A more selective costimulatory blockade of the CD28-B7 pathway

Progress from the last decade in the understanding of T-cell activation has led to new immunotherapeutic strategies for the treatment of immunological diseases. Since the discovery of costimulatory molecules in the 1980s, the field of T-cell costimulation blockade has literally exploded and now spanned 'from bench to bedside'. Such alternative therapies result in more selective effects specializing their action on Ag-experienced T lymphocytes. This can potentially prevent the progression of autoimmune diseases, allograft rejection and may even induce immune tolerance. In the 1990 s, the CD28/B7/CTLA-4 pathway was identified as a crucial regulator of T-cell activation and tolerance induction. Here, we have summarized our current understanding of this complex costimulatory pathway involving co-stimulatory and co-inhibitory molecules and the way we can manipulate these molecules to inhibit, stimulate or kill target cells in experimental preclinical models as well as in clinical trials. We have also reviewed the role of costimulation in the biology of CD4+ CD25+ Foxp3+ regulatory T cells.