Chronic exposure to IFN  drives medullar lymphopoiesis towards T cell differentiation in mice

Scala, Marianna Di; Gil-Fariña, Irene; Vanrell, Lucía; Sánchez-Bayona, Rodrigo; Alignani, Diego; Olagüe, Cristina; Vales, África; Berraondo, Pedro; Prieto, Jesús; González‐Aseguinolaza, Gloria

doi:10.3324/haematol.2014.115410

Cited by 8 publications

(10 citation statements)

References 35 publications

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“…The recombinant AAV8 (rAAV8) vector with WT AAV2 inverted terminal repeats (ITRs) was produced as described previously ( 24 , 25 ). The expression cassette in the AAV–IL-15 vector consists of the murine IL-15 gene (GenBank accession number DQ083237.1 ) under the regulation of a liver-specific promoter ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

“…The expression cassette in the AAV–IL-15 vector consists of the murine IL-15 gene (GenBank accession number DQ083237.1 ) under the regulation of a liver-specific promoter ( 25 ). The expression cassette in the AAV–IFN-α vector has been described previously and contains of the murine IFN-α1 gene under the regulation of the elongation factor 1α promoter ( 24 ). A luciferase-encoding AAV (AAV-LUC) served as a control ( 24 ).…”

Section: Methodsmentioning

confidence: 99%

“…The expression cassette in the AAV–IFN-α vector has been described previously and contains of the murine IFN-α1 gene under the regulation of the elongation factor 1α promoter ( 24 ). A luciferase-encoding AAV (AAV-LUC) served as a control ( 24 ).…”

Section: Methodsmentioning

confidence: 99%

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Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice

Scala

Otano

Gil-Fariña³

et al. 2016

J Virol

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In chronic hepatitis B (CHB), failure to control hepatitis B virus (HBV) is associated with T cell dysfunction. HBV transgenic mice mirror many features of the human disease, including T cell unresponsiveness, and thus represent an appropriate model in which to test novel therapeutic strategies. To date, the tolerant state of CD8+ T cells in these animals could be altered only by strong immunogens or by immunization with HBV antigen-pulsed dendritic cells; however, the effectors induced were unable to suppress viral gene expression or replication. Because of the known stimulatory properties of alpha interferon (IFN-α) and interleukin-15 (IL-15), this study explored the therapeutic potential of liver-directed gene transfer of these cytokines in a murine model of CHB using adeno-associated virus (AAV) delivery. This combination not only resulted in a reduction in the viral load in the liver and the induction of an antibody response but also gave rise to functional and specific CD8+ immunity. Furthermore, when splenic and intrahepatic lymphocytes from IFN-α- and IL-15-treated animals were transferred to new HBV carriers, partial antiviral immunity was achieved. In contrast to previous observations made using either cytokine alone, markedly attenuated PD-L1 induction in hepatic tissue was observed upon coadministration. An initial study with CHB patient samples also gave promising results. Hence, we demonstrated synergy between two stimulating cytokines, IL-15 and IFN-α, which, given together, constitute a potent approach to significantly enhance the CD8+ T cell response in a state of immune hyporesponsiveness. Such an approach may be useful for treating chronic viral infections and neoplastic conditions.IMPORTANCE With 350 million people affected worldwide and 600,000 annual deaths due to HBV-induced liver cirrhosis and/or hepatocellular carcinoma, chronic hepatitis B (CHB) is a major health problem. However, current treatment options are costly and not very effective and/or need to be administered for life. The unprecedented efficacy of the strategy described in our paper may offer an alternative and is relevant for a broad spectrum of readers because of its clear translational importance to other chronic viral infections in which a hyporesponsive antigen-specific T cell repertoire prevents clearance of the pathogen.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice

Scala

Otano

Gil-Fariña³

et al. 2016

J Virol

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“…Again, chronic exposure to polyI:C triggered exhaustion of these stem-cell-like megakaryocyte progenitors and a delayed repletion of platelet counts ( 79 ). Recent work also proposes that chronic exposure to IFNα drives medullar lymphopoiesis toward T-cell differentiation, while impairing the generation of B, NK, myeloid cells, erythrocytes, and platelets ( 80 ). Collectively, these findings suggest that BM aplasia associated with chronic exposure to type I IFN could arise from a depletion or loss of function of progenitors, together with enforced quiescence of HSCs, which become less functional.…”

Section: Mechanisms Of Viral Interference With Hematopoiesismentioning

confidence: 99%

Impact of Viral Infections on Hematopoiesis: From Beneficial to Detrimental Effects on Bone Marrow Output

