title: The Macrophage-depleting Agent Clodronate Promotes Durable Hematopoietic Chimerism and Donor-specific Skin Allograft Tolerance in Mice.
abstract: Hematopoietic chimerism is known to promote donor-specific organ allograft tolerance; however, clinical translation has been impeded by the requirement for toxic immunosuppression and large doses of donor bone marrow (BM) cells. Here, we investigated in mice whether durable chimerism might be enhanced by pre-treatment of the recipient with liposomal clodronate, a macrophage depleting agent, with the goal of vacating BM niches for preferential reoccupation by donor hematopoietic stem cells (HSC). We found that liposomal clodronate pretreatment of C57BL/6 mice permitted establishment of durable hematopoietic chimerism when the mice were given a low dose of donor BM cells and transient immunosuppression. Moreover, clodronate pre-treatment increased durable donor-specific BALB/c skin allograft tolerance. These results provide proof-of-principle that clodronate is effective at sparing the number of donor BM cells required to achieve durable hematopoietic chimerism and donor-specific skin allograft tolerance and justify further development of a tolerance protocol based on this principle.
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zhanzhuo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xingmin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
mesh_terms: D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D046528:Chimerism / Q000187:drug effects*; D004002:Clodronic Acid / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016038:Skin Transplantation / Q000379:methods*; D023001:Transplantation Tolerance / Q000187:drug effects*
chemical_list: D004002:Clodronic Acid