A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer's Disease.

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer's disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aß1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin's effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.

Changes in pulmonary and plasma oxidative stress and inflammation following eccentric and concentric cycling in stable COPD patients.

PURPOSE: The purpose of this study was to compare pulmonary and plasma markers of oxidative stress and inflammation after concentric and eccentric cycling bouts in individuals with chronic obstructive pulmonary disease (COPD). METHODS: Ten patients with moderate COPD level (68.3 ± 9.1 years; forced expiratory volume in 1 s = 68.6 ± 20.4% of predicted) performed 30 min of moderate-intensity concentric (CONC-M: 50% maximum concentric cycling power output; POmax) and eccentric cycling (ECC-M: 50% POmax), and high-intensity eccentric cycling (ECC-H: 100% POmax) in a randomised order. Cardiometabolic demand was monitored during cycling. Indirect markers of muscle damage were assessed before, immediately after, 24 and 48 h after cycling (muscle strength, muscle soreness and creatine kinase activity). Plasma oxidative stress (malondialdehyde: MDA), antioxidant (glutathione peroxidase activity: GPx) and inflammatory markers (IL-6, TNF-α) were measured before and 5 min after cycling. Exhaled breath condensate (EBC) samples were collected before and 15 min after cycling and analysed for hydrogen peroxide (H2O2), nitrites (NO2-) and pH. RESULTS: Cardiometabolic demand was 40-50% lesser for ECC-M than CONC-M and ECC-H. Greater muscle damage was induced after ECC-H than ECC-M and CONC-M. MDA decreased immediately after CONC-M (- 28%), ECC-M (- 14%), and ECC-H (- 17%), while GPx remained unchanged. IL-6 increased only after ECC-H (28%), while TNF-α remained unchanged after exercise. Pulmonary H2O2, NO2- and pH remained unchanged after exercise. CONCLUSION: These results suggest that only moderate muscle damage and inflammation were induced after high-intensity eccentric cycling, which did not induce pulmonary or plasmatic increases in markers of oxidative stress. TRIAL REGISTRATION NUMBER: Trial registration number: DRKS00009755.

Toll-Like Receptor 2 Promoter -196 to -174 Deletion Affects CD4 Levels Along Human Immunodeficiency Virus Infection Progression.

Toll-like receptor 2 (TLR2) plays a key role in innate immune response recognizing molecular patterns expressed by pathogens. rs111200466 is a TLR2 promoter insertion/deletion polymorphism with contradictory data about its role in human immunodeficiency virus type 1 (HIV-1) infection. We analyzed rs111200466 in HIV-1 disease progression and showed a correlation with a faster progression to the CD4+ < 200 cells/µL outcome for deletion allele carriers (Cox regression analysis: hazard ratio, 2.4 [95% confidence interval, 1.4-4]; P = .001). When naive patients with CD4+ < 200 cells/µL started antiretroviral treatment, rs111200466-deletion carriers showed a trend toward a slower, recovery rate (time required to reach CD4+ > 350 cells/µL; Cox P = .36). Our data suggest rs111200466 as a prognosis factor for HIV-1 disease progression.

Pulmonary sarcoidosis is associated with exosomal vitamin D-binding protein and inflammatory molecules.

BACKGROUND: Sarcoidosis is an inflammatory granulomatous disorder characterized by accumulation of TH1-type CD4+ T cells and immune effector cells within affected organs, most frequently the lungs. Exosomes are extracellular vesicles conveying intercellular communication with possible diagnostic and therapeutic applications. OBJECTIVES: We aimed to provide an understanding of the proinflammatory role of bronchoalveolar lavage fluid (BALF) exosomes in patients with sarcoidosis and to find candidates for disease biomarkers. METHODS: We performed a mass spectrometric proteomics characterization of BALF exosomes from 15 patients with sarcoidosis and 5 healthy control subjects and verified the most interesting results with flow cytometry, ELISA, and Western blot analyses in an additional 39 patients and 22 control subjects. RESULTS: More than 690 proteins were identified in the BALF exosomes, several of which displayed significant upregulation in patients, including inflammation-associated proteins, such as leukotriene A4 hydrolase. Most of the complement-activating factors were upregulated, whereas the complement regulator CD55 was seen less in patients compared with healthy control subjects. In addition, for the first time, we detected vitamin D-binding protein in BALF exosomes, which was more abundant in patients. To evaluate exosome-associated vitamin D-binding protein as a biomarker for sarcoidosis, we investigated plasma exosomes from 23 patients and 11 healthy control subjects and found significantly higher expression in patients. CONCLUSION: Together, these data contribute to understanding the role of exosomes in lung disease and provide suggestions for highly warranted sarcoidosis biomarkers. Furthermore, the validation of an exosome-associated biomarker in the blood of patients provides novel, and less invasive, opportunities for disease diagnosis.

