Therapeutic anti-integrin (alpha4 and alphaL) monoclonal antibodies: two-edged swords?

Anti-alpha4 and anti-alphaL integrin chain monoclonal antibodies have shown a clear-cut beneficial effect in different animal models of autoimmune and inflammatory disorders as well as in human diseases, including multiple sclerosis, inflammatory bowel disease, and psoriasis. It has been widely assumed that this therapeutic effect is mainly consequence of the blockade of leucocyte adhesion to endothelium, inhibiting thus their extravasation and the inflammatory phenomenon. However, it is evident that both alpha4beta1 (very late antigen-4) and alphaLbeta2 (leucocyte function-associated antigen-1) integrins have additional important roles in other immune phenomena, including the formation of the immune synapse and the differentiation of T helper 1 lymphocytes. Therefore, it is very feasible that the long-term administration of blocking agents directed against these integrins to patients with inflammatory/autoimmune conditions may have undesirable or unexpected effects.