title: Induction of allograft tolerance by monoclonal CD3 antibodies: a matter of timing.
abstract: Despite remarkable progress in organ transplantation through the development of a wealth of immunosuppressive drugs highly effective at controlling acute rejection, two major problems still remain, the loss of transplants due to chronic rejection and the growing number of sensitized recipients due to previous transplants, transfusions or pregnancies. Induction of immune tolerance appears to be the only way to curb this complex situation. Here we describe that a therapy, already successfully used to restore immune tolerance to self-antigens in overt autoimmunity, is effective at promoting transplant tolerance. We demonstrate that a short low-dose course with CD3 antibodies started after transplantation, at the time of effector T cell priming to alloantigens, induces permanent acceptance of fully mismatched islet allografts. Mechanistic studies revealed that antigen-specific regulatory and effector T cells are differentially affected by the treatment. CD3 antibody treatment preferentially induces apoptosis of activated alloreactive T cells which is mandatory for tolerance induction. In contrast, regulatory T cells are relatively spared from CD3 antibody-induced depletion and can transfer antigen-specific tolerance thus arguing for their prominent role in sustaining long-term graft survival.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité U1013, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: You
authors.forename: J
authors.initials: J
authors.lastname: Zuber
authors.forename: C
authors.initials: C
authors.lastname: Kuhn
authors.forename: M
authors.initials: M
authors.lastname: Baas
authors.forename: F
authors.initials: F
authors.lastname: Valette
authors.forename: V
authors.initials: V
authors.lastname: Sauvaget
authors.forename: S
authors.initials: S
authors.lastname: Sarnacki
authors.forename: B
authors.initials: B
authors.lastname: Sawitzki
authors.forename: J-F
authors.initials: JF
authors.lastname: Bach
authors.forename: H-D
authors.initials: HD
authors.lastname: Volk
authors.forename: L
authors.initials: L
authors.lastname: Chatenoud
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology / Q000494:pharmacology*; D017690:Cell Transplantation / Q000379:methods; D004195:Disease Models, Animal; D006084:Graft Rejection; D006085:Graft Survival; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013997:Time Factors; D014181:Transplantation Immunology / Q000502:physiology; D023001:Transplantation Tolerance / Q000276:immunology* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007519:Isoantigens