Control of Drosophila endocycles by E2F and CRL4(CDT2).

Endocycles are variant cell cycles comprised of DNA synthesis (S)- and gap (G)-phases but lacking mitosis. Such cycles facilitate post-mitotic growth in many invertebrate and plant cells, and are so ubiquitous that they may account for up to half the world's biomass. DNA replication in endocycling Drosophila cells is triggered by cyclin E/cyclin dependent kinase 2 (CYCE/CDK2), but this kinase must be inactivated during each G-phase to allow the assembly of pre-Replication Complexes (preRCs) for the next S-phase. How CYCE/CDK2 is periodically silenced to allow re-replication has not been established. Here, using genetic tests in parallel with computational modelling, we show that the endocycles of Drosophila are driven by a molecular oscillator in which the E2F1 transcription factor promotes CycE expression and S-phase initiation, S-phase then activates the CRL4(CDT2) ubiquitin ligase, and this in turn mediates the destruction of E2F1 (ref. 7). We propose that it is the transient loss of E2F1 during S phases that creates the window of low Cdk activity required for preRC formation. In support of this model overexpressed E2F1 accelerated endocycling, whereas a stabilized variant of E2F1 blocked endocycling by deregulating target genes, including CycE, as well as Cdk1 and mitotic cyclins. Moreover, we find that altering cell growth by changing nutrition or target of rapamycin (TOR) signalling impacts E2F1 translation, thereby making endocycle progression growth-dependent. Many of the regulatory interactions essential to this novel cell cycle oscillator are conserved in animals and plants, indicating that elements of this mechanism act in most growth-dependent cell cycles.

IgG subclass profile among anti-Glutathione S-transferase T1 antibodies in post-transplant de novo immune hepatitis.

Although the pathogenic pathways leading to de novo immune hepatitis (IH) are not completely understood, we have shown strong evidences of an antidonor response against Glutathione S-transferase T1 (GSTT1), an antigen exclusively expressed in the donor liver. The first sign of this process is the production of GSTT1 antibodies that, in 25% of the cases, will precede de novo IH. Because the presence of the antibodies is not sufficient to trigger the disease, we aimed to study GSTT1 IgG subclasses in a group of 18 liver transplant patients, 12 that developed de novo IH and 6 that remained free of disease. Surprisingly, the predominant subclasses were IgG1-GSTT 1 and IgG4-GSTT 1. The presence of IgG4-expressing plasma cells was also investigated in 10 available liver biopsies. Six biopsies coinciding with diagnosis showed a mean value of 32.8 IgG4+ plasma cells/hpf vs. 5.55 in patients without the disease. We have not found a distinctive GSTT1-IgG profile in patients with de novo IH, but the ratio IgG1-GSTT 1 /IgG4-GSTT 1 in samples from close to the time of diagnosis seemed to be important. The novel finding of abundant IgG4-GSTT 1 in liver transplantation is intriguing, but their possible role in pathogenesis of de novo IH remains unknown.

Lethality of Opioid Overdose in a Community Cohort of Young Heroin Users.

