title: Transient depletion of dividing T lymphocytes in mice induces the emergence of regulatory T cells and dominant tolerance to islet allografts.
abstract: We previously showed that transient depletion of dividing T cells at the time of an allogeneic transplantation induces long-term tolerance to the allograft. Here we investigated the role of homeostatic perturbation and regulatory T cells (Treg) in such tolerance. Transient depletion of dividing T cells was induced at the time of an allogeneic pancreatic islets graft, by administration of ganciclovir for 14 days, into diabetic transgenic mice expressing a thymidine kinase (TK) conditional suicide gene in T cells. Allograft tolerance was obtained in 63% of treated mice. It was not due to global immunosuppression, permanent deletion or anergy of donor-alloantigens specific T cells but to a dominant tolerance process since lymphocytes from tolerant mice could transfer tolerance to naïve allografted recipients. The transient depletion of dividing T cells induces a 2- to 3-fold increase in the proportion of CD4(+)CD25(+)Foxp3(+) Treg, within 3 weeks that persisted only in allograft-bearing mice but not in nongrafted mice. Tolerance with similar increased proportion of Treg cells was also obtained after a cytostatic hydroxyurea treatment in normal mice. Thus, the transient depletion of dividing T cells represents a novel means of immuno-intervention based on disturbance of T-cell homeostasis and subsequent increase in Treg proportion.
authors.affiliation: UPMC Univ Paris 06, U543, Laboratoire d'Immunologie Cellulaire et Tissulaire, Paris F-75013 France.
authors.forename: S
authors.initials: S
authors.lastname: Giraud
authors.forename: B
authors.initials: B
authors.lastname: Barrou
authors.forename: S
authors.initials: S
authors.lastname: Sebillaud
authors.forename: P
authors.initials: P
authors.lastname: Debré
authors.forename: D
authors.initials: D
authors.lastname: Klatzmann
authors.forename: V
authors.initials: V
authors.lastname: Thomas-Vaslin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D006918:Hydroxyurea / Q000494:pharmacology; D007108:Immune Tolerance; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D023421:Models, Animal; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D006918:Hydroxyurea