Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig

Am J Transplant. 2018 Jan;18(1):89-101. doi: 10.1111/ajt.14400. Epub 2017 Aug 14.

Abstract

Donor-specific antibodies (DSAs) are a barrier to improved long-term outcomes after kidney transplantation. Costimulation blockade with CTLA4-Ig has shown promise as a potential therapeutic strategy to control DSAs. T follicular helper (Tfh) cells, a subset of CD4+ T cells required for optimal antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8+ T cells relative to CTLA4-Ig, but the impact of CD28-specific blockade on CD4+ Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model and then used this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh cell-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5+ PD-1high Tfh cells, CD95+ GL7+ germinal center B cells and DSA formation compared with CTLA4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA4 expression, suggesting an important role for CTLA4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.

Keywords: T cell biology; alloantibody; basic (laboratory) research/science; costimulation; fusion proteins and monoclonal antibodies: costimulation molecule specific; immunobiology; immunosuppressant; immunosuppression/immune modulation; translational research/science.

Publication types

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

MeSH terms

  • Abatacept / immunology*
  • Animals
  • Antibody Formation / immunology*
  • CD28 Antigens / antagonists & inhibitors*
  • Graft Rejection / etiology
  • Graft Rejection / immunology*
  • Graft Survival / immunology
  • Mice
  • Mice, Inbred C57BL
  • Skin Transplantation / adverse effects*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Tissue Donors*

Substances

  • CD28 Antigens
  • Abatacept