2016

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The ability of the bone marrow (BM) to generate copious amounts of blood cells required on a daily basis depends on a highly orchestrated process of proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). This process can be rapidly adapted under stress conditions, such as infections, to meet the specific cellular needs of the immune response and the ensuing physiological changes. This requires a tight regulation in order to prevent either hematopoietic failure or transformation. Although adaptation to bacterial infections or systemic inflammation has been studied and reviewed in depth, specific alterations of hematopoiesis to viral infections have received less attention so far. Viruses constantly pose a significant health risk and demand an adequate, balanced response from our immune system, which also affects the BM. In fact, both the virus itself and the ensuing immune response can have a tremendous impact on the hematopoietic process. On one hand, this can be beneficial: it helps to boost the cellular response of the body to resolve the viral infection. But on the other hand, when the virus and the resulting antiviral response persist, the inflammatory feedback to the hematopoietic system will become chronic, which can be detrimental for a balanced BM output. Chronic viral infections frequently have clinical manifestations at the level of blood cell formation, and we summarize which viruses can lead to BM pathologies, like aplastic anemia, pancytopenia, hemophagocytic lymphohistiocytosis, lymphoproliferative disorders, and malignancies. Regarding the underlying mechanisms, we address specific effects of acute and chronic viral infections on blood cell production. As such, we distinguish four different levels in which this can occur: (1) direct viral infection of HSPCs, (2) viral recognition by HSPCs, (3) indirect effects on HSPCs by inflammatory mediators, and (4) the role of the BM microenvironment on hematopoiesis upon virus infection. In conclusion, this review provides a comprehensive overview on how viral infections can affect the formation of new blood cells, aiming to advance our understanding of the underlying cellular and molecular mechanisms to improve the treatment of BM failure in patients.

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“…The LSK cell population significantly increased in mIL-15-treated mice in comparison to Luc-treated mice (Supplementary Figure S3). However as we and others have previously demonstrated [31, 32], Sca-1 is an interferon-responsive molecule that is aberrantly up-regulated by IFN-α or IFN-γ on all hematopoietic progenitors preventing the use of this marker for HSC characterization. Using Lin- c-kit+ (LK) as identification markers for hematopoietic progenitor cells, our analysis revealed an increase of LK population in mice treated with AAV-mIL15 compared to AAV-Luc treatment (Figure 6B).…”

Section: Resultsmentioning

confidence: 88%

Identification of IFN-γ-producing T cells as the main mediators of the side effects associated to mouse interleukin-15 sustained exposure

Scala¹,

Gil-Fariña

Olagüe³

et al. 2016

Oncotarget

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Interleukin-15 (IL-15) is a cell growth-factor that regulates lymphocyte function and homeostasis. Its strong immunostimulatory activity coupled with an apparent lack of toxicity makes IL-15 an exciting candidate for cancer therapy, somehow limited by its short half-life in circulation. To increase IL-15 bioavailability we constructed a recombinant adeno-associated vector expressing murine IL-15 (AAV-mIL15) in the liver. Mice injected with AAV-mIL15 showed sustained and vector dose-dependent levels of IL-15/IL-15Rα complexes in serum, production of IFN-γ and activation of CD8+ T-cells and macrophages. The antitumoral efficacy of AAV-mIL15 was tested in a mouse model of metastatic colorectal cancer established by injection of MC38 cells. AAV-mIL15 treatment slightly inhibits MC38 tumor-growth and significantly increases the survival of mice. However, mIL-15 sustained expression was associated with development of side effects like hepatosplenomegaly, liver damage and the development of haematological stress, which results in the expansion of hematopoietic precursors in the bone marrow. To elucidate the mechanism, we treated IFN-γ receptor-, RAG1-, CD1d- and μMT-deficient mice and performed adoptive transfer of bone marrow cells from WT mice to RAG1-defcient mice. We demonstrated that the side effects of murine IL-15 administration were mainly mediated by IFN-γ-producing T-cells.ConclusionIL-15 induces the activation and survival of effector immune cells that are necessary for its antitumoral activity; but, long-term exposure to IL-15 is associated with the development of important side effects mainly mediated by IFN-γ-producing T-cells. Strategies to modulate T-cell activation should be combined with IL-15 administration to reduce secondary adverse events while maintaining its antitumoral effect.

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Chronic exposure to IFN drives medullar lymphopoiesis towards T cell differentiation in mice

Cited by 8 publications

References 35 publications

Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice

Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice

Impact of Viral Infections on Hematopoiesis: From Beneficial to Detrimental Effects on Bone Marrow Output

Identification of IFN-γ-producing T cells as the main mediators of the side effects associated to mouse interleukin-15 sustained exposure

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