Therapeutic Significance of Novel Immunosuppressive Antibody 16G9 and Its Targeting Histone H1 Peptides

The mechanism underlying the molecular and cellular immunology in liver transplant tolerogenicity is still poorly understood. Recent proteomic approach allows us to target on specific molecules of liver suppressor factors underlying the common mechanism between experimental and clinical liver allograft tolerance. We demonstrated that autoantibody (auto-Ab) against histone H1 plays an important role in experimental and clinical liver allograft tolerance as a natural immunosuppressive factor (Nakano T, et al. Transplantation 2004 and Transplantation 2007). To demonstrate the fundamental mechanisms of nuclear histone H1 and corresponding auto-Ab, we have recently generated a novel anti-histone H1 IgM mAb produced by a hybridoma strain: 16G9 (16G9 mAb); the Ab showed MLR-inhibitory activity (Shimada Y, et al. Biomed Chromatogr 2008). We have used a combinatorial phage display peptide library to screen for peptides that bind to 16G9 mAb. In our previous study, two peptides binding directly to 16G9 mAb (SSV and LPQ) were selected from the library (Chiang KC, et al. Journal of Immunology (revised)). Thanks to the present grant support from NSC (NSC-95-2320-B-182A-006: 97/08/01-98/07/31), we demonstrated the involvement of autoimmunity against histone H1 for overcoming rejection and subsequent tolerance induction (Nakano T, et al. Transplant Immunology 2008). Our recent findings suggested that two peptides could be a functional histone H1-binding epitope for 16G9 mAb, which will be capable of determining serum immunoreactivity against histone H1 as an index marker for tolerance and may serve as a potential diagnostic tool in organ transplantation. However, much remains to be solved for understanding the mechanisms and therapeutic significance of 16G9 mAb and its targeting peptides. In this project, we will further explore therapeutic significance of 16G9 mAb and its targeting investigate peptides SSV and LPQ in organ transplantation (1st year). We also will explore the availability of histone H1 peptides as non-invasive diagnostic tool for determining rejection and tolerance both in experimental OLT models and clinical liver transplantation (2nd year). Finally, immune modulation activity of 16G9 mAb or histone H1 peptide vaccine therapy and its mechanisms will be studied in vitro and in vivo for future clinical application not only in organ transplantation but also in autoimmunity and allergy (3rd year).

Project ID:PC9902-1681
External Project ID:NSC98-2320-B182-029-MY3