Lipid Mediators In The Resolution of Asthma Exacerbations

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The long-term objective of this proposal is to utilize cell adhesion receptors for targeting drug molecules to a specific type of cells. The short-term objective is to simultaneously target both antigenic (PLP139-151) and cell adhesion (cIBR-7) peptides to antigen presenting cells (APC) by forming PLP-cIBR conjugate called bifunctional peptide inhibitor (BPI). PLP-cIBR has been shown to suppress the development of experimental allergic encephalomyelitis (EAE) in the mouse model. The central hypothesis is that the PLP-cIBR molecule simultaneously binds to the major histocompatibility complex-II (MHC-II, I-As) and leukocyte function-associated antigen-1 (LFA-1) on APC and inhibits "immunological synapse" formation at the interface between T cell and APC. In a parallel work, two different BPI molecules called PLP-BPI and GAD-BPI suppressed the progress of EAE in SJL mice and type-1 diabetes in NOD mice, respectively. The hypothesis is that targeting BPI molecules to APC alter the activation of T cells in antigenic specific manner. If this hypothesis is proven, BPI molecules have wide implications for inducing other immunotolerance in many different autoimmune diseases such as rheumatoid arthritis, lupus, and psoriasis. In this project, we will design PLP-cIBR derivatives to enhance the in vivo activity and lowering the side effects by altering the linker, PLP peptide, and cIBR7 peptide. Secondly, the long-term effects of treatment with PLP-cIBR and its cross-reactivity with other antigen will be determined. Finally, the mechanism of action of PLP-cIBR will be evaluated by understanding the binding properties of PLP-cIBR to MHC-II and LFA-1 on the surface of APC and the expressed receptors.