title: Pre-treatment of allogeneic bone marrow recipients with the CXCR4 antagonist AMD3100 transiently enhances hematopoietic chimerism without promoting donor-specific skin allograft tolerance.
abstract: Hematopoietic chimerism established by allogeneic bone marrow transplantation is known to promote donor-specific organ allograft tolerance; however, clinical application is limited by the need for toxic host conditioning and "megadoses" of donor bone marrow cells. A potential solution to this problem has been suggested by the observation that recipient bone marrow mobilization by the CXCR4 antagonist AMD3100 promotes chimerism in congenic bone marrow transplantation experiments in mice. Here we report that a single subcutaneous dose of 10 mg/kg AMD3100 in recipient C57BL/6 mice was able to enhance hematopoietic chimerism when complete MHC-mismatched BALB/c donor bone marrow cells were transplanted 1h after drug dosing. However, levels of chimerism measured 30 days post-transplantation were not sustained when mice were reexamined on day 90 post-transplantation. Moreover, transient chimerism induced by this protocol did not support robust donor-specific skin allograft tolerance. Using the same transient immunosuppression protocol, we confirmed that "megadoses" of donor bone marrow cells could induce durable chimerism associated with donor-specific skin allograft tolerance without AMD3100 pre-treatment. We conclude that in this protocol AMD3100 pretreatment may empty bone marrow niches that become reoccupied by allogeneic donor hematopoietic progenitor cells but not by true long-lived donor hematopoietic stem cells, resulting in short-lived chimerism and failure to support durable donor-specific allograft tolerance.
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: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ido D
authors.initials: ID
authors.lastname: Weiss
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health, Bethesda, MD, USA.
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA. Electronic address: pmm@nih.gov.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001596:Benzylamines; D016026:Bone Marrow Transplantation; D046528:Chimerism; D000080027:Cyclams; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D006649:Histocompatibility Antigens / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D016038:Skin Transplantation; D055153:Stem Cell Niche / Q000187:drug effects; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000187:drug effects
chemical_list: D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D006649:Histocompatibility Antigens; D019718:Receptors, CXCR4; C088327:plerixafor
keywords: AMD3100; Bone marrow mobilization; CXCR4; Mixed chimerism; Tolerance