BACKGROUND: The aim of the study was to estimate the lethality of opioid overdose among young heroin users. METHODS: A prospective community cohort study was conducted in Barcelona and Madrid, Spain. Participants included 791 heroin users aged 18-30 years who were followed up between 2001 and 2006. Fatal overdoses were identified by record linkage of the cohort with the general mortality register, while non-fatal overdoses were self-reported at baseline and follow-up interviews. The person-years (py) at risk were computed for each participant. Fatal and non-fatal overdose rates were estimated by city. Transition towards injection shortly before the overdose could not be measured. Overdose lethality (rate of fatal overdose in proportion to total overdose) and its 95% CI was estimated using Bayesian models. RESULTS: The adjusted rates of fatal and non-fatal opioid overdose were 0.7/100 py (95% CI: 0.4-1.1) and 15.8/100 py (95% CI: 14.3-17.6), respectively. The adjusted lethality was 4.2% (95% CI: 2.5-6.5). CONCLUSIONS: Four out of 100 opioid overdoses are fatal. These are preventable deaths that could be avoided before or after the overdose takes place. Resources are urgently needed to prevent fatal opioid overdose.

Mismatch on glutathione S-transferase T1 increases the risk of graft-versus-host disease and mortality after allogeneic stem cell transplantation.

Several drug-metabolizing enzymes, preferentially expressed in the liver, have the potential to act as minor histocompatibility antigens. In the present study, we analyzed the impact of glutathione S-transferase T1 (GSTT1), glutathione S-transferase M1, glutathione S-transferase P1, and UDP glucuronosyl transferase 2B17 (UGT2B17) disparities on the outcome of 125 patients undergoing allogeneic hematopoietic stem cell transplantation. Grades 2 to 4 acute graft-versus-host disease (aGVHD) developed in 56.2% versus 73.3% of GSTT1-matched versus mismatched patients (P = .048). Remarkably, 8.6% GSTT1-matched patients developed grades 2 to 4 liver aGVHD, compared with 36.8% among GSTT1-mismatched recipients (P < .001). Regarding chronic graft-versus-host disease (cGVHD), 34.8% versus 70.7% matched versus mismatched patients developed overall cGVHD (P = .038) and 16.3% versus 48% developed hepatic cGVHD (P = .006). We also found a strong association between the UGT2B17 mismatch and the risk of severe aGVHD (P = .001), especially with gut involvement (P < .001). Most striking was the influence of the GSTT1 mismatch on nonrelapse mortality (26.8% versus 52.6%, P = .031) and overall survival (62% versus 36.9%, P = .045). In summary, UGT2B17 and GSTT1 mismatch are risk factors for the development of GVHD and the latter also influences on mortality and survival after allogeneic transplantation from HLA-identical donors.

The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study).

BACKGROUND & AIMS: It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). OBJECTIVE: To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. PATIENTS AND METHODS: In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. RESULTS: It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. CONCLUSIONS: Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.

An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

Unlocking New Avenues in Breast Cancer Treatment: The Synergy of Kinase Inhibitors and Immunotherapy.

Cancer is one of the world's most significant health problems today. Currently, breast cancer has globally surpassed lung cancer as the most commonly diagnosed cancer in women. In 2020, an estimated 2,261,419 new cases were diagnosed in women worldwide. Therefore, there is a need to understand the processes that can help us better treat this disease. In recent years, research in the fight against cancer has often been based on two treatment modalities. One of them is the use of protein kinase inhibitors, which have been instrumental in the development of new therapeutic strategies. Another crucial route is the use of immunotherapy, which has been touted as a great promise for cancer treatment. Protein kinase alterations can interfere with the effectiveness of other treatments, such as immunotherapy. In this review, we will analyze the role played by protein kinase alterations in breast cancer and their possible impact on the effectiveness of the response to immunotherapy treatments.

A metagenome-wide association study of HIV disease progression in HIV controllers.

Some HIV controllers experience immunologic progression with CD4+ T cell decline. We aimed to identify genetic factors associated with CD4+ T cell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

Characteristics and outcomes of the Spanish registry for pediatric patients with bicuspid aortic valve (REVAB).

