title: Selective blockade of CD28-mediated T cell costimulation protects rhesus monkeys against acute fatal experimental autoimmune encephalomyelitis.
abstract: Costimulatory and coinhibitory receptor-ligand pairs on T cells and APC control the immune response. We have investigated whether selective blockade of CD28-CD80/86 costimulatory interactions, which preserves the coinhibitory CTLA4-CD80/86 interactions and the function of regulatory T (Treg) cells, abrogates the induction of experimental autoimmune encephalomyelitis (EAE) in rhesus monkeys. EAE was induced by intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) in CFA on day 0. FR104 is a monovalent, PEGylated-humanized Fab' Ab fragment against human CD28, cross-reactive with rhesus monkey CD28. FR104 or placebo was administered on days 0, 7, 14, and 21. FR104 levels remained high until the end of the study (day 42). Placebo-treated animals all developed clinical EAE between days 12 and 27. FR104-treated animals did not develop clinical EAE and were sacrificed at the end of the study resulting in a significantly prolonged survival. FR104 treatment diminished T and B cell responses against rhMOG, significantly reduced CNS inflammation and prevented demyelination. The inflammatory profile in the cerebrospinal fluid and brain material was also strongly reduced. Recrudescence of latent virus was investigated in blood, spleen, and brain. No differences between groups were observed for the β-herpesvirus CMV and the polyomaviruses SV40 and SA12. Cross-sectional measurement of lymphocryptovirus, the rhesus monkey EBV, demonstrated elevated levels in the blood of FR104-treated animals. Blocking rhesus monkey CD28 with FR104 mitigated autoreactive T and B cell activation and prevented CNS pathology in the rhMOG/CFA EAE model in rhesus monkeys.
authors.affiliation: Biomedical Primate Research Centre, 2280 GH Rijswijk, the Netherlands; haanstra@bprc.nl.
authors.forename: Krista G
authors.identifier: http://orcid.org/0000-0002-7654-5096
authors.initials: KG
authors.lastname: Haanstra
authors.affiliation: Biomedical Primate Research Centre, 2280 GH Rijswijk, the Netherlands;
authors.forename: Karin
authors.initials: K
authors.lastname: Dijkman
authors.affiliation: Biomedical Primate Research Centre, 2280 GH Rijswijk, the Netherlands;
authors.forename: Noun
authors.initials: N
authors.lastname: Bashir
authors.affiliation: Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.affiliation: Effimune SAS, 44035 Nantes, France;
authors.forename: Caroline
authors.initials: C
authors.lastname: Mary
authors.affiliation: Effimune SAS, 44035 Nantes, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poirier
authors.affiliation: Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom;
authors.forename: Paul
authors.initials: P
authors.lastname: Baker
authors.forename: Claire L
authors.initials: CL
authors.lastname: Crossan
authors.affiliation: Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom;
authors.forename: Linda
authors.initials: L
authors.lastname: Scobie
authors.affiliation: Biomedical Primate Research Centre, 2280 GH Rijswijk, the Netherlands; University of Groningen, University Medical Center, Department of Neuroscience, 9713 GZ Groningen, the Netherlands; and.
authors.forename: Bert A
authors.initials: BA
authors.lastname: 't Hart
authors.affiliation: Effimune SAS, 44035 Nantes, France; Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1064, 44093 Nantes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D018106:CD28 Antigens / Q000037:antagonists & inhibitors*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000821:virology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008253:Macaca mulatta; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014777:Virus Diseases / Q000150:complications; D017735:Virus Latency
chemical_list: D018106:CD28 Antigens; D011994:Recombinant Proteins