{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:47:16Z","timestamp":1788788836074,"version":"build-2803163510"},"reference-count":73,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Graft versus host disease (GvHD) is a major clinical problem with a significant unmet medical need. We examined the role of cytotoxic T lymphocyte antigen-4 (CTLA-4) in a xenogenic GvHD (xeno-GvHD) model induced by injection of human peripheral mononuclear cells (hPBMC) into irradiated non-obese diabetic (NOD) SCID gamma (NSG) mice. Targeting the CTLA-4 pathway by treatment with CTLA-4 immunoglobulin (Ig) prevented xeno-GvHD, while anti-CTLA-4 antibody treatment exacerbated the lethality and morbidity associated with GvHD. Xeno-GvHD is associated with infiltration of hPBMCs into the lungs, spleen, stomach, liver and colon and an increase in human proinflammatory cytokines, including interferon (IFN)-\u03b3, tumor necrosis factor (TNF)-\u03b1 and interleukin (IL)-5. Infiltration of donor cells and increases in cytokines were attenuated by treatment with CTLA-4 Ig, but remained either unaffected or enhanced by anti-CTLA-4 antibody. Further, splenic human T cell phenotyping showed that CTLA-4 Ig treatment prevented the engraftment of human CD45+ cells, while anti-CTLA-4 antibody enhanced donor T cell expansion, particularly CD4+ (CD45RO+) subsets, including T box transcription factor TBX21 (Tbet)+ CXCR3+ and CD25+ forkhead box protein 3 (FoxP3) cells. Comprehensive analysis of transcriptional profiling of human cells isolated from mouse spleen identified a set of 417 differentially expressed genes (DEGs) by CTLA-4 Ig treatment and 13 DEGs by anti-CTLA-4 antibody treatment. The CTLA-4 Ig regulated DEGs mapped to down-regulated apoptosis, inflammasome, T helper type 17 (Th17) and regulatory T cell (Treg) pathways and enhanced Toll-like receptor (TLR) receptor signaling, TNF family signaling, complement system and epigenetic and transcriptional regulation, whereas anti-CTLA-4 antibody produced minimal to no impact on these gene pathways. Our results show an important role of co-inhibitory CTLA-4 signaling in xeno-GvHD and suggest the therapeutic utility of other immune checkpoint co-inhibitory pathways in the treatment of immune-mediated diseases driven by hyperactive T cells.<\/jats:p>","DOI":"10.1111\/cei.13659","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T18:38:48Z","timestamp":1630953528000},"page":"422-438","source":"Crossref","is-referenced-by-count":11,"title":["Cytotoxic T lymphocyte antigen-4 regulates development of xenogenic graft versus host disease in mice via modulation of host immune responses induced by changes in human T cell engraftment and gene expression"],"prefix":"10.1093","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6017-2611","authenticated-orcid":false,"given":"Chunxu","family":"Gao","sequence":"first","affiliation":[{"name":"Immunology Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra","family":"Gardner","sequence":"additional","affiliation":[{"name":"Immunology Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6633-7763","authenticated-orcid":false,"given":"Marie-Clare","family":"Theobalds","sequence":"additional","affiliation":[{"name":"Immunology Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Hitchcock","sequence":"additional","affiliation":[{"name":"Immunology Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Deutsch","sequence":"additional","affiliation":[{"name":"Immunology 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IFCC method for creatine kinase (ATP: creatine N-phosphotransferase, EC 2.7.3.2)","volume":"29","author":"H\u00f8rder","year":"1991","journal-title":"Eur J Clin Chem Clin Biochem"},{"key":"2022030414003083800_cei13659-bib-0041","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S0272-2712(18)30363-9","article-title":"The advance of technology as a prelude to the laboratory of the twenty-first century","volume":"14","author":"Woo","year":"1994","journal-title":"Clin Lab Med"},{"key":"2022030414003083800_cei13659-bib-0042","first-page":"603","article-title":"Covalent immobilization of lipase, glycerol kinase, glycerol-3-phosphate oxidase & horseradish peroxidase onto plasticized polyvinyl chloride (PVC) strip & its application in serum triglyceride determination","volume":"139","author":"Chauhan","year":"2014","journal-title":"Indian J Med 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