本帖最后由 StephenW 于 2011-3-9 17:32 编辑
Evaluated byDhaya Seshasayee and Flavius Martin new evaluation | Raphaelle Parker and Irini Sereti | Tobias Boettler and Matthias von Herrath | Barry Rouse
In this study, the authors report that exogenous interleukin (IL)-7 can help mice to clear a chronic lymphocytic choriomeningitis virus (LCMV) infection, through a mechanism involving suppressor of cytokine signaling 3 (SOCS3) repression. The most interesting aspect of the article is the observation that IL-7 administration increases IL-22 production in the liver (potentially limiting liver pathology), which suggests dual roles for IL-7 in promoting inflammation while simultaneously acting to limit host-tissue damage. The importance of IL-7 in generation and maintenance of T-cell responses has been documented in numerous studies. Administration of recombinant IL-7 to humans has been shown to result in an increase in T-cell numbers and diversity of the T-cell repertoire. Similar effects have been observed in mouse models of viral infection, and these effects have been thought to contribute to enhanced viral clearance. However, exact mechanisms by which IL-7 exerts its effects have not been elucidated. In the present study, the authors propose that IL-7 administration results in increased cytokine expression (IL-6, interferon [IFN]gamma, IL-17), likely by relieving SOCS3-mediated suppression of these cytokines. The authors also observe that this IL-7-induced boost in inflammatory cytokine production is not accompanied by liver pathology, normally observed in LCMV, which may be due to the significantly elevated local IL-22 production in the liver by CD4 T cells. This observation adds to the growing body of evidence on protective roles for IL-22 in organs such as the gut. Precise mechanisms by which IL-7 induces induction of IL-22 in the liver are not clear and need to be investigated. Competing interests: None declared
Seshasayee D, Martin F:
"In this study, the authors report that exogenous interleukin (IL)-7 can help mice..." Evaluation of: [Pellegrini M et al. IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology. Cell. 2011 Feb 18; 144(4):601-13; doi: 10.1016/j.cell.2011.01.011]. Faculty of 1000, 04 Mar 2011. F1000.com/8506956
Dhaya Seshasayee and Flavius Martin
Genentech, USA
Immunology
04 Mar 2011
Over the past few years, interleukin-7 (IL-7) has become a cytokine of great interest for immune-based therapies in diseases characterized by lymphopenia or immune deficiency. We found this article interesting because it studied the impact of in vivo IL-7 administration on pathways that influence the control of chronic viral infections. The authors described how IL-7 administration in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection led to viral clearance by down regulation of suppressor of cytokine signaling 3 (SOCS3) via enhanced IL-6 production. The authors studied the effects of human recombinant IL-7 injections in mice infected with clone-13 of LCMV, which induces chronic infection. Eight days after infection, the mice received daily injections of either 10g of IL-7 or phosphate buffered saline (PBS) for three weeks. IL-7 treatment allowed clearance of the virus in the spleen, liver, brain and kidney within one to two months post infection.
As previously shown, IL-7 injections induced an increase in CD4 and CD8 T cells, including dramatic expansion, albeit transient, of antigen-specific T cells. Of note, IL-7 treatment permitted the development of NP396-specific T cells that are typically elicited during acute (Armstrong strain) and not chronic LCMV infection as well as naive, non-LCMV specific T cells. Moreover, similarly to previous work (see ref {1}, on which Raphaelle Parker is listed as an author), IL-7 treatment induced a higher percent of functional effector CD8 T cells expressing lower levels of PD-1 and CD69. IL-7-treated animals showed higher levels of IL-6, IL-17 and interferon (IFN)gamma together with a lower level of the inhibitory cytokine transforming growth factor (TGF)beta compared to controls. Despite the induction of a pro-inflammatory milieu and a low percent of T regulatory (Treg) cells, there was no evidence of hepatotoxicity; this was attributed to the cytoprotective effect of increased IL-22 production.
The highlight of the study was the demonstration that IL-7 modulated the immune response allowing viral clearance through the repression of SOCS3. SOCS3 is expressed by T cells during clone-13 but not Armstrong infection, suggesting that inhibition of its expression could be implicated in the control of viremia. Indeed, the authors succeeded in mimicking the effects of IL-7 treatment during clone-13 infection by SOCS3 deletion in T cells. Down regulating SOCS3 expression (possibly through FoxO transcription factors) required enhanced production of IL-6.
