title: Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection.
abstract: Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab' antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preexisting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.|Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Ville
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.|Effimune, Nantes, France; and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poirier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.|Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Branchereau
authors.affiliation: Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Vianney
authors.initials: V
authors.lastname: Charpy
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.|Effimune, Nantes, France; and.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pengam
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Nerriere-Daguin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Bas-Bernardet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Coulon
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.|Effimune, Nantes, France; and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Mary
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.|Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Chenouard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hervouet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.
authors.forename: David
authors.initials: D
authors.lastname: Minault
authors.affiliation: MicroPiCell Facility, Structure Fédérative de Recherche (SFR) Bonamy, Structure Fedérative de recherche (FED) 4203, Unité Mixte de Service (UMS) 016, Nantes, France.
authors.forename: Steven
authors.initials: S
authors.lastname: Nedellec
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.|Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Renaudin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.|Effimune, Nantes, France; and.
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France; gilles.blancho@chu-nantes.fr.|Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.|Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000187:drug effects* / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D010215:Papio
chemical_list: D000906:Antibodies; D018106:CD28 Antigens; D007166:Immunosuppressive Agents; D000069594:Abatacept
keywords: acute rejection; immunology; immunosuppression; kidney transplantation; lymphocytes