Inhibition of lymphocyte adherence to vascular endothelium utilizing a novel extracellular matrix receptor-ligand interaction

Abstract

The present invention relates to a method for inhibiting the adhesion of one cell to another comprising interfering with the interaction between the extracellular matrix receptor and its ligand. The invention is based upon the discovery that the α4β1 extracellular matrix receptor promotes adhesion of lymphocytes to endothelial cells via attachment to a defined peptide sequence. Prior to the present invention, the ligand of the α4β1 receptor had not been identified, nor had the function of the α4β1 receptor in lymphocyte attachment been known. By preventing the interaction between the α4β1 receptor and its ligands using antibodies or defined peptide sequences, the present invention enables, for the first time, specific intervention in the migration of lymphocytes through the vascular endothelium and into tissues. The present invention, therefore, has particular clinical utility in suppression of the immune response; in various specific embodiments of the invention, the adherence of lymphocytes to endothelium may be inhibited systemically, or may, alternatively, be localized to particular tissues or circumscribed areas. Accordingly, the present invention provides for treatment of diseases involving autoimmune responses as well as other chronic or relapsing activations of the immune system, including allergy, asthma, and chronic inflammatory skin conditions.

1 . A method for inhibiting the interaction of α 4 β 1  on a lymphocyte and its ligand on a cytokine activated endothelial cell comprising exposing the α 4 β 1  to an agent which specifically inhibits the interaction of the α 4 β 1  and its ligand.  
     
     
         2 . The method of  claim 1 , wherein the agent competitively inhibits α 4 β 1 -binding of a monoclonal antibody selected from the group consisting of P4C2, P3E3, and P4G9.  
     
     
         3 . The method of  claim 1 , wherein the agent competitively inhibits α 4 β 1 -binding of a peptide consisting of from three to about twelve amino acid residues of the CS-1 region of fibronectin, wherein said peptide comprises the amino acid sequence Leu Asp Val (SEQ ID NO: 3)  
     
     
         4 . The method of  claim 1 , wherein the inhibition of binding of α 4 β 1  and its ligand by the agent interferes with the adhesion of the lymphocyte to the cytokine activated endothelial cell.