Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection

Am J Transplant. 2016 Aug;16(8):2312-23. doi: 10.1111/ajt.13761. Epub 2016 Apr 4.

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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • CTLA-4 Antigen / immunology*
  • Female
  • Graft Rejection / etiology
  • Graft Rejection / prevention & control*
  • Graft Survival / immunology
  • Heart Transplantation / adverse effects*
  • Immunoconjugates / immunology*
  • Isoantibodies / immunology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transplantation, Homologous

Substances

  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Isoantibodies