Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder

Sato, Taku; Ikeda, Mahoko; Yotsumoto, Satoshi; Shimada, Yohta; Higuchi, Takashi; Kobayashi, Hiroshi; Fukuda, Takahiro; Ohashi, Toya; Suda, Toshio; Ohteki, Toshiaki

doi:10.1182/blood-2012-07-443713

Cited by 5 publications

(3 citation statements)

References 37 publications

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“…Given the success of full myeloablative conditioning the results have been attributed to insufficient myeloablation of host cells. To enhance the level of myeloablation without the accompanying undesirable systemic effects, chemo/irradiation-reduced regimens have been combined with myelospecific treatments (Fewkes et al, 2010) or interferon induction (Sato et al, 2013) to reduce host stem cells, and promising results using these strategies have been documented in mice. In the present study we attempted to incorporate similar strategies in an autologous hematopoietic stem cell transplantation (HSCT) setting in the nonhuman primate model using pigtailed macaques.…”

Section: Discussionmentioning

confidence: 99%

“…Injection of anti-host HLA MHC class I antibody resulted in transient, partial, and reversible reduction in colony-forming unit-spleen (CFU-S) and colony-forming unit-erythroid (CFU-E) cells in bone marrow (BM) (Sadelain et al, 1990). Further insightful studies have predicted and demonstrated improved donor engraftment with low-dose irradiation, or nonmyeloablative chemotherapy (5-fluorouracil or cyclophosphamide [Cytoxan]) when combined with Kit ligand (KL) (Neta et al, 1993;van Os et al, 1997), granulocyte colony-stimulating factor (G-CSF), or interferon alfa-2a induction (Sato et al, 2013). Inhibition of c-Kit and its binding to stem cell factor (SCF), using monoclonal antibodies (ACK2) and multitargeted tyrosine kinase inhibitors (Sunitinib) alone, has also been demonstrated to improve engraftment in immunodeficient mice but only in combination with low-dose irradiation in immunocompetent mice (Fewkes et al, 2010;Xue et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Modeling Promising Nonmyeloablative Conditioning Regimens in Nonhuman Primates

et al. 2014

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Minimal conditioning or even no conditioning would be the preferred preparation for most gene therapy applications for nonmalignant diseases. However, reduced intensity conditioning (RIC) regimens in patients with nonhematologic malignancies have not led to long-term engraftment unless a selective advantage was present for the transplanted donor cells. Similar findings have also been observed in a number of large animal studies. Inadequate myelosuppression levels were thought to be responsible for the outcomes. To address this issue several innovative protocols in small animals have been presented with selective hematopoietic myelosuppression and less systemic toxicity. Such protocols promised to curb the transplant-related morbidity and mortality in myeloablative conditioning and provide effective long-term engraftment, especially in patients with gene-corrected autografts. In the present study we have tested some of these promising RIC regimens in nonhuman primates, a clinically relevant large animal model. Our data suggest that transient myelosuppression induced by anti-c-Kit antibody in conjunction with low-dose irradiation may lead to long-term engraftment, albeit at low levels. The animals with busulfan conditioning with or without anti-c-Kit that received gene-modified autologous transplants with green fluorescent protein expression had similar myelosuppression, but failed long-term engraftment and despite immunosuppressive treatment had all the hallmarks seen previously in similar models without immunosuppression. Our preliminary data expand current knowledge of RIC and emphasize the need to explore whether specific and directed myelosuppression alone is adequate in the absence of microenvironmental modulation, or whether innovative combinations are necessary for safe and effective engraftment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modeling Promising Nonmyeloablative Conditioning Regimens in Nonhuman Primates

et al. 2014

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“…This suggests that IFN-γ may participate in the pathogenesis of IDDM [ 144 ]. A study demonstrated that type I IFN-based pre-BM transplant conditioning was applicable to the treatment of congenital metabolic disorder-Sly syndrome [ 145 ]. IFN-λ1 has been demonstrated to play an important role in regulating metabolic disease.…”

Section: Therapeutic Perspective Of Ifn In Obesity and Insulin Sensit...mentioning

confidence: 99%

Interferon Family Cytokines in Obesity and Insulin Sensitivity

Huang

Chiu

Hsing

et al. 2022

Cells

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Obesity and its associated complications are global public health concerns. Metabolic disturbances and immune dysregulation cause adipose tissue stress and dysfunction in obese individuals. Immune cell accumulation in the adipose microenvironment is the main cause of insulin resistance and metabolic dysfunction. Infiltrated immune cells, adipocytes, and stromal cells are all involved in the production of proinflammatory cytokines and chemokines in adipose tissues and affect systemic homeostasis. Interferons (IFNs) are a large family of pleiotropic cytokines that play a pivotal role in host antiviral defenses. IFNs are critical immune modulators in response to pathogens, dead cells, and several inflammation-mediated diseases. Several studies have indicated that IFNs are involved in the pathogenesis of obesity. In this review, we discuss the roles of IFN family cytokines in the development of obesity-induced inflammation and insulin resistance.

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