Browse
Submit Data
Databases
API
Help

Dataset Information

6 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction.

ABSTRACT: T-cell products derived from third-party donors are clinically applied, but harbor the risk of off-target toxicity via induction of allo-HLA cross-reactivity directed against mismatched alleles. We used third-party donor-derived virus-specific T cells as model to investigate whether virus-specificity, HLA restriction and/or HLA background can predict the risk of allo-HLA cross-reactivity. Virus-specific CD8^pos T cells were isolated from HLA-A^*01:01/B^*08:01 or HLA-A^*02:01/B^*07:02 positive donors. Allo-HLA cross-reactivity was tested using an EBV-LCL panel covering 116 allogeneic HLA molecules and confirmed using K562 cells retrovirally transduced with single HLA-class-I alleles of interest. HLA-B^*08:01-restricted T cells showed the highest frequency and diversity of allo-HLA cross-reactivity, regardless of virus-specificity, which was skewed toward multiple recurrent allogeneic HLA-B molecules. Thymic selection for other HLA-B alleles significantly influenced the level of allo-HLA cross-reactivity mediated by HLA-B^*08:01-restricted T cells. These results suggest that the degree and specificity of allo-HLA cross-reactivity by T cells follow rules. The risk of off-target toxicity after infusion of incompletely matched third-party donor-derived virus-specific T cells may be reduced by selection of T cells with a specific HLA restriction and background.

SUBMITTER: Huisman W

PROVIDER: S-EPMC8039299 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity.

Project description:We hypothesized that third-party fecal microbiota transplantation (FMT) may restore intestinal microbiome diversity after allogeneic hematopoietic cell transplantation (allo-HCT). In this open-label single-group pilot study, 18 subjects were enrolled before allo-HCT and planned to receive third-party FMT capsules. FMT capsules were administered no later than 4 weeks after neutrophil engraftment, and antibiotics were not allowed within 48 hours before FMT. Five patients did not receive FMT because of the development of early acute gastrointestinal (GI) graft-versus-host disease (GVHD) before FMT (n = 3), persistent HCT-associated GI toxicity (n = 1), or patient decision (n = 1). Thirteen patients received FMT at a median of 27 days (range, 19-45 days) after HCT. Participants were able to swallow and tolerate all FMT capsules, meeting the primary study endpoint of feasibility. FMT was tolerated well, with 1 treatment-related significant adverse event (abdominal pain). Two patients subsequently developed acute GI GVHD, with 1 patient also having concurrent bacteremia. No additional cases of bacteremia occurred. Median follow-up for survivors is 15 months (range, 13-20 months). The Kaplan-Meier estimates for 12-month overall survival and progression-free survival after FMT were 85% (95% confidence interval, 51%-96%) and 85% (95% confidence interval, 51%-96%), respectively. There was 1 nonrelapse death resulting from acute GI GVHD (12-month nonrelapse mortality, 8%; 95% confidence interval, 0%-30%). Analysis of stool composition and urine 3-indoxyl sulfate concentration indicated improvement in intestinal microbiome diversity after FMT that was associated with expansion of stool-donor taxa. These results indicate that empiric third-party FMT after allo-HCT appears to be feasible, safe, and associated with expansion of recipient microbiome diversity. This trial was registered at www.clinicaltrials.gov as #NCT02733744.

| S-EPMC5894265 | biostudies-literature

Infectious pathogens may trigger specific allo-HLA reactivity via multiple mechanisms.

Project description:Transplant recipients can be sensitized against allo-HLA antigens by previous transplantation, blood transfusion, or pregnancy. While there is growing awareness that multiple components of the immune system can act as effectors of the alloresponse, the role of infectious pathogen exposure in triggering sensitization and allograft rejection has remained a matter of much debate. Here, we describe that exposure to pathogens may enhance the immune response to allogeneic HLA antigens via different pathways. The potential role of allo-HLA cross-reactivity of virus-specific memory T cells, activation of innate immunity leading to a more efficient induction of the adaptive alloimmune response by antigen-presenting cells, and bystander activation of existing memory B cell activation will be discussed in this review.

| S-EPMC5537314 | biostudies-other

The impact of belatacept on third-party HLA alloantibodies in highly sensitized kidney transplant recipients.

