Impact of Immunosenescence on Bone Marrow Transplantation (BMT) and Chimerism, The
Department of Surgery, Medical University of Vienna, Vienna, Austria
Division of Transplant Surgery and Transplant Surgery Research Lab, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
Meeting: 2013 American Transplant Congress
Abstract number: B1108
Background:
Tolerance induction through mixed chimerism holds promise for clinical translation but has only been investigated in young recipients. Changing demographics and an accumulation of older individuals seeking treatment require to investigate the impact of immunosenescence on the outcome of mixed chimerism based tolerance induction.
Methods:
Young (2mth;20g) and old (12mth;30g) recipients (C57BL/6) were treated with 5 different BMT protocols: Animals received 1) 3Gy total body irradiation (TBI) and costimulation blockade (CB: anti-CD154mAb and CTLA4Ig), 2) T-cell-depletion (TCD: anti-CD4 and anti-CD8), 3) 1Gy and CB or 4 and 5) rapamycin with and without irradiation. In each protocol recipients were transplanted with un-separated Balb/c BM cells adjusted to body weight (1×103/kg, i.e. young 20×106/mouse; old 30×106/mouse). Lymphocyte subsets and cytokine production were compared between young and old naÏve mice and multi-lineage chimerism was assessed by flow cytometry.
Results:
Successful chimeras were achieved age-independently following non-myeloablative TBI (3Gy) together with CB (7/8 old vs. 11/11 young). Of note, following T-cell-depletion chimerism levels were significantly higher in older recipients in all tested lineages (i.e. donor B-cell chimerism: 56.33% old vs. 18.17% young; p<0.0001; by week 8 after BMT). Moreover, under a less vigorous conditioning regimen (1Gy/CB), chimerism was achieved in most animals in an age-independent fashion (7/10 old vs. 6/6 young). In contrast, 1Gy irradiation in combination with rapamycin led to chimerism in only 2/6 old recipients and none of the young recipients; neither old nor young recipients became chimeric when animals were only treated with rapamycin. Notably, frequencies of Tregs among splenocytes of old BMT recipients had significantly increased. Moreover, T cell proliferation and IFN-Γ production after polyclonal but not allogeneic stimulation was increased in old mice.
Conclusion:
BM engraftment and chimerism were successfully induced in older recipients through Treg maintenance and a reduced alloreactivity response. Those results are of critical clinical relevance and support BMT and chimerism based tolerance induction for older patients.
To cite this abstract in AMA style:
Hock K, Oberhuper R, Lee Y, Wekerle T, Tullius S. Impact of Immunosenescence on Bone Marrow Transplantation (BMT) and Chimerism, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/impact-of-immunosenescence-on-bone-marrow-transplantation-bmt-and-chimerism-the/. Accessed May 17, 2025.« Back to 2013 American Transplant Congress