title: Inducing CTLA-4-dependent immune regulation by selective CD28 blockade promotes regulatory T cells in organ transplantation.
abstract: Transplantation is the treatment of choice for patients with end-stage organ failure. Its success is limited by side effects of immunosuppressive drugs, such as inhibitors of the calcineurin pathway that prevent rejection by reducing synthesis of interleukin-2 by T cells. Moreover, none of the existing drugs efficiently prevent the eventual rejection of the organ. Blocking the CD28-mediated T cell costimulation pathway is a nontoxic alternative immunosuppression strategy that is now achieved by blockade of CD80/86, the receptor for CD28 on antigen-presenting cells. However, interaction of CD80/86 with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is required for immune regulation. Therefore, CD28 blockade, instead of CD80/86 blockade, might preserve regulatory signals mediated by CTLA-4 and preserve immune regulation. By using monovalent antibodies, we identified true CD28 antagonists that induced CTLA-4-dependent decreased T cell function compatible with regulatory T (Treg) cell suppression. In transplantation experiments in primates, blocking CD28 augmented intragraft and peripheral blood Treg cells, induced molecular signatures of immune regulation, and prevented graft rejection and vasculopathy in synergy with calcineurin inhibition. These findings suggest that targeting costimulation blockade at CD28 preserves CTLA-4-dependent immune regulation and promotes allograft survival.
authors.affiliation: INSERM U643, ITERT-Uro-Nephro, Centaure Network, CHU Nantes, 30 Bl J. Monnet, 44093 Nantes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poirier
authors.forename: Agnes M
authors.initials: AM
authors.lastname: Azimzadeh
authors.forename: Tianshu
authors.initials: T
authors.lastname: Zhang
authors.forename: Nahzli
authors.initials: N
authors.lastname: Dilek
authors.forename: Caroline
authors.initials: C
authors.lastname: Mary
authors.forename: Bao
authors.initials: B
authors.lastname: Nguyen
authors.forename: Xavier
authors.initials: X
authors.lastname: Tillou
authors.forename: Guosheng
authors.initials: G
authors.lastname: Wu
authors.forename: Karine
authors.initials: K
authors.lastname: Reneaudin
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hervouet
authors.forename: Bernard
authors.initials: B
authors.lastname: Martinet
authors.forename: Flora
authors.initials: F
authors.lastname: Coulon
authors.forename: Emma
authors.initials: E
authors.lastname: Allain-Launay
authors.forename: Georges
authors.initials: G
authors.lastname: Karam
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.forename: Richard N
authors.initials: RN
authors.lastname: Pierson
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D018106:CD28 Antigens / Q000378:metabolism*; D060908:CTLA-4 Antigen; D019703:Calcineurin / Q000378:metabolism; D006085:Graft Survival; D006801:Humans; D007107:Immune System; D008214:Lymphocytes / Q000166:cytology; D008252:Macaca fascicularis; D016377:Organ Transplantation / Q000379:methods*; D010215:Papio; D050378:T-Lymphocytes, Regulatory / Q000166:cytology
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019703:Calcineurin