title: Immunosenescence does not abrogate engraftment of murine allogeneic bone marrow.
abstract: BACKGROUND
  Allogeneic bone marrow transplantation is under investigation for a range of nonmalignant indications, including tolerance induction through mixed chimerism. This strategy has so far been tested experimentally only in young recipients. Due to immunosenescence, older patients have an increase in memory T cells (TMEM) as well as other alterations to their immune system, which may influence the potential to induce tolerance. We therefore investigated the impact of immunosenescence on chimerism-based tolerance induction.
  
  
  METHODS
  Groups of young (2 months) and old (12 months) C57BL/6 recipients received BALB/c bone marrow under nonmyeloablative (3 Gy) and minimal (1 Gy) total body irradiation and treatment with costimulation blockade, T-cell depletion, or rapamycin. Multilineage chimerism, clonal deletion, and lymphocyte subsets were analyzed by flow cytometry. Tolerance was assessed by skin and heart grafts and enzyme-linked immunospot, intracellular cytokine, and mixed lymphocyte reaction assays.
  
  
  RESULTS
  Unexpectedly, chimerism and tolerance were established in old recipients with comparable-and in some cases increased-efficacy as in young recipients employing costimulation blockade-based or T-cell depletion-based conditioning with 1 or 3 Gy total body irradiation. TMEM reactivity in (naïve) old mice was augmented in response to polyclonal but not to allogeneic stimulation, providing a mechanistic underpinning for the susceptibility to chimerism induction despite increased TMEM frequencies. Tolerance in old recipients was associated with peripheral and central clonal deletion and a higher frequency of regulatory T cells.
  
  
  CONCLUSIONS
  Advanced age does not impair bone marrow engraftment, thereby widening the clinical potential of experimental protocols inducing transplantation tolerance through mixed chimerism.
authors.affiliation: Division of Transplant Surgery, and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Hock
authors.forename: Rupert
authors.initials: R
authors.lastname: Oberhuber
authors.forename: Ying-Lung
authors.initials: YL
authors.lastname: Lee
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Tullius
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007156:Immunologic Memory; D008212:Lymphocyte Depletion; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D018183:Transplantation Chimera / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology*
chemical_list: D016207:Cytokines