Nephrotoxicity of calcineurin inhibitors and uncontrolled effector function of alloreactive T lymphocytes are main drivers of transplant dysfunctions. T lymphocytes either directly damage tissues or indirectly promote inflammation and antibody responses. Beside inhibitors of calcium-dependent pathways and antimetabolites, modulators of T-cell costimulation are elected pharmacological tools to enable interference with immune-mediated transplant dysfunctions. CD28 and CTLA-4 are major costimulatory and coinhibitory cell surface signaling molecules interacting with CD80/86, known to be critically important for immune response of committed T cells and regulation. Initial bench to beside translation, 2 decades ago, resulted in the development of belatacept CTLA-4 fused with an immunoglobulin Fc domain, a biologic inhibiting interaction of both CD28 and CTLA-4 with CD80/86. Despite proven effectiveness in inhibiting alloimmune responses, clinical use of belatacept in kidney transplantation revealed a substantially high incidence of acute, cell-mediated rejection. The cause of belatacept-resistant graft rejection was allocated to elevated pretransplant frequencies of CD28+ memory T cells. Owing to different requirements in CD28 costimulatory and CTLA-4 coinhibitory signals to control naive and memory T cells, selective antagonists of CD28–CD80/86 interactions have been developed on the rationale that preservation of CTLA-4-mediated regulatory mechanisms would result in a better control of alloreactivity and would represent a regulatory T-cell–compatible immunosuppression. After the successful testing of selective CD28 antagonists in First In Human studies, this review delineates how this shift in paradigm performed in preclinical transplantation models and evaluates its clinical potential.
1 Xenothera, Nantes, France.
2 Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.
3 Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
4 OSE Immunotherapeutics, Nantes, France.
Received 19 November 2018. Revision received 13 March 2019.
Accepted 13 March 2019.
N.P. is a shareholder and employee, and B.V. and J-P.S. are the shareholders of OSE Immunotherapeutics, a biotech company developing CD28 antagonists. The other author declares no conflicts of interest.
The authors declare no funding.
B.V. wrote the article. N.P., J-P.S., and G.B. edited, commented, and corrected the article.
Correspondence: Bernard Vanhove, PhD, INSERM UMR1064, 30 Bl Jean Monnet, 44093 Nantes, France. (email@example.com).