title: Rapid regulatory T-cell response prevents cytokine storm in CD28 superagonist treated mice.
abstract: Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of regulatory T-cells (Treg cells) in rats, but a first-in-man trial of the human CD28SA TGN1412 resulted in an unexpected cytokine release syndrome. Using a novel mouse anti-mouse CD28SA, we re-investigate the relationship between Treg activation and systemic cytokine release. Treg activation by CD28SA was highly efficient but depended on paracrine IL-2 from CD28SA-stimulated conventional T-cells. Systemic cytokine levels were innocuous, but depletion of Treg cells prior to CD28SA stimulation led to systemic release of proinflammatory cytokines, indicating that in rodents, Treg cells effectively suppress the inflammatory response. Since the human volunteers of the TGN1412 study were not protected by this mechanism, we also tested whether corticosteroid prophylaxis would be compatible with CD28SA induced Treg activation. We show that neither the expansion nor the functional activation of Treg cells is affected by high-dose dexamethasone sufficient to control systemic cytokine release. Our findings warn that preclinical testing of activating biologicals in rodents may miss cytokine release syndromes due to the rapid and efficacious response of the rodent Treg compartment, and suggest that polyclonal Treg activation is feasible in the presence of antiphlogistic corticosteroid prophylaxis.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Tea
authors.initials: T
authors.lastname: Gogishvili
authors.forename: Daniela
authors.initials: D
authors.lastname: Langenhorst
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.forename: Fernando
authors.initials: F
authors.lastname: Elias
authors.forename: Karin
authors.initials: K
authors.lastname: Elflein
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Dennehy
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D016207:Cytokines