title: Recombinant CD95-Fc (APG101) prevents graft-versus-host disease in mice without disabling antitumor cytotoxicity and T-cell functions.
abstract: Graft-versus-host disease (GVHD) induced by transplant-derived T cells represents a major complication after allogeneic bone marrow transplantation (BMT). However, these T cells support engraftment, early T-cell immunity, and mediate the graft-versus-tumor (GVT) effect. Cytotoxic effector functions by transplanted T cells are predominantly mediated by the perforin/granzyme and the CD95/CD95L system. APG101, a novel recombinant human fusion protein consisting of the extracellular domain of CD95 and the Fc domain of an IgG1 antibody inhibited CD95L-induced apoptosis without interfering with T-cell function in vitro and was therefore tested for its ability to prevent GVHD in murine BMT models across minor or major histocompatibility barriers. Starting APG101 treatment either 1 day before or 6 days after transplantation effectively reduced clinical GVHD and rescued survival between 60% and 100% if GVHD was CD95L mediated. APG101 did not interfere with the GVT effect, because P815 mastocytoma and most importantly primary Bcr-Abl-transformed B-cell leukemias were completely eradicated by the alloantigen-specific T cells. Phenotype and homing of alloantigen-specific T cells or their perforin/granzyme-mediated cytotoxicity and proliferative capacity were not affected by APG101 treatment suggesting that APG101 therapy might be useful in GVHD prophylaxis without impairing T-cell function and most importantly preserving GVT activity.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstrasse 24, Ulm, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Hartmann
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Messmann
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.forename: Maxi
authors.initials: M
authors.lastname: Weiswange
authors.forename: Michael
authors.initials: M
authors.lastname: Kluge
authors.forename: Harald
authors.initials: H
authors.lastname: Fricke
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Gudrun
authors.initials: G
authors.lastname: Strauss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009369:Neoplasms / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology*; D014184:Transplantation, Homologous; D019014:fas Receptor / Q000276:immunology / Q000494:pharmacology*
chemical_list: D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; C574675:APG101