Selective blockade of CD28 on human T cells facilitates regulation of alloimmune responses

JCI Insight. 2017 Oct 5;2(19):e89381. doi: 10.1172/jci.insight.89381.

Abstract

T cells are central to the detrimental alloresponses that develop in autoimmunity and transplantation, with CD28 costimulatory signals being key to T cell activation and proliferation. CTLA4-Ig molecules that bind CD80/86 and inhibit CD28 costimulation offer an alternative immunosuppressive treatment, free from some of the chronic toxicities associated with calcineurin inhibition. However, CD80/86 blockade by CTLA4-Ig also results in the loss of coinhibitory CTLA4 signals that are critical to the regulation of T cell activation. Here, we show that a nonactivating monovalent anti-CD28 that spares CTLA4 signaling is an effective immunosuppressant in a clinically relevant humanized mouse transplant model. We demonstrate that selective CD28 blockade prolongs human skin allograft survival through a mechanism that includes a reduction in the cellular graft infiltrate. Critically, selective CD28 blockade promotes Treg function in vivo and synergizes with adoptive Treg therapy to promote transplant survival. In contrast to CTLA4-Ig treatment, selective CD28 blockade promotes regulation of alloimmune responses and facilitates Treg-based cellular therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity
  • CD28 Antigens / immunology*
  • CTLA-4 Antigen / immunology
  • Cytokines / blood
  • Graft Survival / immunology
  • Heterografts
  • Humans
  • Inflammation Mediators / metabolism
  • Lymphocyte Activation / immunology
  • Mice, Inbred BALB C
  • Skin Transplantation
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / immunology
  • Transplantation Immunology

Substances

  • CD28 Antigens
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Cytokines
  • Inflammation Mediators