Project description:Recent evidence suggests that belatacept reduces the durability of preexisting antibodies to class I and class II human leukocyte antigens (HLAs). In this case series of 163 highly sensitized kidney transplant candidates whose calculated panel-reactive antibody (cPRA) activity was ?98% to 100%, the impact of belatacept on preexisting HLA antibodies was assessed. Of the 163 candidates, 72 underwent transplantation between December 4, 2014 and April 15, 2017; 60 of these transplanted patients remained on belatacept consecutively for at least 6 months. We observed a decrease in the breadth and/or strength of HLA class I antibodies as assessed by FlowPRA in belatacept-treated patients compared to controls who did not receive belatacept. Specifically, significant HLA antibody reduction was evident for class I (P < .0009). Posttransplant belatacept-treated patients also had a clinically significant reduction in their cPRA compared to controls (P < .01). Collectively, these findings suggest belatacept can reduce HLA class I antibodies in a significant proportion of highly sensitized recipients and could be an option to improve pretransplant compatibility with organ donors.

| S-EPMC6984982 | biostudies-literature

No third-party punishment in chimpanzees.

Project description:Punishment can help maintain cooperation by deterring free-riding and cheating. Of particular importance in large-scale human societies is third-party punishment in which individuals punish a transgressor or norm violator even when they themselves are not affected. Nonhuman primates and other animals aggress against conspecifics with some regularity, but it is unclear whether this is ever aimed at punishing others for noncooperation, and whether third-party punishment occurs at all. Here we report an experimental study in which one of humans' closest living relatives, chimpanzees (Pan troglodytes), could punish an individual who stole food. Dominants retaliated when their own food was stolen, but they did not punish when the food of third-parties was stolen, even when the victim was related to them. Third-party punishment as a means of enforcing cooperation, as humans do, might therefore be a derived trait in the human lineage.

| S-EPMC3443148 | biostudies-literature

Allo-Specific Humoral Responses: New Methods for Screening Donor-Specific Antibody and Characterization of HLA-Specific Memory B Cells.

Project description:Antibody-mediated allograft rejection (AMR) causes more kidney transplant failure than any other single cause. AMR is mediated by antibodies recognizing antigens expressed by the graft, and antibodies generated against major histocompatibility complex (MHC) mismatches are especially problematic. Most research directed towards the management of clinical AMR has focused on identifying and characterizing circulating donor-specific HLA antibody (DSA) and optimizing therapies that reduce B-cell activation and/or block antibody secretion by inhibiting plasmacyte survival. Here we describe a novel set of reagents and techniques to allow more specific measurements of MHC sensitization across different animal transplant models. Additionally, we have used these approaches to isolate and clone individual HLA-specific B cells from patients sensitized by pregnancy or transplantation. We have identified and characterized the phenotypes of individual HLA-specific B cells, determined the V(D)J rearrangements of their paired H and L chains, and generated recombinant antibodies to determine affinity and specificity. Knowledge of the BCR genes of individual HLA-specific B cells will allow identification of clonally related B cells by high-throughput sequence analysis of peripheral blood mononuclear cells and permit us to re-construct the origins of HLA-specific B cells and follow their somatic evolution by mutation and selection.

| S-EPMC8313870 | biostudies-literature

Single umbilical cord blood with or without CD34<sup>+</sup> cells from a third-party donor in adults with leukemia.

Project description:We retrospectively compared the clinical outcomes of adults with acute leukemia who received single-unit umbilical cord blood (UCB) transplantation (sUCBT) (n = 135) or stem cell transplant using coinfusion of a UCB graft with CD34+ cells from a third-party donor (Haplo-Cord) (n = 72) at different institutions within the Grupo Español de Trasplante Hematopoyético. In multivariable analysis, patients in the Haplo-Cord group showed more rapid neutrophil (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.5-3.3; P < .001) and platelet recovery (HR, 1.6; 95% CI, 1.2-2.3; P = .015) and lower incidence of chronic graft-versus-host disease (GVHD) (relative risk, 0.5; 95% CI, 0.3-0.8; P = .01). Nonrelapse mortality, relapse, disease-free survival (DFS), and GVHD/relapse-free survival were similar in the 2 groups. Regarding disease-specific outcomes, DFS in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients was not significantly different; however, a significantly higher relapse rate was found in patients with AML treated with Haplo-Cord (HR, 2.3; 95% CI, 1-5.4; P = .04). Our study confirms that Haplo-Cord was an effective strategy to accelerate neutrophil and platelet recovery and shows that, in the context of specific treatment platforms, sUCBT and Haplo-Cord offer similar long-term outcomes.

| S-EPMC5728323 | biostudies-literature

Curated eutherian third party data gene data sets.

