The purpose of this work is to describe and test the functionality of the EpHLA software, a program that automates the analysis of acceptable and unacceptable HLA epitopes on the basis of the HLAMatchmaker algorithm. HLAMatchmaker considers small configurations of polymorphic residues referred to as eplets as essential components of HLA-epitopes. Currently, the analyses require the creation of temporary files and the manual cut and paste of laboratory tests results between electronic spreadsheets, which is time-consuming and prone to administrative errors. RESULTS: The EpHLA software was developed in Object Pascal programming language and uses the HLAMatchmaker algorithm to generate histocompatibility reports. The automated generation of reports requires the integration of files containing the results of laboratory tests (HLA typing, anti-HLA antibody signature) and public data banks (NMDP, IMGT). The integration and the access to this data were accomplished by means of the framework called eDAFramework. The eDAFramework was developed in Object Pascal and PHP and it provides data access functionalities for software developed in these languages. The tool functionality was successfully tested in comparison to actual, manually derived reports of patients from a renal transplantation program with related donors. CONCLUSIONS: We successfully developed software, which enables the automated definition of the epitope specificities of HLA antibodies. This new tool will benefit the management of recipient/donor pairs selection for highly sensitized patients. (read more)

HLA alleles and drug hypersensitivity reactions

The human leucocyte antigen (HLA) system is well known for its association with certain diseases such as ankylosing spondylitis, celiac disease and many others. More recently, severe and even fatal drug hypersensitivity reactions linked to particular HLA alleles have been discovered. The significance of these discoveries has led the European Medicines Agency (EMA) and its member state agencies to recommend HLA gene testing before initiation of drug treatment. To date, the following drugs have been identified as causing significant drug hypersensitivity reactions in patients who have the following HLA alleles: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02/A*31:01 and finally allopurinol and HLA-B*58:01. This review will outline and discuss these three drugs and their associated HLA alleles as well as examine the pathogenesis of the drug hypersensitivity reactions (read more).

Frequency and prognostic value of D alloantibodies after D-mismatched allogeneic hematopoietic stem cell transplantation after reduced-intensity conditioning:

BACKGROUND: Due to the fact that the ABO and D system is inherited independently from the HLA system, approximately 40% of allogeneic hematopoietic stem cell transplants (HSCT) are performed across the blood group barrier. Reports on the development of de novo anti-D in patients undergoing reduced-intensity conditioning (RIC) followed by D-mismatched allogeneic HSCT are rare. The objective of this study was to evaluate the frequency of anti-D alloimmunization after D-mismatched HSCT following RIC and its prognostic impact on transplant outcome. STUDY DESIGN AND METHODS: Forty patients with hematologic diseases who underwent D-mismatched HSCT were retrospectively analyzed: 19 D− patients with a D+ donor and 21 D+ patients with a D− donor. Routine serologic testing for blood group typing and antibody screening was performed by a column agglutination method every time when transfusion of red blood cell units was requested and in the posttransplantation course to demonstrate establishment of donor ABO type and to detect alloimmunization. RESULTS: After a median serologic follow-up of 21 (range, 0 to 73) months after HSCT, anti-D was identified in 2 of 21 (10%) D+ patients receiving a D− transplant, 23 and 34 months after HSCT. None of the 19 D− patients with a D+ donor developed an anti-D. CONCLUSION: We observed an infrequent de novo anti-D formation that is more likely in D+ recipients of D− grafts. However, the development of anti-D does not normally impair the transplant outcome and is not of clinical relevance in the posttransplant course. (read more)

Haploidentical hematopoietic transplantation: current status and future perspectives:
For patients with hematologic malignancies at high risk of relapse who do not have matched donors, a suitable alternative stem cell source is the HLAhaploidentical 2 or 3-loci mismatched family donor who is readily available for nearly all patients. Transplantation across the major HLA barrier is associated with strong T-cell alloreactions, which were originally manifested as a high incidence of severe GVHD and graft rejection. The present review shows how these obstacles to successful transplantation were overcome in the last 15 years, making full haplotype-mismatched transplantation a clinical reality that provides similar outcomes to transplantation from matched unrelated donors. The review also discusses the advantages and drawbacks of current options for full haplotypemismatched transplantation and highlights innovative approaches for re-building immunity after transplantation and improving survival (read more)