title: Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice.
abstract: One of the main unresolved questions in solid organ transplantation is how to establish indefinite graft survival that is free from long-term treatment with immunosuppressive drugs and chronic rejection (i.e., the establishment of tolerance). The failure to achieve this goal may be related to the difficulty in identifying the phenotype and function of the cell subsets that participate in the induction of tolerance. To address this issue, we investigated the suppressive roles of recipient myeloid cells that may be manipulated to induce tolerance to transplanted hearts in mice. Using depleting mAbs, clodronate-loaded liposomes, and transgenic mice specific for depletion of CD11c+, CD11b+, or CD115+ cells, we identified a tolerogenic role for CD11b+CD115+Gr1+ monocytes during the induction of tolerance by costimulatory blockade with CD40L-specific mAb. Early after transplantation, Gr1+ monocytes migrated from the bone marrow into the transplanted organ, where they prevented the initiation of adaptive immune responses that lead to allograft rejection and participated in the development of Tregs. Our results suggest that mobilization of bone marrow CD11b+CD115+Gr1+ monocytes under sterile inflammatory conditions mediates the induction of indefinite allograft survival. We propose that manipulating the common bone marrow monocyte progenitor could be a useful clinical therapeutic approach for inducing transplantation tolerance.
authors.affiliation: Inmunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Madrid, Spain.
authors.forename: Mercedes Rodriguez
authors.initials: MR
authors.lastname: Garcia
authors.forename: Levi
authors.initials: L
authors.lastname: Ledgerwood
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.forename: Jiangnan
authors.initials: J
authors.lastname: Xu
authors.forename: Girdhari
authors.initials: G
authors.lastname: Lal
authors.forename: Bryna
authors.initials: B
authors.lastname: Burrell
authors.forename: Ge
authors.initials: G
authors.lastname: Ma
authors.forename: Daigo
authors.initials: D
authors.lastname: Hashimoto
authors.forename: Yansui
authors.initials: Y
authors.lastname: Li
authors.forename: Peter
authors.initials: P
authors.lastname: Boros
authors.forename: Marcos
authors.initials: M
authors.lastname: Grisotto
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Rafael
authors.initials: R
authors.lastname: Matesanz
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.forename: Florent
authors.initials: F
authors.lastname: Ginhoux
authors.forename: Yaozhong
authors.initials: Y
authors.lastname: Ding
authors.forename: Shu-Hsia
authors.initials: SH
authors.lastname: Chen
authors.forename: Gwendalyn
authors.initials: G
authors.lastname: Randolph
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bromberg
authors.forename: Jordi C
authors.initials: JC
authors.lastname: Ochando
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D023201:CD40 Ligand