title: Anti-IL6-receptor-alpha (tocilizumab) does not inhibit human monocyte-derived dendritic cell maturation or alloreactive T-cell responses.
abstract: Significant comorbidites and lethality complicate GVHD and its treatment. Targeting the cytokine milieu may improve GVHD control; and IL6 is an attractive candidate, given its role in dendritic cell activation and T-cell differentiation. Tocilizumab is a humanized mAb to IL6-receptor-α (IL6R-α), which is Food and Drug Administration-approved for treatment of rheumatoid arthritis. Mouse transplant models have demonstrated that IL6 blockade also improves GVHD scores and survival. Definitive immunologic effects of IL6 inhibition have not emerged given inconsistent alterations in regulatory T cells (Tregs) and suppression of T-cell proliferation. Despite on-target suppression of IL6R-α signaling in human monocyte-derived dendritic cells (moDCs) and T cells, our data show no effect on moDC maturation/activation, alloreactive T-cell proliferation, Treg expansion, or allogeneic Th1/Th17 responses in vitro. These findings merit attention in any clinical trials of tocilizumab for GVHD prevention or treatment and provide a rationale for evaluating more specific inhibitors of downstream JAK2/STAT3 signaling as well.
authors.affiliation: Laboratory of Cellular Immunobiology, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Betts
authors.forename: Erin T
authors.initials: ET
authors.lastname: St Angelo
authors.forename: Michael
authors.initials: M
authors.lastname: Kennedy
authors.forename: James W
authors.initials: JW
authors.lastname: Young
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D006801:Humans; D066298:In Vitro Techniques; D007519:Isoantigens; D053614:Janus Kinase 2 / Q000276:immunology; D051379:Mice; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C508603:IL6R protein, human; D007519:Isoantigens; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C502936:tocilizumab