title: Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.
abstract: De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Kwun
authors.forename: A C
authors.initials: AC
authors.lastname: Gibby
authors.forename: J J
authors.initials: JJ
authors.lastname: Hong
authors.forename: A B
authors.initials: AB
authors.lastname: Farris
authors.forename: N N
authors.initials: NN
authors.lastname: Iwakoshi
authors.forename: F
authors.initials: F
authors.lastname: Villinger
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
authors.forename: S J
authors.initials: SJ
authors.lastname: Knechtle
mesh_terms: D000069594:Abatacept; D000077944:Alefacept; D000818:Animals; D000906:Antibodies; D001402:B-Lymphocytes / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018858:Germinal Center / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D018796:Immunoconjugates / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D018796:Immunoconjugates; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D000077944:Alefacept; D016559:Tacrolimus
keywords: Antibody-mediated rejection; costimulation blockade; follicular helper T cells; germinal center reaction