Inhibition of LFA‐1/ICAM‐1 and VLA‐4/VCAM‐1 as a therapeutic approach to inflammation and autoimmune diseases

Abstract

This review focuses on providing insights into the structural basis and clinical relevance of LFA-1 and VLA-4 inhibition by peptides and small molecules as adhesion-based therapeutic strategies for inflammation and autoimmune diseases. Interactions of cell adhesion molecules (CAM) play central roles in mediating immune and inflammatory responses. Leukocyte function-associated antigen (LFA-1, alpha(L)beta(2), and CD11a/CD18) and very late antigen (VLA-4, alpha(4)beta(1), and CD49d/CD29) are members of integrin-type CAM that are predominantly involved in leukocyte trafficking and extravasation. LFA-1 is exclusively expressed on leukocytes and interacts with its ligands ICAM-1, -2, and -3 to promote a variety of homotypic and heterotypic cell adhesion events required for normal and pathologic functions of the immune systems. VLA-4 is expressed mainly on lymphocyte, monocytes, and eosinophils, but is not found on neutrophils. VLA-4 interacts with its ligands VCAM-1 and fibronectin (FN) CS1 during chronic inflammatory diseases, such as rheumatoid arthritis, asthma, psoriasis, transplant-rejection, and allergy. Blockade of LFA-1 and VLA-4 interactions with their ligands is a potential target for immunosuppression. LFA-1 and VLA-4 antagonists (antibodies, peptides, and small molecules) are being developed for controlling inflammation and autoimmune diseases. The therapeutic intervention of mostly mAb-based has been extensively studied. However, due to the challenging relative efficacy/safety ratio of mAb-based therapy application, especially in terms of systemic administration and immunogenic potential, strategic alternatives in the forms of peptide, peptide mimetic inhibitors, and small molecule non-peptide antagonists are being sought. Linear and cyclic peptides derived from the sequences of LFA-1, ICAM-1, ICAM-2, VCAM-1, and FN C1 have been shown to have inhibitory effects in vitro and in vivo. Finally, understanding the mechanism of LFA-1 and VLA-4 binding to their ligands has become a fundamental basis in developing therapeutic agents for inflammation and autoimmune diseases.

Regulation of dextran sodium sulfate induced colitis by leukocyte beta 2 integrins

“…Importantly, the anti-CD11a blocking antibody Efalizumab is currently approved for the treatment of psoriasis with several other novel small molecule CD11a antagonists currently under development. [64][65][66][67][68] Our findings together with previous reports of CD11a and CD18 expression in human IBD specimens suggest that targeting of these molecules may provide another therapeutic treatment for IBD.…”

Trypanosoma cruzi-elicited CD8+ T cell-mediated myocarditis: chemokine receptors and adhesion molecules as potential therapeutic targets to control chronic inflammation?

“…The use of immunomodulators such as IFN-β able to downregulate the expression of VLA-4 or monoclonal antibodies and antagonists specific for adhesion molecules are being proposed and successfully used to ameliorate inflammatory processes (Silu-Hännien et al 1995, Yusuf-Makagiansar et al 2002. Therefore, our results point to the possibility that adhesion molecules may constitute a logic target to control the inflammation elicited by T. cruzi infection.…”

Inhibition of ICAM-1/LFA-1-mediated heterotypic T-cell adhesion to epithelial cells: design of ICAM-1 cyclic peptides

“…1 The process of T-cell migration from the blood stream to tissues involves the interaction between lymphocyte associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1). 2 T-cell adhesion to vascular endothelial cells is mediated by the activated form of the LFA-1 integrin receptor. The activated form of LFA-1 can be induced in vivo by inflammatory cytokines and in vitro by anti CD-2 antibody or phorbol esters.…”

“…10,11 This experimental model of T-cell adhesion to intestinal mucosa is relevant to autoimmune diseases such as Crohn's disease and ulcerative colitis. 2,12 Figure 1. Concentration-dependent activity of ICAM-1 peptides in heterotypic T-cell adhesion assay.…”