{"doi":"10.1101/2020.11.18.388595","title":"A short course of Tofacitinib sustains the immunoregulatory effect of CTLA4-Ig in presence of inflammatory cytokines and promotes long-term survival of murine cardiac allografts","abstract":"Abstract Costimulation blockade-based regimens are a promising strategy for management of transplant recipients. However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency of rejection episodes. Recent evidence suggests that inflammatory cytokines contribute to alloreactive T cell activation in a CD28-independent manner, a reasonable contributor to the limited efficacy of CTLA4-Ig. In this study, we investigated the possible synergism of a combined short-term inhibition of cytokine signaling and CD28 engagement on the modulation of rejection. Our results demonstrate that the JAK/STAT inhibitor Tofacitinib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in presence of inflammatory cytokines. Tofacitinib exposure conferred dendritic cells with a tolerogenic phenotype reducing their cytokine secretion and costimulatory molecules expression. JAK inhibition also directly affected T cell activation. In vivo, the combination of CTLA4-Ig and Tofacitinib induced long-term survival of heart allografts and, importantly, it was equally effective when using grafts subjected to prolonged ischemia. Transplant survival correlated with a reduction in effector T cells and intragraft accumulation of regulatory T cells. Collectively, our studies demonstrate a powerful synergism between CTLA4-Ig and Tofacitinib and suggest their combined use is a promising strategy for improved management of transplanted patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":131679,"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":0.9532,"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":389688,"name":"Saami Khalifian","orcid":null,"position":1,"is_corresponding":false},{"id":328911,"name":"Byoung Chol Oh","orcid":"0000-0003-3337-7739","position":2,"is_corresponding":false},{"id":388905,"name":"Yichuan Zhang","orcid":"0000-0003-1199-4162","position":3,"is_corresponding":false},{"id":388906,"name":"Devin Miller","orcid":"0000-0002-2896-3955","position":4,"is_corresponding":false},{"id":388907,"name":"Sarah E. Beck","orcid":"0000-0002-6376-5276","position":5,"is_corresponding":false},{"id":388908,"name":"Gerald Brandacher","orcid":"0000-0001-7790-441X","position":6,"is_corresponding":false},{"id":388909,"name":"Giorgio Raimondi","orcid":"0000-0003-1373-2203","position":7,"is_corresponding":false},{"id":388904,"name":"Marcos Iglesias","orcid":"0000-0002-7523-5950","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-18T23:16:03.875886Z","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":[]}