title: The role of non-deletional tolerance mechanisms in a murine model of mixed chimerism with costimulation blockade.
abstract: Peripheral and central clonal deletion are important tolerance mechanisms in models using bone marrow transplantation (BMT) with costimulation blockade (CB). However, since tolerance can be found before peripheral deletion is complete and since elimination of recipient CD4(+) cells at the time of BMT prevents tolerance induction, we investigated the potential roles of regulation and anergy in such a murine model. We found that transient elimination of CD25(+) cells or neutralization of IL2 immediately after BMT and CB prevented the induction of skin graft tolerance. Cotransfer into SCID mice of CD4(+) cells taken from chimeras early after BMT, together with naive recipient-type CD4(+) cells significantly prolonged donor skin graft survival. In contrast, cotransfer of CD4(+) cells harvested from chimeras late after BMT did not prolong donor skin graft survival. Besides, depletion of CD25(+) cells in established chimeras several months post-BMT did not break tolerance. In vivo administration of recombinant IL2 inhibited chimerism and tolerance neither early nor late post-BMT, arguing against a decisive role for classical anergy. Thus, CD4 cell-mediated regulation contributes significantly to tolerance induction early after BMT, but appears to have no critical role in the maintenance of tolerance.
authors.affiliation: Division of Transplantation, Department of Surgery, Vienna General Hospital, Medical University of Vienna, Austria.
authors.forename: Sinda
authors.initials: S
authors.lastname: Bigenzahn
authors.forename: Peter
authors.initials: P
authors.lastname: Blaha
authors.forename: Zvonimir
authors.initials: Z
authors.lastname: Koporc
authors.forename: Ines
authors.initials: I
authors.lastname: Pree
authors.forename: Edgar
authors.initials: E
authors.lastname: Selzer
authors.forename: Helga
authors.initials: H
authors.lastname: Bergmeister
authors.forename: Friedrich
authors.initials: F
authors.lastname: Wrba
authors.forename: Christoph
authors.initials: C
authors.lastname: Heusser
authors.forename: Kathrin
authors.initials: K
authors.lastname: Wagner
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Muehlbacher
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology / Q000502:physiology*; D017637:Clonal Deletion / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D016038:Skin Transplantation / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D023201:CD40 Ligand