Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients
| Autor: | Natalie Lister, Maree V. Hammett, J. Homann, M A Malin, Daniel S. Layton, Jessica Kate Morison, Alison N. Thorburn, Richard L. Boyd, Ann P. Chidgey, Tracy Heng |
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| Rok vydání: | 2014 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male Aging Transplantation Conditioning medicine.medical_treatment CD8-Positive T-Lymphocytes Mice 03 medical and health sciences 0302 clinical medicine Immune system Transplantation Immunology Immune Tolerance medicine Animals Immunology and Allergy Pharmacology (medical) Progenitor cell 030304 developmental biology Mice Inbred BALB C 0303 health sciences Transplantation business.industry Immunosuppression 3. Good health Mice Inbred C57BL Tolerance induction medicine.anatomical_structure Sirolimus Immunology Bone marrow business Whole-Body Irradiation Busulfan 030215 immunology medicine.drug |
| Zdroj: | American Journal of Transplantation. 14:2478-2490 |
| ISSN: | 1600-6135 |
| DOI: | 10.1111/ajt.12929 |
| Popis: | Mixed hematopoietic chimerism is a powerful means of generating donor-specific tolerance, allowing long-term graft acceptance without lifelong dependence on immunosuppressive drugs. To avoid the need for whole body irradiation and associated side effects, we utilized a radiation-free minimal conditioning regime to induce long-term tolerance across major histocompatibility barriers. We found that low-dose busulfan, in combination with host T cell depletion and short-term sirolimus-based immunosuppression, facilitated efficient donor engraftment. Tolerance was achieved when mice were transplanted with whole or T cell-depleted bone marrow, or purified progenitor cells. Tolerance induction was associated with an expansion in regulatory T cells and was not abrogated in the absence of a thymus, suggesting a dominant or compensatory peripheral mode of tolerance. Importantly, we were able to generate durable chimerism and tolerance to donor skin grafts in both young and aged mice, despite age-related thymic atrophy and immune senescence. Clinically, this is especially relevant as the majority of transplant recipients are older patients whose immune recovery might be dangerously slow and would benefit from radiation-free minimal conditioning regimes that allow efficient donor engraftment without fully ablating the recipient immune system. |
| Databáze: | OpenAIRE |
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