title: Rapid lethality of hosts by interleukin-12 following H-2 compatible allogeneic bone marrow transplantation: Reminiscence of gut-associated acute graft-versus-host reaction.
abstract: T lymphocytes and NK cells play an important role in the graft-versus-host (GVH) disease. IL-12 is known to activate both lymphocyte subpopulations. Here, we examined the effect of IL-12 on the outcome after allogenic bone marrow transplantation (allo-BMT). Experiments were performed in a major histocompatibility complex (MHC)-matched allo-BMT model from DBA/2 to BALB/c mice. We administered IL-12 subcutaneously to recipient BALB/c mice at the day of BMT and 2 days later. At a dose of 200 ng IL-12, mice died between day 4 and day 10. When 50 ng of IL-12 was administered, 50% of the animals died, at a dose of 25 ng all mice recovered. In vivo blocking experiments with antagonistic monoclonal antibodies indicated that the early lethality was mediated by FasL, IFNgamma and TNFalpha. Recognition of third party antigens by donor, but not recipient lymphocytes caused lethality. HE staining of the large intestine of IL-12 treated animals showed a severe mucosal injury associated with infiltrating lymphocytes and apoptotic bodies. In IL-12 treated mice in contrast to untreated control animals, flow cytometry analysis revealed numerous CD3+ T cells and CD11c+ dendritic cells (DC) were found in the large intestine. The interaction of T cells and antigen presenting DC might contribute to the lethality in our system. In light of these findings, the usefulness of IL-12 application for patients after BMT is rather questionable.
authors.affiliation: Third Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany. michael.schmitt@medizin.uni-ulm.de
authors.forename: Michael
authors.initials: M
authors.lastname: Schmitt
authors.forename: Masanori
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyahara
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Gu
authors.forename: Katanori
authors.initials: K
authors.lastname: Mukai
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hartmut
authors.initials: H
authors.lastname: Dohner
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000401:mortality; D039521:CD11c Antigen / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002469:Cell Separation; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D007420:Intestine, Large / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009092:Mucous Membrane / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D039521:CD11c Antigen; D017252:CD3 Complex; D018664:Interleukin-12; D007371:Interferon-gamma