Adhesion molecules as therapeutic targets for autoimmune diseases and transplant rejection.
Inflammatory disorders such as autoimmune diseases and graft rejection are mediated by activated leukocytes, particularly T lymphocytes, which penetrate the inflamed tissue and perpetuate or amplify the immune reaction. In an unstimulated state, leukocytes do not readily adhere to the vascular endothelium. However, inflammatory signals induce the expression of proteins on the endothelial cell surface that promote the adhesion and extravasation of activated immune cells from the circulation into the underlying tissues. Key among these molecules are P- and E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the endothelial cells, and their respective counter receptors, P-selectin glycoprotein ligand-1 (PSGL-1), leukocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4), on the leukocytes. In vitro blockade of these molecules inhibits the adhesion of leukocytes. In many cases there is attenuation of leukocyte activation as well. Adhesion blockade in animal models prevents or ameliorates graft rejection and disease severity in autoimmune models. Clinical studies with humanised monoclonal antibodies which interfere with LFA-1/ICAM-1 or VLA-4/VCAM-1 interactions have shown significant efficacy and good safety profiles in autoimmune disease, including psoriasis, multiple sclerosis and inflammatory bowel disease. Thus, adhesion blockade is emerging as a useful therapeutic strategy in several inflammatory settings.
Dedrick
Russell L
RL
Xoma (US) LLC, 2910 Seventh Street, Berkeley, CA 94710, USA. dedrick@xoma.com
Bodary
Sarah
S
Garovoy
Marvin R
MR
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism* / Q000628:therapy*; D001691:Biological Therapy / Q000639:trends; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism* / Q000628:therapy*; D006801:Humans
D015815:Cell Adhesion Molecules