Costimulatory molecule inhibitors

In the adaptive immune response, nonspecific signals are generated from the interaction of pairs of receptors, so-called co-stimulatory molecules.30 Inhibition of the co-stimulatory signal results in suppression of the immune response. The CD28:B7, CTLA4:B7, and CD40:CD40L receptor:ligand pairs of co-stimulatory molecules have been the targets of drug development for autoimmune disease. There are two conceptually different approaches to blocking co-stimulation: by inhibiting either the induced expression of co-stimulatory molecules or the transmission of their specific intracytoplasmic signal. The latter approach is described here.

CTLA4 (cytotoxic T lympocyte antigen 4) is a co-stimulatory molecule expressed cytoplasmically in activated T cells, but found on the surface of mainly antigen-experienced T cells; this finding has therapeutic relevance, since established Tcell responses driven by antigen-experienced T cells often underly chronic immunopathology. CTLA4 is homologous to CD28 - both are members of the immunoglobulin superfamily, and both bind the ligand B7, which is expressed almost exclusively on antigen-presenting cells. However, CTLA4 transmits an inhibitory signal to T cells (a negative regulator of Tcell activation), whereas CD28 transmits a stimulatory signal. Indeed, in experimental models of SLE, CTLA4 inhibited the autoimmune response. While CTLA4 is a transmembrane protein, two companies have developed soluble fusion protein versions (CTLA4-Ig), which appear to mimic the effects of endogenous CTLA4. One of these products (abatacept) has been recommended to receive US FDA approval for the treatment of RA. In addition, clinical trials of CTLA4-Ig are underway for SLE and RRMS.

Two therapies targeting the CD40:CD40L interaction failed at the clinical trial stage. Both were monoclonal antibodies to CD40L - one was associated with life-threatening prothrombotic activity, and the other failed to demonstrate efficacy.

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Blood Pressure Health

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