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Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice.

ABSTRACT: The goal of this work was to determine the effect of nonablative syngeneic transplantation of young bone marrow (BM) to laboratory animals (mice) of advanced age upon maximum duration of their lifespan. To do this, transplantation of 100 million nucleated cells from BM of young syngeneic donors to an old nonablated animal was performed at the time when half of the population had already died. As a result, the maximum lifespan (MLS) increased by 28 ± 5%, and the survival time from the beginning of the experiment increased 2.8 ± 0.3-fold. The chimerism of the BM 6 months after the transplantation was 28%.

SUBMITTER: Kovina MV

PROVIDER: S-EPMC6473025 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice.

Kovina Marina V MV Karnaukhov Alexey V AV Krasheninnikov Mikhail E ME Kovin Artem L AL Gazheev Sarul T ST Sergievich Larisa A LA Karnaukhova Elena V EV Bogdanenko Elena V EV Balyasin Maxim V MV Khodarovich Yury M YM Dyuzheva Tatyana G TG Lyundup Alexey V AV

Frontiers in genetics 20190412

The goal of this work was to determine the effect of nonablative syngeneic transplantation of young bone marrow (BM) to laboratory animals (mice) of advanced age upon maximum duration of their lifespan. To do this, transplantation of 100 million nucleated cells from BM of young syngeneic donors to an old nonablated animal was performed at the time when half of the population had already died. As a result, the maximum lifespan (MLS) increased by 28 ± 5%, and the survival time from the beginning o ...[more]

PMID: 31031800

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Project description:BackgroundType 1 diabetes (T1D) is a multiple factor autoimmune disease characterized by T cell-mediated immune destruction of islet β cells. Autologous hematopoietic stem cell transplantation (AHSCT) has been a novel strategy for patients with new-onset T1D, but not for those with a later diagnosis. Disturbance of regulatory T cells (Tregs) likely contributes to poor response after transplantation in later-stage T1D. Inhibition of phosphoinositide 3-kinases (PI3K)/Akt signaling maintains Tregs' homeostasis.MethodsWe built a later-stage streptozotocin (STZ)-induced T1D mouse model. Syngeneic bone marrow transplantation (syn-BMT) was performed 20 days after the onset of diabetes in combination with BKM120 (a PI3K inhibitor). Meanwhile, another group of STZ-diabetic mice were transplanted with bone marrow cells cocultured with BKM120 in vitro for 24 h. Fasting glucose and glucose tolerance were recorded during the entire experimental observation after syn-BMT. Samples were collected 126 days after syn-BMT. Hematoxylin and eosin (H&E) staining was used to detect the effect of PI3K inhibitor combined with syn-BMT on morphology of the T1D pancreas. CD4+CD25- T cells and CD4+CD25+ T cells were sorted by magnetic cell sorting (MACS), then fluorescence activated cell sorting (FACS) and quantitative real-time PCR (qPCR) were used to detect the effect of PI3K inhibitor on modulating immune disorder and restoring the function of Treg cells.ResultsOur investigation showed syn-BMT in combination with BKM120 effectively maintained normoglycemia in later-stage T1D. The disease remission effects may be induced by the rebalance of Th17/Tregs dysregulation and restoration of Tregs' immunosuppressive function by BKM120 after syn-BMT.ConclusionsThese results may reveal important connections for PI3K/Akt inhibition and Tregs' homeostasis in T1D after transplantation. AHSCT combining immunoregulatory strategies such as PI3K inhibition may be a promising therapeutic approach in later-stage T1D.

Project description:Outcomes of nonmyeloablative (NMA), HLA-haploidentical (haplo), related-donor allogeneic blood or marrow transplantation (allo-BMT) with high-dose post-transplantation cyclophosphamide (PTCy) appear to be similar to those using HLA-matched donors. Thus, it may be possible to prioritize donor factors other than HLA matching that could enhance antitumor activity. The Fc receptor polymorphism FCGR3A-158VV may confer greater sensitivity to rituximab than FCGR3A-158FF. In a prospective phase II study of NMA, related-donor allo-BMT with PTCy and post-transplantation rituximab for patients with B cell lymphomas, we hypothesized that donor selection that prioritized FCGR3A-158 polymorphism over HLA matching would be feasible, safe, and improve outcomes. The primary endpoint was 1-year progression-free survival (PFS). Of 83 patients transplanted (median age, 59 years), 69 (83%) received haplo grafts. Fifty-four (65%) received a graft that maintained or improved their Fc receptor polymorphism status. With 2.6-year median follow-up, the 1-year PFS and overall survival (OS) probabilities were 71% and 86%, respectively, with 1-year relapse and nonrelapse mortality (NRM) probabilities of 20% and 8%. At 1 year, the probability of acute grades II to IV graft-versus-host disease (GVHD) was 41%, with acute grades III to IV GVHD probability of 5% and chronic GVHD probability of 11%. Among haplo transplants, the 1-year probabilities of PFS, OS, relapse, and NRM were 70%, 83%, 20%, and 10%, respectively. No differences in outcomes were observed based on donor FCGR3A-158 polymorphism. Excess infection risk was not apparent with post-transplantation rituximab. Although donor selection based on FCGR3A-158 polymorphism was not shown to influence PFS, this study suggests that donor selection based on criteria other than best HLA match is feasible and safe. This study opens the way for the future investigation of donor prioritization based on promising non-HLA factors that may improve antitumor activity and decrease relapse after allo-BMT. This study was registered at www.clinicaltrials.gov as NCT00946023.

Dataset Information

Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice.

Publications

Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice.

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