title: Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection.
abstract: Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein cytotoxic T lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocks T cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective with naïve T cells and less so with activated or memory T cells. In this study, we used a mouse model of allosensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allospecific germinal center B cell response and inhibited alloantibody production. Using adoptively transferred T cell receptor transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4(+) and T follicular helper responses. Remarkably, delaying CTLA4-Ig until day 6 after transplantation in a fully mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, whereas transferred hyperimmune sera reversed the effects of delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig for inhibiting ongoing B cell responses even when the graft-specific T cell response was robustly established.
authors.affiliation: Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
authors.forename: J S
authors.initials: JS
authors.lastname: Young
authors.affiliation: Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL.
authors.forename: M L
authors.initials: ML
authors.lastname: Miller
authors.affiliation: Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
authors.forename: V
authors.initials: V
authors.lastname: Vu
authors.affiliation: Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
authors.forename: C
authors.initials: C
authors.lastname: Tian
authors.affiliation: Center for Immunology and Inflammatory Diseases and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital; and Harvard Medical School, Boston, MA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Moon
authors.affiliation: Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL.
authors.forename: M-L
authors.initials: ML
authors.lastname: Alegre
authors.affiliation: Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
authors.forename: R
authors.initials: R
authors.lastname: Sciammas
authors.affiliation: Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
authors.forename: A S
authors.initials: AS
authors.lastname: Chong
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000009:adverse effects*; D018796:Immunoconjugates / Q000276:immunology*; D007518:Isoantibodies / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007518:Isoantibodies
keywords: B cell biology; alloantibody; animal models: murine; basic (laboratory) research/science; fusion proteins and monoclonal antibodies: belatacept; immunobiology; immunosuppressant; immunosuppression/immune modulation; immunosuppressive regimens; organ transplantation in general; rescue