The blockade of T-cell co-stimulation as a therapeutic stratagem for immunosuppression: Focus on belatacept

Abstract

The development of immunosuppressive drugs has in recent years been focused on prevention of acute rejection. This has led to an increase in one-year allograft survival. However, these drugs have non-immune effects which contribute to the high incidence of late graft loss, as a consequence of chronic allograft nephropathy, and the death of patients. As an immune-specific alternative to conventional immunosuppressants, new biotechnology tools have been developed; they target the costimulation signal of T-cell activation, particularly by the "classical" B7/CD28 and CD40/CD40L pathways. Here, we review the limitations of current immunosuppressive protocols, the benefits of classical B7/CD28 costimulation blockade, and the first large-scale clinical application of this strategy to human transplantation with belatacept. We will also consider novel costimulatory molecules of the B7/CD28 and TNF/TNF-R families, which appear to be important for the functions of memory and effector T-cells.

Keywords: belatacept; chronic allograft nephropathy; costimulation; fusion protein; immunosuppressants; kidney transplantation.

Figure 1

T-cell activation by three signals. The first involves T-cell receptor (TCR) triggering by donor antigen on APCs (antigen presenting cells). The second signal or “costimulation signal” is delivered when B7-1/CD80 and B7-2/CD86 on the surface of APCs engage CD28 on T-cells. These two signals activate three transduction pathways (the Nuclear Factor-κB or Nf-κB pathway, the mitogen-activated protein (MAP) kinase pathway and the calcium-calcineurin pathway) that result in the production of numerous factors, including interleukin-2 (IL-2), the α–chain of its receptor, CD25, and the CD40 Ligand. CD40 is expressed on all APCs (including B cells) and its ligand (CD40L or CD154) is on activated CD4⁺ T-cells and on a subset of CD8⁺ T-cells and NK cells. Stimulation of CD40 on APC by CD40L triggers important signals for antibody production by B cells and strongly induces B7 and Major Histocompatibility Complex (MHC) expression on APCs. IL-2 binding to its receptor activates the mTOR (“target of rapamycin”) pathway – the third signal – resulting in T-cell clonal proliferation.