Effective intervention against inflammation, autoimmune disease and transplant rejection requires the ability to down regulate the immune response. Traditional clinical approaches to these conditions have relied on the administration of immunosuppressive drugs that result in a global attenuation of the immune response. As evidenced by patients suffering from AIDS, or those receiving immunosuppressive agents to prevent transplant rejection, an individual with a weakened immune response is susceptible to a wide range of opportunistic infectious agents and an increased risk for developing malignancies. These potentially fatal side effects continue to be the limiting factors of current immunosuppressive drugs. A more effective approach would involve inactivating only those lymphocytes that have a given antigen specificity or are attacking a given tissue type (tissue specificity). T cell activation and inhibition depend, in part, on signals mediated through the molecules of the costimulation pathway. Accumulating evidence supports a central role for the costimulatory molecule CTLA-4 found on the T cell surface in the inhibition of the immune response. T cells that simultaneously engage their cognate antigen and CTLA4-ligand are inhibited. The clinical application of this natural inhibitory pathway in autoimmune disease would require the ability to engage the CTLA4 receptor on the autoreactive T cells as they attack the cells expressing their cognate autoantigen. Therapeutic injection of a bispecific antibody that links an anti-CTLA4 antibody to an antibody that binds to a tissue under autoimmune attack could create a protective cloak around that tissue and lead to the specific inhibition of an ongoing autoimmune response. A decrease in tissue destruction could result in less inflammation, less autoantigen release and a break in the cycle that perpetuates autoimmune disease. The down modulation of T lymphocytes involved in an ongoing immune response, without affecting T cells displaying other antigen specificities, would have important and immediate clinical applications. Therefore, in the present study we propose to test the following Hypothesis: Tissue specific immunomodulation can be induced in vivo through control of the costimulatory pathway in autoreactive T cells.
Aims 1) To test the homing properties and pharmacokinetics of a bispecific antibody that links a thyroid specific antibody with an anti-CTLA4 antibody. 2). To characterize the tissue specific therapeutic approach in vivo using anti-thyroidanti-CTLA-4 bispecific antibody. 3) To investigate the mechanism by which the bispecific antibody modulates the autoimmune response.
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| Perez, Nicolas; Karumuthil-Melethil, Subha; Li, Ruobing et al. (2008) Preferential costimulation by CD80 results in IL-10-dependent TGF-beta1(+) -adaptive regulatory T cell generation. J Immunol 180:6566-76 |
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| Vasu, Chenthamarakshan; Gorla, Seema R; Prabhakar, Bellur S et al. (2003) Targeted engagement of CTLA-4 prevents autoimmune thyroiditis. Int Immunol 15:641-54 |
