T lymphocytes are key components of host immune defenses but they are also implicated in immunologic diseases including chronic inflammatory and autoimmune diseases and graft rejection. T cell integrins typified by LFA-1 play a critical role in T cell immunity. The beneficial roles of LFA-1 in T cell immunity are well known, however overexpression of LFA-1 and its natural ligand ICAM-1 is often observed in tissues affected by chronic inflammation and autoimmune diseases. This suggests that LFA-1/ICAM-1 interaction is a critical element in disease initiation and/or deterioration. Indeed, it has been observed that treating patients of chronic inflammatory and autoimmune diseases with anti LFA-1 mAb significantly reduces the disease progression. Although clinical efficacy has been demonstrated for anti-LFA-1 mAbs, their therapeutic uses are limited by their high cost of manufacture, lack of oral bioavailability (i.e. can't not orally administered) and their immunogenecity following long term treatments. For these reasons, small molecule drugs which inhibit the LFA-1/ICAM-1 interaction are actively being sought. P.I. has previously shown that T cells absorb nano-sized membrane vesicles (< 200 nm in diameter) expressing cognate MHC/pep complex and ICAM-1 via specific receptor/ligand interactions (i.e. TCR/MHC/pep and LFA-1/ICAM-1 interactions). Follow-up experiments demonstrated that an intracellular signaling network ('inside-out' signaling) is absolutely necessary for LFA-1 activation and hence T cell absorption of membrane vesicles. Based on these previous studies, P.I. proposes here a cell-based high throughput screening platform to isolate small molecules which inhibit the absorption process. Inhibition of T cell absorption of membrane vesicles can be effected through at least three different mechanisms: (i) interruption of the TCR/MHC/pep interaction, (ii) interruption of the LFA-1/ICAM-1 interaction, i) disruption of the 'inside-out' signaling network. In summary, this proposal seeks to identify and develop small molecule drugs which interfere with T cell absorption of membrane vesicles as potential treatments for chronic inflammatory and autoimmune diseases and graft rejection. In addition, careful examination of inhibitory mechanisms of identified small molecules will provide valuable information for elucidating the molecular mechanisms of the 'inside-out' signaling and structural biology of the TCR/MHC/pep and LFA-1/ICAM-1 interactions. ? ? ?
| Hwang, Inkyu; Ki, DaLim (2011) Receptor-mediated T cell absorption of antigen presenting cell-derived molecules. Front Biosci (Landmark Ed) 16:411-21 |
| Kim, Kwangmi; Wang, Lin; Hwang, Inkyu (2009) LFA-1-dependent Ca2+ entry following suboptimal T cell receptor triggering proceeds without mobilization of intracellular Ca2+. J Biol Chem 284:22149-54 |
| Kim, Kwangmi; Wang, Lin; Hwang, Inkyu (2009) Acute inhibition of selected membrane-proximal mouse T cell receptor signaling by mitochondrial antagonists. PLoS One 4:e7738 |
| Kim, Kwangmi; Wang, Lin; Hwang, Inkyu (2009) A novel flow cytometric high throughput assay for a systematic study on molecular mechanisms underlying T cell receptor-mediated integrin activation. PLoS One 4:e6044 |