Project description:The free available eutherian genomic sequence data sets advanced scientific field of genomics. Of note, future revisions of gene data sets were expected, due to incompleteness of public eutherian genomic sequence assemblies and potential genomic sequence errors. The eutherian comparative genomic analysis protocol was proposed as guidance in protection against potential genomic sequence errors in public eutherian genomic sequences. The protocol was applicable in updates of 7 major eutherian gene data sets, including 812 complete coding sequences deposited in European Nucleotide Archive as curated third party data gene data sets.

| S-EPMC4707174 | biostudies-literature

Identification of a tumor-specific allo-HLA-restricted ??TCR.

Project description:??T cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of cancer. However, the biological mechanisms of how ??T-cell receptors (TCRs) interact with their ligands are poorly understood. Within this context, we describe the novel allo-HLA-restricted and CD8?-dependent V?5V?1TCR. In contrast to the previous assumption of the general allo-HLA reactivity of a minor fraction of ??TCRs, we show that classic anti-HLA-directed, ??TCR-mediated reactivity can selectively act on hematological and solid tumor cells, while not harming healthy tissues in vitro and in vivo. We identified the molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 as the essential determinant for recognition and describe the critical role of CD8 as a coreceptor. We conclude that alloreactive ??T-cell repertoires provide therapeutic opportunities, either within the context of haplotransplantation or as individual ??TCRs for genetic engineering of tumor-reactive T cells.

| S-EPMC6784524 | biostudies-literature

Molecular Classification of AIDS-Related Lymphomas [including third-party data]

Project description:Gene expression profiling (GEP) of ARL patient samples was done to determine whether gene expression signatures derived from HIV- lymphomas retained their ability to molecularly classify HIV+ lymphomas. The GEP-based predictors robustly classified ARL tumors, distinguishing molecular Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as well as activated B-cell-like (ABC) and germinal center B-cell-like (GCB) molecular subtypes of DLBCL. Gene expression profiles were used to identify coordinately regulated gene sets and pathways that differ between HIV+ and HIV- lymphomas of corresponding molecular subtype. Frozen tumor biopsies were obtained from 20 HIV-positive patients with an AIDS-defining lymphoma. Cases were ascertained at the University of Nebraska Medical Center and through the NCI AIDS and Cancer Specimen Resource tumor bank. Sufficient RNA for hybridization to Affymetrix U133 plus 2 arrays was obtained on 17 ARL cases. Details of all 20 HIV-positive patients can be found in the supplementary file below. Third party array data from HIV- lymphomas of corresponding molecular subtype were used for the comparison and molecular classification of the HIV+ cases in this study. The third party HIV- lymphoma samples include the following. [1] HIV- lymphoma, BL cases: 84 samples profiled on the Affymetrix HG U133 Plus 2 array. The data are publicly available on the website companion to Dave et al. NEJM 2006; Volume 354:13-24 (http://llmpp.nih.gov/BL/) and were used 'as is' (ie, not reanalyzed). [2] HIV- lymphoma, DLBCL cases: 200 of the 414 cases in Series GSE10846 (listed in the supplementary file below). These included all R-CHOP treated cases of either ABC or GCB subtype. These data were also used as is. These data were published in Lenz et al. NEJM 2008; Volume 359: 2313-2323.

2012-07-17 | E-GEOD-17372 | biostudies-arrayexpress

'To quarterback behind the scenes, third-party efforts': the tobacco industry and the Tea Party.

Project description:BackgroundThe Tea Party, which gained prominence in the USA in 2009, advocates limited government and low taxes. Tea Party organisations, particularly Americans for Prosperity and FreedomWorks, oppose smoke-free laws and tobacco taxes.MethodsWe used the Legacy Tobacco Documents Library, the Wayback Machine, Google, LexisNexis, the Center for Media and Democracy and the Center for Responsive Politics (opensecrets.org) to examine the tobacco companies' connections to the Tea Party.ResultsStarting in the 1980s, tobacco companies worked to create the appearance of broad opposition to tobacco control policies by attempting to create a grassroots smokers' rights movement. Simultaneously, they funded and worked through third-party groups, such as Citizens for a Sound Economy, the predecessor of AFP and FreedomWorks, to accomplish their economic and political agenda. There has been continuity of some key players, strategies and messages from these groups to Tea Party organisations. As of 2012, the Tea Party was beginning to spread internationally.ConclusionsRather than being a purely grassroots movement that spontaneously developed in 2009, the Tea Party has developed over time, in part through decades of work by the tobacco industry and other corporate interests. It is important for tobacco control advocates in the USA and internationally, to anticipate and counter Tea Party opposition to tobacco control policies and ensure that policymakers, the media and the public understand the longstanding connection between the tobacco industry, the Tea Party and its associated organisations.

| S-EPMC3740007 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data