Selective immunomodulation: utilization of CD29/VLA molecules.
Accumulating evidence suggests that the VLA/CD29 molecule plays an important role in T-cell costimulation, and CD4+CD29/VLA+ memory T cells play a key role in induction of CD8 killer effector T cells which are considered to be a major population involved in graft rejection. To target limited elements of the T-lymphocyte population, we have described the preparation of a bispecific antibody-toxin conjugate designed to target CD4+CD29+ memory T cells. We also showed that the solid-phase crosslinking of VLA-4 by the antibody against this molecule or by its ligand, the CS-1 region of fibronectin, stimulates tyrosine phosphorylation of 140, 120-105, 80-70, 60-55, 50 and 45 kilodalton proteins. In addition, we identified the pp140 protein as PLC gamma, pp120 protein as pp125FAK, pp70 and pp50 proteins as paxillin, and pp60-55 proteins as pp59fyn and pp56lck, and pp45 as MAP kinase, respectively. Moreover, we demonstrated that pp125FAK is directly associated with paxillin. The paxillin binding domain of pp125FAK is homologous to the paxillin binding domain of vinculin. Mutations in the conserved amino acid residues between pp125FAK and vinculin result in the loss of paxillin-binding activity. Because VLA/CD29 is preferentially expressed on CD4 memory T cells, the above described system will be used to develop a novel drug design for providing selective immunosuppression useful for organ transplantation.
Morimoto
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Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Sato
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Tachibana
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D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins / Q000627:therapeutic use; D015195:Drug Design; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000276:immunology*; D008970:Molecular Weight; D016377:Organ Transplantation; D051419:Paxillin; D010750:Phosphoproteins / Q000627:therapeutic use; D010766:Phosphorylation; D016029:Receptors, Very Late Antigen / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016596:Vinculin / Q000627:therapeutic use
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D019012:Integrin beta1; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D016029:Receptors, Very Late Antigen; D016596:Vinculin