Lymphocyte function-associated

Key PMN, polymorphonuclear leukocytes EC, endothelial cell lymphs, lymphocytes CD, cluster of differentiation iCAM, intercellular adhesion molecule LFA-1, lymphocyte function-associated antigen-1 PECAM-1, platelet endothelial cell adhesion cell molecule-1. 

Majeau, G.R. et al., Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice, J. Immunol., 152, 2753, 1994. 

Yung, R. et al., Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice, J. Clin. Invest., 97, 2866, 1996. 

Figure 5 Structure of some new lymphocyte function-associated antigen-1 inhibitors.

Note LFA-1 = lymphocyte function-associated molecule, VLA-4 = very late antigen 4 see text for details. 

Kurzinger, K., Springer, T. A. (1982). Purification and structural characterization of LFA-1, a lymphocyte function-associated antigen, and Mac-1, a related macrophage differentiation antigen associated with the type three complement receptor. J. Biol. Chem. 257,12412-18. 

Marlin, S. D. and Springer, T. A. (1987). Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell 51, 813-819. 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

Tozeren, P. K.-L. Sung, L. A. Sung, M. L. Dustin, P. Y. Chan, T. A. Springer, and S. Chien, Micromanipulation of adhesion of a jurkat cell to a planar bilayer-membrane containing lymphocyte function-associated antigen 3 molecules, J. Cell. Biol. 116, 997-1066 (1992). 

Nakayama, H., Sano, H., Nishimura, T., Yoshidi, S., and Iwamoto, I. (1994) Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue. J. Exp. Med. 179,1145-1154. 

Kawasaki et al. (1995) studied the therapeutic effect of combined treatment with monoclonal antibodies against intercellular adhesion moleculel (ICAM-1) and lymphocyte-function-associated antigenl (LFA-1) in Masugi nephritis of Wistar-Kyoto rats. 

Casasnovas, J., Pieroni, C., and Springer, T. A. (1999). Lymphocyte function-associated antigen-1 binding residues in intercellular adhesion molecule-2 (ICAM-2) and the integrin binding surface in the ICAM subfamily. Proc. Natl. Acad. Sci. USA 96, 3017-3022. 

Lymphocyte-specific protein tyrosine kinase Lymphocyte function-associated antigen Ligand-gated ion channel Luteinizing hormone Laser-induced fluorescence... 

Adhesion of different immune cells to one another or to epithelial cells has also been studied using planar bilayer models. For example, lymphocyte function-associated protein-1 (LFA-1) promotes cell adhesion in inflammation [i.e., a reaction that can be mimicked by binding to purified ICAM-1 in supported membranes (70)]. Similarly, purified LFA-3 reconstituted into supported bilayers mediates efficient CD2-dependent adhesion and differentiation of lymphoblasts (71). This work was followed by a study in which transmembrane domain-anchored and GPl-anchored isoforms of LFA-3 were compared (72). Because this research occurred before the introduction of polymer cushions and because the bilayers were formed by the simple vesicle fusion technique, the transmembrane domain isoform was immobile, whereas the GPl isoform was partially mobile. By comparing results with these two isoforms at different protein densities in the supported bilayer, the authors showed that diffusible proteins at a sufficient minimal density in the supported membrane were required to form strong cell adhesion contacts in this system. 

Dustin ML, Sanders ME, Shaw S, Springer TA. Purified lymphocyte function-associated antigen 3 hinds to CD2 and mediates T lymphoc)de adhesion. J. Exp. Med. 1987 165 677-692. 

Richardson B, Powers D, Hooper F, Yung RL, O Rourke K Lymphocyte function-associated antigen 1 overexpression and cell autoreactivity. Arthritis Rheum 1994 37 1363-72. 

BIRT-377 (1), a small molecule inhibitor of lymphocyte function-associated antigen 1 (LFA-1), was first discovered by Kelly and coworkers in 1999. It was shown to have potential therapeutic utility in the treatment of a variety of inflammatory and immune disorders. In binding to intercellular adhesion molecules, the cell-surface receptor LFA-1 allows many cell-cell adhesion events that control immunological functions. A lack of these synaptic functions leads to potentially life-threatening immunodeficiency diseases. In case of overactive immune responses, an LFA-1 inhibitor can be used to attenuate the inflammatory responses. These immunosuppressive activities have been tested in vitro, and early clinical trials on transplantation have already been undertaken. ... 

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