CTLA4Ig and the therapeutic potential of T cell co-stimulation blockade.

It is now generally accepted that CD4 T cells are critical players in the initiation of adaptive immune responses by contributing to the terminal differentiation of effector B cells or CD8+ T cells. It is therefore not surprising that CD4+ T cell activation is tightly controlled through the concerted action of a large number of molecular interactions. Activation requires not only the recognition of the appropriate antigen within a MHC molecule by the T cell receptor TCR but also the delivery of co-stimulatory signals by the antigen presenting cell APC . As a consequence therapeutic modulation of co-stimulatory molecules for instance with CTLA4Ig can lead to interference with T cell activation and consequently abrogation of pro-inflammatory manifestations mediated by cell types influenced by CD4+ T cells such as B cells CD8+ T cells or macrophages. This type of observations provided the rationale for the use of co-stimulatory blockade in autoimmunity and other immunopathology characterized by inappropriate immune activation such as rheumatoid arthritis RA . Several studies have also suggested that besides the non-specific anti-inflammatory effects co-stimulation blockade may in certain conditions promote the induction of long term immune tolerance.