title: Primary vascularization of allografts governs their immunogenicity and susceptibility to tolerogenesis.
abstract: We investigated the influence of allograft primary vascularization on alloimmunity, rejection, and tolerance in mice. First, we showed that fully allogeneic primarily vascularized and conventional skin transplants were rejected at the same pace. Remarkably, however, short-term treatment of mice with anti-CD40L Abs achieved long-term survival of vascularized skin and cardiac transplants but not conventional skin grafts. Nonvascularized skin transplants triggered vigorous direct and indirect proinflammatory type 1 T cell responses (IL-2 and IFN-γ), whereas primarily vascularized skin allografts failed to trigger a significant indirect alloresponse. A similar lack of indirect alloreactivity was also observed after placement of different vascularized organ transplants, including hearts and kidneys, whereas hearts placed under the skin (nonvascularized) triggered potent indirect alloresponses. Altogether, these results suggest that primary vascularization of allografts is associated with a lack of indirect T cell alloreactivity. Finally, we show that long-term survival of vascularized skin allografts induced by anti-CD40L Abs was associated with a combined lack of indirect alloresponse and a shift of the direct alloresponse toward a type 2 cytokine (IL-4, IL-10)-secretion pattern but no activation/expansion of Foxp3(+) regulatory T cells. Therefore, primary vascularization of allografts governs their immunogenicity and tolerogenicity.
authors.affiliation: Transplantation Unit and Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Cavit D
authors.initials: CD
authors.lastname: Kant
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tanaka
authors.forename: Susan
authors.initials: S
authors.lastname: Shea
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Connolly
authors.forename: Sharon
authors.initials: S
authors.lastname: Germana
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Winn
authors.forename: Christian
authors.initials: C
authors.lastname: LeGuern
authors.forename: Georges
authors.initials: G
authors.lastname: Tocco
authors.forename: Gilles
authors.initials: G
authors.lastname: Benichou
mesh_terms: D064591:Allografts; D000714:Anastomosis, Surgical; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival; D016027:Heart Transplantation; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D012867:Skin / Q000098:blood supply*; D016038:Skin Transplantation; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology*; D019737:Transplants / Q000098:blood supply*
chemical_list: D000911:Antibodies, Monoclonal; D023201:CD40 Ligand; D007371:Interferon-gamma