{"doi":"10.17615/1jc5-ck58","title":"Ex vivo Inhibition of NF-κB Signaling in Alloreactive T-cells Prevents Graft-Versus-Host Disease","abstract":"The ex vivo induction of alloantigen-specific hyporesponsiveness by costimulatory pathway blockade or exposure to immunoregulatory cytokines has been shown to inhibit proliferation, IL-2 production, and the GVHD capacity of adoptively transferred T-cells. We hypothesized that inhibition of the intracellular NF-κB pathway in alloreactive T-cells, which is critical for T cell activation events including IL-2 transcription, could lead to alloantigen hyporesponsiveness and loss of GVHD capacity. We demonstrate that treatment of mixed lymphocyte reaction (MLR) cultures with PS1145, a potent inhibitor of NF-κB activation, can induce T cell hyporesponsiveness to alloantigen in primary and secondary responses while preserving in vitro responses to potent mitogenic stimulation. GVHD lethality in recipients of ex vivo PS1145-treated cells was profoundly inhibited. Parking of control- or PS1145- treated MLR cells in syngeneic Rag−/− recipients resulted in intact contact hypersensitivity responses. However, GVHD lethality capacity also was restored, suggesting that lymphopenic expansion uncoupled alloantigen hyporesponsiveness. These results indicate that the NF-κB pathway is a critical regulator of alloresponses and provide a novel small molecule inhibitor based approach that is effective in preventing early post-transplant GVHD lethality but that also permits donor T cell responses to recover after a period of lymphopenic expansion.","journal":"UNC Libraries","year":2020,"id":139194,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":408391,"name":"A. S. Baldwin","orcid":null,"position":1,"is_corresponding":false},{"id":538643,"name":"R. Sitcheran","orcid":null,"position":2,"is_corresponding":false},{"id":602476,"name":"E. Palmer","orcid":null,"position":3,"is_corresponding":false},{"id":602477,"name":"B. Jaffee","orcid":null,"position":4,"is_corresponding":false},{"id":538642,"name":"W. J. Murphy","orcid":null,"position":5,"is_corresponding":false},{"id":602478,"name":"Lan Dang","orcid":null,"position":6,"is_corresponding":false},{"id":537974,"name":"Matthew J. O’Shaughnessy","orcid":"0000-0001-6380-0839","position":7,"is_corresponding":false},{"id":538646,"name":"J. S. Serody","orcid":null,"position":8,"is_corresponding":false},{"id":538644,"name":"B. R. Blazar","orcid":null,"position":9,"is_corresponding":false},{"id":20830,"name":"K. Sun","orcid":null,"position":10,"is_corresponding":false},{"id":602475,"name":"C. Vogtenhuber","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:10.185988Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}