INTRODUCTION AND OBJECTIVES: Bicuspid aortic valve (BAV) disorder is the most common congenital heart disease. The aim of this study was to describe the characteristics of 0- to 18-year olds with BAV in a population-based registry. METHODS: Data from all pediatric patients were obtained from the Spanish registry for pediatric patients with bicuspid aortic valve (REVAB) (< 18 years). For data analysis, patients with BAV were divided into 2 groups by their features: isolated BAV and BAV with associated congenital heart disease. RESULTS: We included 1681 patients from 33 hospitals. Males accounted for 69.6% (n = 1158). Valve morphology was horizontal in 63.4% (n = 1012) and pure (Sievers type 0) in 28.4% (n=469). Isolated BAV was present in 63.7% (n=1060), and concomitant left-sided obstructive lesions in 23.4% (n=390). Interventions were required in 8.6% (n=145). CONCLUSION: These data represent the first large, population-based description of the clinical presentations and outcomes of patients enrolled in the Spanish registry for pediatric patients with bicuspid aortic valve.

Proton Pump Inhibitors and the Risk of Early Aseptic Loosening in Hip and Knee Arthroplasty.

Introduction: The use of proton pump inhibitors (PPIs) has been associated with a higher risk of osteoporotic fractures and non-unions rates. However, the relation between the use of PPIs and the development of aseptic loosening in arthroplasty procedures has not been studied. The objective of this study is to analyze the relation between the use of PPIs, and the risk of early aseptic loosening in total knee arthroplasty (TKA) and total hip arthroplasty (THA). Materials and methods: A nested case-control study was conducted on patients who were subjected THA or TKA in our center between 2010 and 2014. Cases were patients subjected to revision surgery due to early aseptic loosening during the study period. Cases were matched with controls who did not require any type of revision surgery by type of joint replacement (THA/TKA), gender, age (+/- 2 years), and follow-up time (±6 months). Odds Ratios were adjusted to potential confounders. Results: The crude and adjusted ORs (95% CI) of undergoing revision surgery for aseptic loosening following primary total knee arthroplasty or total hip arthroplasty, were 6.25 (2.04-19.23) and 6.10 (1.71-21.73), respectively, for any use PPIs compared with non-users. Crude and adjusted ORs, were 11.6 (2.93-45.88) and 17.1 (2.41-121.66), respectively, for patients with a Proportion of Days Covered (PDC) for PPIs <.5 (Table 2). In addition, the crude and adjusted ORs of undergoing revision surgery, were 5.05 (1.59-16.02) and 5.01 (1.36-18.44), respectively, for patients with a PDC for PPIs ≥.5. Discussion: These results suggest that PPIs should be used with caution in patients with TKA and THA, and that the use of these drugs should not be prolonged unless there was a justifiable indication. Conclusions: The use of PPIs and was associated with a higher risk of early aseptic loosening in patients subjected to THA and TKA.

TGF-beta1 and IL-6 gene polymorphism in Spanish brucellosis patients.

Polymorphisms in the cytokine genes have allowed for the understanding of the genetic determinants in several diseases. We investigated the polymorphism of the transforming growth factor (TGF)-beta1 and IL-6 genes in relation to susceptibility to human brucellosis. We typed 82 Spanish brucellosis patients and 102 healthy controls for TGF-beta1 polymorphisms in codons 10 and 25, and IL-6 promoter polymorphism at position -174 by PCR-SSP methods. The T/T G/G genotype of the TGF-beta1 gene was significantly increased in patients compared to controls (49% vs. 32%) P=0.02; OR=1.99 (1.05-3.80) and the T/C G/G genotype was significantly less common in the patients compared to the controls (32% vs. 49%) P=0.01; OR=0.48 (0.25-0.92). The CC genotype of codon 10 was significantly increased in the patients who had focal forms of the disease as compared with those who did not develop focal forms (19% vs. 4%), P=0.03; OR=0.19 (0.02-1.10). No differences were found in the IL-6 variants between the patients and the controls. These results suggest that polymorphism of the TGF-beta1 gene may be involved in susceptibility to brucellosis and to developing focal forms of the disease in a group of patients from southern Spain.

Prevalence of and risk factors for hepatitis B virus infection among street-recruited young injection and non-injection heroin users in Barcelona, Madrid and Seville.

