ABSTRACT
Introduction: T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86.
Areas covered: This review discusses past, current and future biological therapies that have been utilized to block the CD28/CTLA-4 cosignaling pathway in the settings of autoimmunity and transplantation, as well the challenges facing successful implementation of these therapies.
Expert opinion: The development of CD28 blockers Abatacept and Belatacept provided a more targeted therapy approach for transplant rejection and autoimmune disease relative to calcineurin inhibitors and anti-proliferatives, but overall efficacy may be limited due to their collateral effect of simultaneously blocking CTLA-4 coinhibitory signals. As such, current investigations into the potential of selective CD28 blockade to block the costimulatory potential of CD28 while exploiting the coinhibitory effects of CTLA-4 are promising. However, as selective CD28 blockade inhibits the activity of both effector and regulatory T cells, an important goal for the future is the design of therapies that will maximize the attenuation of effector responses while preserving the suppressive function of T regulatory cells.
Article Highlights
CD28 costimulation blockade is advantageous for inhibiting unwanted T cell responses during autoimmunity and transplantation because the targets are confined to the immune system, limiting off-target toxicities associated with calcineurin inhibitors and anti-proliferatives
Blocking CD28 using conventional CTLA-4 Ig fusion proteins (abatacept, belatacept) that bind to the shared receptors CD80/CD86 has the collateral effect of also inhibiting CTLA-4 coinhibitory signaling
Due to both relative CD28 independence and the loss of regulation via CTLA-4 coinhibitory signals, memory T cells, Th17 cells, and impaired Treg function may play a role in breakthrough T cell responses in patients treated with CTLA-4Ig fusion proteins
Novel CD28-specific domain antibodies have been developed in order to selectively block CD28 signals while leaving CTLA-4 coinhibitory signaling intact
Inhibition of CD28 signals on Foxp3+ Treg populations may still pose a challenge for the use of selective CD28 blocking reagents in transplantation and autoimmunity
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Declaration of interest
M Ford has received honoraria from Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.