Chimerism and gene therapy — Lessons learned from non‐conditioned murine bone marrow transplantation models

Jazbec, Katerina; Jež, Mojca; Smrekar, Boštjan; Miceska, Simona; Rozman, Jasmina-Ziva; Švajger, Urban; Završnik, Janja; Rožman, Primož

doi:10.1111/ejh.13024

Cited by 6 publications

(12 citation statements)

References 30 publications

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“…These phenomena are similar to clinical GVHD symptoms and signs including dry eye, myalgia, asthenia, and change in fur characteristics 28 . These findings clearly demonstrated that the mouse model of allogeneic BMT is an ideal tool to explore the pathogenesis of GVHD 10 .…”

Section: By Fcm Through An Incubation With Fitc-conjugated Anti-h-2k ...mentioning

confidence: 72%

“…BMT can create a permanently chimeric individual containing original diseased cells and newly transplanted healthy cells that convey a therapeutic effect in the form of a healthy gene. The level of chimerism can effectively evaluate the occurrence of moderate to severe aGVHD after transplantation 10 . Monitoring variations in cell chimerism early after transplantation help to identify patients at risk for graft rejection or grade II-IV aGVHD 11,12 .…”

Section: Introductionmentioning

confidence: 99%

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Evaluación del quimerismo celular en un modelo de enfermedad aguda de injerto contra huésped establecido en ratones knockout para TLR4

Zhao,

Huang,

Zhang

et al. 2023

CIRU

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Background: Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Objective: To elucidate the role of Toll-like receptor 4 (TLR4), the major receptor for bacterial lipopolysaccharide, in the development of GVHD, we constructed a GVHD model in TLR4 knockout (TLR4 -/-) mice and monitored the cell chimerism. Methods: In this study, we used polymerase chain reaction to identify whether TLR4 knockout (TLR4 -/-) mice were established. Before transplantation, we pretreated mice with irradiation so as to obtain an appropriate irradiation dose. Flow cytometry was applied to measure the chimerism status, the distributions of antigen-presenting cells (APCs), and T-cells in TLR4 +/+ and TLR4 -/recipient mice. Results: The general condition of TLR4 -/recipients was better than that of TLR4 +/+ recipients, and the TLR4 -/recipient mice showed less severe GVHD manifestations than the TLR4 +/+ recipient mice. Most of the APCs and T-cells in the host mouse spleen were derived from donor cells, and CD4 + T-cells, including memory T-cells, were in the majority in host mice. Conclusion: In general, our data show that TLR4 deletion attenuated GVHD development, which suggests that TLR4 could be used as a novel target and therapeutic paradigm in GVHD therapies.

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Section: By Fcm Through An Incubation With Fitc-conjugated Anti-h-2k ...mentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Evaluación del quimerismo celular en un modelo de enfermedad aguda de injerto contra huésped establecido en ratones knockout para TLR4

Zhao,

Huang,

Zhang

et al. 2023

CIRU

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“…Also, we have recently shown in an animal model that the non-conditioned haHSCT leads to a stable chimerism in the bone marrow HSCs as well as in the myeloid and lymphoid progenitor subpopulations of the recipient, clearly showing a linear dose-dependent response. Extrapolating these results to the human setting, we found that approximately 44 million CD34+ HSCs would be needed to achieve 20% donor chimerism in a 70-kg human, which is probably sufficient for a substantial replacement of aged HSCs (Jazbec et al 2018).…”

Section: What Could Be Expected From Heterochronous Autologous Hematopoietic Stem Cell Transplantation?mentioning

confidence: 86%

The potential of non-myeloablative heterochronous autologous hematopoietic stem cell transplantation for extending a healthy life span

Rožman

2018

GeroScience

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Aging is a complex multifactorial process, a prominent component being the senescence of the immune system. Consequently, immune-related diseases develop, including atherosclerosis, cancer, and life-threatening infections, which impact on health and longevity. Rejuvenating the aged immune system could mitigate these diseases, thereby contributing to longevity and health. Currently, an appealing option for rejuvenating the immune system is heterochronous autologous hematopoietic stem cell transplantation (haHSCT), where healthy autologous bone marrow/peripheral blood stem cells are collected during the youth of an individual, cryopreserved, and re-infused when he or she has reached an older age. After infusion, young hematopoietic stem cells can reconstitute the compromised immune system and improve immune function. Several studies using animal models have achieved substantial extension of the life span of animals treated with haHSCT. Therefore, haHSCT could be regarded as a potential procedure for preventing age-related immune defects and extending healthy longevity. In this review, the pros, cons, and future feasibility of this approach are discussed.

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“…Since a completely autologous setting is practically unattainable in mice due to the scarcity of biological materials of an individual mouse, we used a syngeneic heterosexual donor/recipient combination to closely mimic the autologous tissue compatibility setting [15][16][17]. Old female BALB/c mice as recipients, and young inbred BALB/c males as donors were also chosen for enabling precise determination of the post-transplantation mixed chimerism, based on the presence of the Y chromosome, as already set in our previous studies [18,19]. Similarly, since the isolation of large numbers of pure HSCs from young mice needed for consequent long-term cryopreservation and transplantation is practically impossible, HSCT was substituted by transplantation of the whole BM of young donors.…”

Section: Introductionmentioning

confidence: 99%

The Influence of Heterochronic Non-Myeloablative Bone Marrow Transplantation on the Immune System, Frailty, General Health, and Longevity of Aged Murine Recipients

et al. 2022

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The stem cell theory of aging postulates that stem cells become inefficient at maintaining the original functions of the tissues. We, therefore, hypothesized that transplanting young bone marrow (BM) to old recipients would lead to rejuvenating effects on immunity, followed by improved general health, decreased frailty, and possibly life span extension. We developed a murine model of non-myeloablative heterochronic BM transplantation in which old female BALB/c mice at 14, 16, and 18(19) months of age received altogether 125.1 ± 15.6 million nucleated BM cells from young male donors aged 7–13 weeks. At 21 months, donor chimerism was determined, and the immune system’s innate and adaptive arms were analyzed. Mice were then observed for general health and frailty until spontaneous death, when their lifespan, post-mortem examinations, and histopathological changes were recorded. The results showed that the old mice developed on average 18.7 ± 9.6% donor chimerism in the BM and showed certain improvements in their innate and adaptive arms of the immune system, such as favorable counts of neutrophils in the spleen and BM, central memory Th cells, effector/effector memory Th and Tc cells in the spleen, and B1a and B1b cells in the peritoneal cavity. Borderline enhanced lymphocyte proliferation capacity was also seen. The frailty parameters, pathomorphological results, and life spans did not differ significantly in the transplanted vs. control group of mice. In conclusion, although several favorable effects are obtained in our heterochronic non-myeloablative transplantation model, additional optimization is needed for better rejuvenation effects.

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Chimerism and gene therapy — Lessons learned from non‐conditioned murine bone marrow transplantation models

Cited by 6 publications

References 30 publications

Evaluación del quimerismo celular en un modelo de enfermedad aguda de injerto contra huésped establecido en ratones knockout para TLR4

Evaluación del quimerismo celular en un modelo de enfermedad aguda de injerto contra huésped establecido en ratones knockout para TLR4

The potential of non-myeloablative heterochronous autologous hematopoietic stem cell transplantation for extending a healthy life span

The Influence of Heterochronic Non-Myeloablative Bone Marrow Transplantation on the Immune System, Frailty, General Health, and Longevity of Aged Murine Recipients

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