BACKGROUND: To evaluate the prevalence of hepatitis B virus (HBV) and associated factors in 949 heroin users (HU): injectors (IHUs) and non-injectors (NIHUs). METHODS: Cross-sectional study; structured questionnaire administered by computer-assisted personal interviewing and audio computer-assisted self-interviewing; dry blood samples analysed for the hepatitis B core antigen and hepatitis B surface antigen; bivariate analysis and logistic regression. RESULTS: The prevalence of infection was significantly higher in IHUs (22.5%) than in NIHUs (7.4%) in the three cities. In the logistic analysis of male IHUs, infection was found to be associated with living in Seville, age over 25, foreign nationality, having had a sexual partner who traded sex, hepatitis C virus infection, and having injected for more than 5 years. In female IHUs, HBV infection was associated with age over 25, having injected as the first main route of administration, and having begun to inject before 18 years of age. In NIHUs, the associated factors were female gender, foreign nationality and having been tattooed. In young IHUs, the prevalence of HBV infection remains four times higher than in the general population of the same age group. CONCLUSION: The vaccination strategy urgently needs to be reinforced and redesigned to achieve acceptable control of the HBV infection in the most vulnerable groups, with special attention to immigrants.

Risk of stroke in prescription and other amphetamine-type stimulants use: A systematic review.

INTRODUCTION AND AIMS: Amphetamine-type stimulants (ATS) are a putative cause of stroke with high abuse potential. We aim to systematically review the association between use of ATS and stroke. DESIGN AND METHODS: To assure a sensitive search strategy, a broad definition of ATS was used. Cochrane Plus, EMBASE, IBECS/Lilacs, ISI WOK, Medline and Scopus were searched through 2016. Three researchers independently reviewed studies (Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-analyses). Validity and bias were appraised. RESULTS: Of 3998 articles, four cohort studies and eight case-control studies (CCS) were selected; 11 focused on prescribed or over-the-counter ATS. Current ATS users showed a higher ischaemic stroke risk than non-users in two cohort studies {adjusted rate ratio = 1.6 [95% confidence interval (CI) = 1.1, 2.4] and 3.4 [95% CI = 1.1, 10.6]}. One study observed increased risk of haemorrhagic stroke in former users versus non-users [adjusted rate ratio = 2.3 (95% CI = 1.3, 4.1)]. Higher haemorrhagic stroke risk was seen in two CCS among women using ATS [adjusted odds ratio (aOR) = 16.6 (95% CI = 1.5, 182.2) and 3.9 (95% CI = 1.1, 13.1)]. All-stroke was negatively associated with ATS in another CCS [aOR = 0.4 (95% CI = 0.2, 0.8)] and positively associated in the only study on non-medical ATS [aOR = 3.8 (95% CI = 1.2, 12.6)]. Selection bias and uncontrolled confounding were common. DISCUSSION AND CONCLUSIONS: This is the first systematic review on ATS and stroke. Limited epidemiological evidence suggests that ATS use increases stroke risk. Possible disparities in ATS effect across stroke type and higher effect in women deserve further clarification. Studies on non-medical ATS use should be a priority. [Indave BI, Sordo L, Bravo MJ, Sarasa-Renedo A, Fernández-Balbuena S, De la Fuente L, Sonego M, Barrio G. Risk of stroke in prescription and other amphetamine-type stimulants use: A systematic review. Drug Alcohol Rev 2018;37:56-69].

De novo recipient-specific Glutathione S-transferase T1 antibody development after HLA-identical hematopoietic cell transplantation.

Donor-specific antibodies against Glutathione S-transferase T1 (GSTT1) have been associated with de novo immune hepatitis after liver transplantation. These antibodies have also been found very early in allo-HCT associated with acute hepatic GvHD but in all the cases the donor cells had experienced previous priming through pregnancies. It remained to be explored whether or not primary recognition of the antigen occurs after HCT and what could be the consequences in the long term outcome. We genotyped a cohort of 68 HCT patients and found 11 with the GSTT1 null donor/positive recipient mismatch. After testing 114 serum samples, we found a unique case of a 33-year-old patient transplanted from his HLA-identical sibling donor in which IgG GSTT1 antibodies were detected for the first time on day +178. After stimulation of peripheral blood mononuclear cells with GSTT1 peptides we could demonstrate that this patient also had GSTT1-specific T lymphocytes that became activated upon exposure to the GSTT1 antigen. In this report, we describe the first case in which simultaneous T and B cell response against GSTT1 is developed in HCT although the clinical consequences in GvHD are still unclear.