Should Belatacept Be the Centrepiece of Renal Transplantation?

Monika Huber; Stephan Kemmner; Lutz Renders; Uwe Heemann

Disclosures

Nephrol Dial Transplant. 2016;31(12):1995-2002. 

In This Article

Mode of Action

A balance of different T cell types, destructive effector T cells (Teff) cells, protective regulatory T (Treg) cells and memory T cells is required for transplant tolerance and allograft survival. T cells require at least two signals for full activation. The first signal is antigen specific through engagement of the T cell receptor and peptide antigens presented by the major histocompatibility complex (MHC) on antigen-presenting cells (APCs) (Figure 1). The second signal is antigen independent and called the co-stimulatory signal.[5,6]

Figure 1.

T cell activation by at least two signals and mechanism of action of belatacept. This first signal is between the T cell receptor and the antigen presented via MHC on APCs. The second signal is the co-stimulation signal between CD28 on T cells and CD80/CD86 (B7 molecules) on APCs. The CTLA-4 component of belatacept binds to CD80/CD86 with high affinity and therefore effectively blocks signal 2.

There exist numerous co-stimulatory and co-inhibitory pathways that are able to promote or inhibit T cell activation, the CD28–CD80/86 pathway being the most prominent. CD28 is expressed on all naive CD4+ and CD8+ T cells, while APCs and many other cell types express CD80 or CD86 (Figure 1).[5]

Belatacept acts as a competitive antagonist of the CD28–CD80/CD86 pathway as it binds to CD80 and CD86 molecules on APCs and thereby blocks the CD28-mediated activation of T cells (Figure 1).[7] As this effect was antagonized by CNIs in animal models of transplantation as well as in in vitro experiments, belatacept is not combined with CNIs in current clinical applications.[5]

processing....