title: Novel CD28 antagonist mPEG PV1-Fab' mitigates experimental autoimmune uveitis by suppressing CD4+ T lymphocyte activation and IFN-γ production.
abstract: Autoimmune Uveitis is an important chronic inflammatory disease and a leading cause of impaired vision and blindness. This ocular autoimmune disorder is mainly mediated by T CD4+ lymphocytes poising a TH1 phenotype. Costimulatory molecules are known to play an important role on T cell activation and therefore represent interesting therapeutical targets for autoimmune disorders. CD28 is the prototypical costimulatory molecule for T lymphocytes, and plays a crucial role in the initiation, and maintenance of immune responses. However, previous attempts to use this molecule in clinical practice achieved no success. Thus, we evaluated the efficacy of mPEG PV1-Fab' (PV1), a novel selective CD28 antagonist monovalent Fab fragment in the treatment of Experimental Autoimmune Uveitis (EAU). Here, we showed that PV1 treatment decreases both average disease score and incidence of EAU. A decrease in the activation profile of both T CD4+ and T CD8+ eye-infiltrating lymphocytes was evidenced. In the periphery, T CD4+ cells from PV1-treated mice also showed a decrease in their activation status, with reduced expression of CD69, CD25, and PD-1 molecules. This suppression was not dependent on Treg cells, as both their frequency and absolute number were lower in PV1-treated mice. In addition, frequency of CD4+IFN-γ+ T cells was significantly lower in PV1-treated group, but not of IL-17-producing T cells. Moreover, after specific restimulation, PV1 blockade selectively blocked IFN-γ production by CD4+ lymphocytes Taken together, our data suggest that mPEG PV1-Fab' acts mainly on IFN-γ-producing CD4+ T cells and emphasize that this specific CD28 blockade strategy is a potential specific and alternative tool for the treatment of autoimmune disorders in the eye.
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Pedro Henrique
authors.initials: PH
authors.lastname: Papotto
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Eliana Blini
authors.initials: EB
authors.lastname: Marengo
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Luiz Roberto
authors.initials: LR
authors.lastname: Sardinha
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Karina Inácio
authors.initials: KI
authors.lastname: Carvalho
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Ana Eduarda Zulim
authors.initials: AE
authors.lastname: de Carvalho
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Sheyla
authors.initials: S
authors.lastname: Castillo-Mendez
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Carina Calixto
authors.initials: CC
authors.lastname: Jank
authors.affiliation: OSE Immunotherapeutics SA, Nantes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Anna Carla
authors.initials: AC
authors.lastname: Goldberg
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Luiz Vicente
authors.initials: LV
authors.lastname: Rizzo
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000494:pharmacology*; D004195:Disease Models, Animal; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: D018106:CD28 Antigens; D002352:Carrier Proteins; C000611649:IFNG protein, mouse; D007140:Immunoglobulin Fab Fragments; D008565:Membrane Proteins; C486772:Plvap protein, mouse; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma