The Role Of ICOS:ICOSL Costimulatory Pathway In Allograft Immunology And Its Related Mechanisms

This study has five parts: In the first part we constructed the human inducible costimulator and human IgG1 Fc fusion protein expression system in Chinese hamster ovary (CHO) cells. In the second part we identified the physical and chemical properties of ICOS-Ig fusion protein. In the third part we used ICOS-Ig to block ICOS:ICOSL costimulation to certain ICOS:ICOSL forward signaling into T cells. ICOS-Ig could inhibit alloreactive T cell proliferation, and induce donor-specific T cell hyporesponsiveness, that is to say, induction of donor-specific tolerance. In the fourth part we used ICOS-Ig to binding its ligand ICOSL on dendritic cells (DCs) to investigate whether ICOS:ICOSL could activate a functional response in ICOSL-expressing APCs through reverse signaling. ICOS-Ig inhibited the maturation of DCs and the allostimulatory capacity of DCs. MAPK signaling pathways were involved in the ICOS-Ig-mediated impairment of DCs maturation. In the fifth part we established a cardiac transplantation model to investigate the role of ICOS:ICOSL bidirectional signaling in allograft immunology. ICOS-Ig prolonged allocardiac engraftment, and ICOS-Ig combined CsA group leaded even longer engraftment than ICOS-Ig and CsA single usage.