Bind another day: The LFA-1/ICAM-1 interaction as therapeutic target
Introduction
Cell adhesion receptors are known to play an essential role in multicellular organisms by mediating the direct association of cells with each other and with proteins of the extracellular matrix [1], [2]. Among these receptors is lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, αLβ2) that actively contributes to the molecular interactions responsible for cellular adhesion and migration in the immune system [3], [4], [5], [6].
In this context, LFA-1 needs to be tightly regulated, which occurs through conformational changes [7], [8], [9], [10], [11] and controlled association with the cytoskeleton [12], [13] and various proteins such as its ligands, intercellular adhesion molecules (ICAMs)-1 to -5 and junctional adhesion molecule (JAM)-A.
Section snippets
Intercellular adhesion molecule-1
The first counterreceptor identified for LFA-1 was the ICAM-1 (CD54), a member of the immunoglobulin superfamily, providing the first example of an interaction between a member of the integrin family and a member of the immunoglobulin superfamily [14], [15]. ICAM-1 is a cell surface glycoprotein that promotes adhesion in immunological and inflammatory reactions [15]. It is constitutively expressed on some tissues and induced on other by inflammatory cytokines such as interleukin-1 or
Ligand-binding site
The identification of the molecular motifs involved in ligand binding has been the subject of intensive work because it is of great importance, for example, for drug design. In the absence of tertiary structures of an intact LFA-1 complexed with its natural ligands, several alternatives, each with its advantages and drawbacks, have been used: generation of ligand-binding integrin chimera, ligand cross-linking, epitope mapping of mAbs, and mutation of residues [56].
The major ligand-binding site
Antibodies
Various animal models for ischemia reperfusion injury, trauma, asthma, lung injury, rheumatoid arthritis, and organ transplantation have indicated that anti-adhesion therapy can reduce the serious vascular and tissue injury mediated by infiltrating leukocytes. In this way, anti–LFA-1 antibodies inhibit immunoreactivity, including cytotoxic T lymphocyte–mediated lysis and leukocyte migration to sites of inflammation [64].
Moreover, an improved understanding regarding the pathophysiology of
Conclusion
LFA-1 is able to engage several ligands expressed on many cell types, leading to various cellular normal or pathologic responses.
Studying these interactions and what they entail is thus a promising research field that has already allowed the development of therapeutic antibodies, peptides, and small inhibitory molecules for several major disorders such as cancers, allergies, and autoimmune diseases.
Summary
LFA-1 (CD11a/CD18, αLβ2) binds ICAM-1 to -5 and JAM-A, which elicit key immune functions. These molecular interactions could also be associated to several diseases and have thus been extensively studied, particularly the relation between LFA-1 and its major ligand ICAM-1 (CD54), leading to the development of potential therapeutic tools such as antibodies, allosteric inhibitors, peptides, and peptidomimetics.
The paper globally reviews LFA-1 ligands and the more recent findings regarding the
Acknowledgments
This study is supported by the Belgian federal services for public health and security of the food chain and environment, grant S-6107. P. Vanden Bergh is a recipient of a studentship from the “Fonds pour la formation à la Recherche dans l'Industrie et l'Agriculture,” rue d'Egmont 5, B-1000 Bruxelles.
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