title: Immunologic considerations for therapeutic strategies utilizing allogeneic hepatocytes: hepatocyte-expressed membrane-bound major histocompatibility complex class I antigen sensitizes while soluble antigen suppresses the immune response in rats.
abstract: Understanding the immunologic effects of hepatocytes is critical because of the potential to use these cells for bioartificial livers, as a vehicle for gene transfer, and as a means to induce donor-specific immunosuppression in organ transplantation. However, this understanding is complicated by the fact that hepatocytes express membrane-bound and soluble forms of major histocompatibility complex (MHC) class I antigen, each with the potential to induce different immune responses. In the present study we first determined the immunologic effect of normal donor-derived hepatocytes in a rat heart transplant model. We then used ex vivo hepatocyte gene transfer to examine the immunologic effects of different forms of hepatocyte-expressed MHC class I antigen. Results showed that intrasplenic injection of purified, donor-strain-specific hepatocytes into recipients primes alloimmunity, as evidenced by acceleration of heart allograft rejection. Interestingly, injection of autologous hepatocytes transfected ex vivo with DNA encoding only membrane-bound donor MHC class I antigen (RT1.A(a)) also accelerated allograft rejection. However, hepatocytes transfected to express only secreted donor MHC antigen prolonged transplant survival. Limiting-dilution analysis of lymphocytes from animals treated with hepatocytes producing only secreted alloantigen showed an antigen-specific reduction in cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) precursors. Further analysis of CTL populations by flow cytometry revealed a relatively high percentage of nonviable cells, implying that soluble antigen promotes allospecific CTL death. In summary, this study suggests that hepatocyte-expressed MHC class I molecules have opposing immunologic effects, with the membrane-bound antigen inducing immunologic sensitization, and the soluble antigen promoting donor-specific immunosuppression.
authors.affiliation: University of South Alabama, Department of Clinical Laboratory Sciences, Mobile, AL, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Scherer
authors.forename: C
authors.initials: C
authors.lastname: Graeb
authors.forename: S
authors.initials: S
authors.lastname: Tange
authors.forename: C
authors.initials: C
authors.lastname: Dyson
authors.forename: K W
authors.initials: KW
authors.lastname: Jauch
authors.forename: E K
authors.initials: EK
authors.lastname: Geissler
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000502:physiology; D002462:Cell Membrane / Q000276:immunology; D017690:Cell Transplantation; D018014:Gene Transfer Techniques; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology* / Q000502:physiology; D007114:Immunization; D007167:Immunotherapy / Q000379:methods*; D007519:Isoantigens / Q000276:immunology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012995:Solubility; D013234:Stem Cells / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D006649:Histocompatibility Antigens; D015395:Histocompatibility Antigens Class I; D007519:Isoantigens; C038353:histocompatibility antigens RT, rat