TET2 Driven Clonal Hematopoiesis Promotes Allograft Tolerance in a Mouse Heart Transplant Model
| Autor: | Inessa Lokshina, Hao Dun, L.R. Gokanapudy Hahn, Andrea L. Bredemeyer, Daniel Kreisel, Luigi Adamo, Kory J. Lavine, S. Yang, F. Kadyrov |
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| Rok vydání: | 2021 |
| Předmět: |
Pulmonary and Respiratory Medicine
Heart transplantation Transplantation Adoptive cell transfer education.field_of_study business.industry medicine.medical_treatment Population Immunosuppression medicine.anatomical_structure Immunology medicine Surgery Bone marrow Progenitor cell Cardiology and Cardiovascular Medicine business education Survival analysis |
| Zdroj: | The Journal of Heart and Lung Transplantation. 40:S228 |
| ISSN: | 1053-2498 |
| Popis: | Purpose Clonal hematopoiesis (CH) is the result of clonal expansion of hematopoietic progenitors within the bone marrow (BM) that harbor mutations that confer fitness advantage relative to the background population. These clones can expand to become a dominant source of peripheral blood cells. Clonal mutations in TET2 (chromatin demethylase) have the strongest association with cardiovascular mortality and are prevalent in heart failure patients. Increased production of cytokines (i.e., interleukin-1β) by monocytes and macrophages may represent the underlying mechanism by which TET2 CH contributes to accelerated atherosclerosis and heart failure progression. The impact of TET2 CH on heart transplantation remains unexplored. Methods We established an adoptive BM transplantation CH model. Unfractionated BM (1.5 × 107cells) harvested from C57/B6 control or TET2-/- mice was injected into syngeneic C57/B6 UBC-GFP animals on three consecutive days. The extent of peripheral chimerism was assessed by flow cytometry 4-8 weeks after adoptive transfer. We then transplanted Balb/c donor hearts into chimeric C57/B6 recipient mice. All mice received CTLA4 Ig (days 0, 2 4, 6) for immunosuppression. The primary endpoint was a time to event analysis of allograft survival assessed by daily palpation. Secondary endpoints included histology, immunohistochemistry, and measurement of donor alloreactive T-cells and antibodies. Results Adoptive transfer of C57/B6 control BM into C57/B6 UBC-GFP mice led to diminished chimerism (0.6% - 3.6%) compared to adoptive transfer of C57/B6 TET2-/- BM into C57/B6 UBC-GFP mice (32 - 34.6%). We observed marked differences in donor heart survival between experimental groups. Following transplantation, recipient mice that received control BM displayed an average survival of 18 days, whereas recipient mice that received TET2-/- BM demonstrated evidence of long-term survival with 2/3 of mice surviving beyond 60 days (p Conclusion TET2 driven CH confers protection from allograft rejection and promotes long-term allograft acceptance in mice. |
| Databáze: | OpenAIRE |
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