title: Neutralizing BAFF/APRIL with atacicept prevents early DSA formation and AMR development in T cell depletion induced nonhuman primate AMR model.
abstract: Depletional strategies directed toward achieving tolerance induction in organ transplantation have been associated with an increased incidence and risk of antibody-mediated rejection (AMR) and graft injury. Our clinical data suggest correlation of increased serum B cell activating factor/survival factor (BAFF) with increased risk of antibody-mediated rejection in alemtuzumab treated patients. In the present study, we tested the ability of BAFF blockade (TACI-Ig) in a nonhuman primate AMR model to prevent alloantibody production and prolong allograft survival. Three animals received the AMR inducing regimen (CD3-IT/alefacept/tacrolimus) with TACI-Ig (atacicept), compared to five control animals treated with the AMR inducing regimen only. TACI-Ig treatment lead to decreased levels of DSA in treated animals at 2 and 4 weeks posttransplantation (p < 0.05). In addition, peripheral B cell numbers were significantly lower at 6 weeks posttransplantation. However, it provided only a marginal increase in graft survival (59 ± 22 vs. 102 ± 47 days; p = 0.11). Histological analysis revealed a substantial reduction in findings typically associated with humoral rejection with atacicept treatment. More T cell rejection findings were observed with increased graft T cell infiltration in atacicept treatment, likely secondary to the graft prolongation. We show that BAFF/APRIL blockade using concomitant TACI-Ig treatment reduced the humoral portion of rejection in our depletion-induced preclinical AMR model.
authors: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA.
authors: J
authors: J
authors: Kwun
authors: E
authors: E
authors: Page
authors: J J
authors: JJ
authors: Hong
authors: A
authors: A
authors: Gibby
authors: J
authors: J
authors: Yoon
authors: A B
authors: AB
authors: Farris
authors: F
authors: F
authors: Villinger
authors: S
authors: S
authors: Knechtle
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000917:Antibody Formation; D053264:B-Cell Activating Factor / Q000276:immunology*; D006085:Graft Survival; D006801:Humans; D016030:Kidney Transplantation; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D008297:Male; D023421:Models, Animal; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D053264:B-Cell Activating Factor; D011993:Recombinant Fusion Proteins; C505719:TNFSF13B protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C524618:TACI receptor-IgG Fc fragment fusion protein
keywords: B cell biology; alloantibody; animal models: nonhuman primate; basic (laboratory) research/science; immunosuppression/immune modulation; kidney transplantation/nephrology; rejection: antibody-mediated (ABMR); translational research/science