Modulating co-stimulation: a rational strategy in the treatment of rheumatoid arthritis?

Abstract

Rheumatoid arthritis (RA) is a common destructive inflammatory disease that affects 0.5-1% of the population in many countries. Even though several new treatments have been introduced for patients with RA, a considerable proportion of patients do not benefit from these, and the need for alternative treatment strategies is clear. This review explores the potential for a therapy targeting the adaptive immune system by modulating co-stimulation of T cells with a CTLA4-Ig fusion protein (abatacept).

Figure 1

Activation of naïve T cells requires (a) T cell receptor (TCR)–peptide–MHC interaction (signal 1) and (b) co-stimulation (signal 2) for full activation. This can be provided by so-called professional antigen-presenting cells (APCs; i.e. dendritic cells, macrophages and B cells). In the absence of co-stimulation the T cells will become anergic.

Figure 2

CD28 is constitutively expressed on T cells and CD86 is expressed on antigen-presenting cells (APCs). (a) Upon activation CD80 is also expressed on the APC and CD86 is further upregulated. (b) Cytotoxic T lymphocyte-associated antigen (CTLA)4 expression is induced later during activation, and out-competes CD28 for the interactions, thereby inducing a downregulation in immune response.

Figure 3

CTLA4–Ig (cytotoxic T lymphocyte-associated antigen 4–immunoglobulin fusion protein) blocks the T cell–antigen presenting cell (APC) interaction by binding to both CD80 and CD86, thus preventing CD28 interaction. CTLA4 has a higher affinity for the B7 molecules than does CD28. TCR, T cell receptor.

Figure 4

Interfering at an early stage in an immune response (i.e. T cell activation) is likely to block subsequent inflammatory events mediated by several different effector cells. APC, antigen-presenting cell; IL, interleukin; TNF, tumour necrosis factor.