title: Human regulatory T cells are selectively activated by low-dose application of the CD28 superagonist TGN1412/TAB08.
abstract: CD28 superagonists (CD28SAs) are potent T-cell-activating monoclonal antibodies (mAbs). In contrast to their benign behavior and marked therapeutic efficacy as activators of regulatory T (Treg) cells in preclinical rodent models, a phase I trial of the human CD28SA TGN1412 (now called TAB08) in 2006 resulted in a life-threatening cytokine release syndrome (CRS). We studied TAB08-mediated Treg-cell activation in a recently developed in vitro system of human PBMCs, which also reproduces the CRS experienced by the healthy volunteers. We show that just as in rodents, CD28SAs are potent activators and expanders of Treg cells from healthy donors and rheumatoid arthritis patients, even under effective blockade of pro-inflammatory cytokine release by a corticosteroid. Moreover, CD28SA titration identifies a dose range where pro-inflammatory cytokine secretion from conventional T cells is absent while appreciable Treg-cell activation is maintained. Finally, we report that low-dose application of TAB08 to healthy volunteers results in dose-dependent systemic release of the Treg-cell signature cytokine IL-10 in the absence of the pro-inflammatory factors associated with the CRS of the 2006 TGN1412 study. These results demonstrate the potential of appropriately dosed CD28SA and corticosteroid comedication to mobilize human Treg cells for the treatment of autoimmune and inflammatory conditions.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Paula
authors.initials: P
authors.lastname: Tabares
authors.forename: Susanne
authors.initials: S
authors.lastname: Berr
authors.forename: Paula S
authors.initials: PS
authors.lastname: Römer
authors.forename: Sergej
authors.initials: S
authors.lastname: Chuvpilo
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Matskevich
authors.forename: Dmitry
authors.initials: D
authors.lastname: Tyrsin
authors.forename: Yury
authors.initials: Y
authors.lastname: Fedotov
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Tony
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000819:agonists / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D016753:Interleukin-10; C509303:TGN-1412
keywords: CD28; Regulatory T cells; Rheumatoid arthritis; TAB08; TGN142