title: A novel approach inducing transplant tolerance by activated invariant natural killer T cells with costimulatory blockade.
abstract: Invariant natural killer T (iNKT) cells are one of the innate lymphocytes that regulate immunity, although it is still elusive how iNKT cells should be manipulated for transplant tolerance. Here, we describe the potential of a novel approach using a ligand for iNKT cells and suboptimal dosage of antibody for CD40-CD40 ligand (L) blockade as a powerful method for mixed chimerism establishment after allogenic bone marrow transplantation in sublethally irradiated fully allo recipients. Mixed-chimera mice accepted subsequent cardiac allografts in a donor-specific manner. High amounts of type 2 helper T cytokines were detected right after iNKT cell activation, while subsequent interferon-gamma production by NK cells was effectively inhibited by CD40/CD40L blockade. Tolerogenic components, such as CD11c(low) mPDCA1(+) plasmacytoid dendritic cells and activated regulatory T cells (Tregs) expressing CD103, KLRG-1 and PD-1, were subsequently augmented. Those activating Tregs seem to be required for the establishment of chimerism because depletion of the Tregs 1 day before allogenic cell transfer resulted in a chimerism brake. These results collectively suggest that our new protocol makes it possible to induce donor-specific tolerance by enhancement of the innate ability for immune tolerance in place of the conventional immunosuppression.
authors: Department of Urology, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan; Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors: T
authors: T
authors: Hirai
authors: Y
authors: Y
authors: Ishii
authors: M
authors: M
authors: Ikemiyagi
authors: E
authors: E
authors: Fukuda
authors: K
authors: K
authors: Omoto
authors: M
authors: M
authors: Namiki
authors: M
authors: M
authors: Taniguchi
authors: K
authors: K
authors: Tanabe
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000276:immunology; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage; D006085:Graft Survival / Q000276:immunology*; D006331:Heart Diseases / Q000276:immunology / Q000628:therapy*; D016027:Heart Transplantation; D007165:Immunosuppression Therapy; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D018183:Transplantation Chimera / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D005699:Galactosylceramides; D008081:Liposomes; C493154:alpha-galactosylceramide; D023201:CD40 Ligand
keywords: Costimulation blockade; invariant NKT; mixed chimerism; tolerance