It will be necessary to expand this work and elucidate these pathways in humans, particularly in people with lymphopenia where IL-7 signaling may not be intact, to better understand their role in the clearance of chronic viral infections such as chronic hepatitis and HIV. In addition to optimism about possible anti-viral effects of IL-7, this study also sheds light on possible new targets for strategies aimed at prevention of establishment or clearance of established chronic viral infections. References:
{1} Parker et al. Blood 2010, 116:5589-99 [PMID:20841508]. Competing interests: None declared
Parker R, Sereti I: "Over the past few years, interleukin-7 (IL-7) has become a cytokine..." Evaluation of: [Pellegrini M et al. IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology. Cell. 2011 Feb 18; 144(4):601-13; doi: 10.1016/j.cell.2011.01.011]. Faculty of 1000, 25 Feb 2011. F1000.com/8506956
National Institute of Allergy and Infectious Diseases , USA
Immunology
25 Feb 2011 Rating 8
Must Read
This comprehensive report demonstrates that treatment with the cytokine interleukin (IL)-7 improves immune-mediated control of viral replication during a persistent viral infection. Enhancing the endogenous anti-viral immune response in order to achieve clearance of a chronic pathogen has been proven to be very difficult, especially after establishment of persistence. Here, the authors propose that treatment with recombinant IL-7 could fill this gap. They show that chronically lymphocytic choriomeningitis virus (LCMV)-infected mice treated with IL-7 more rapidly cleared the virus compared to control animals. Treatment largely increased the numbers of tissue infiltrating lymphocytes, LCMV-specific and unspecific, and resulted in a vigorous increase of serum cytokine levels, such as interferon (IFN)-gamma, IL-6, IL-17, IL12p70 and IL-1, while reducing transforming growth factor (TGF)-beta levels. Mechanistically, this was due to IL-7-mediated repression of the cytokine-signaling suppressor Socs3. Interestingly, the authors did not observe significant signs of immunopathological damage. They show that this might be a result of IL-22-mediated protection from cytokine damage, as liver inflammation was increased in IL-7-treated animals treated with a neutralizing IL-22 antibody. The observation that IL-7 is able to potently enhance unspecific and specific immune responses, and at the same time prevent immunopathological damage, is fascinating and astounding. Unfortunately, one major caveat for immediate translation to the clinic is the finding that IL-7 treatment also potently promotes the development of autoreactive T cells, published two years ago by the same group {1}. References:
{1} Calzascia et al. Proc Natl Acad Sci U S A 2008, 105:2999-3004 [PMID:18287017]. Competing interests: None declared
Boettler T, von Herrath M: "This comprehensive report demonstrates that treatment with the cytokine interleukin (IL)-7 improves immune-mediated..." Evaluation of: [Pellegrini M et al. IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology. Cell. 2011 Feb 18; 144(4):601-13; doi: 10.1016/j.cell.2011.01.011].
La Jolla Institute for Allergy and Immunology, USA
Immunology
22 Feb 2011 Rating 8
Must Read
I found this report by Tak-Mak and colleagues quite astonishing. The concept that we fail to control some persistent infections because our immune cells are present but dysfunctional has become an accepted immunological paradigm. We also know that there are multiple events that account for this so-called 'immune exhaustion' and that blocking only one of these events is at best partially effective. What we need is an elixir that reverses all effects that contribute to dysfunction. Conceivably one such elixir is at hand and its name is interleukin (IL)-7. These observations by Tak-Mak and colleagues, using the classic model of immune exhaustion clone 13 lymphocytic choriomeningitis virus (LCMV), now show that T cell intrinsic SOCS3 induction is a major factor that contributes to immune dysfunction. Moreover, the administration of IL-7 acts to counteract the SOCS3 effects, restoring immunity to the chronically infected mice. Indeed, the infected mice were able to shake off their chronic infection, with effects on viral titers being far greater than reported reversals by singular exhaustion mediating effects {1}, or even when combinations of singular exhaustion effects were used {2}. The results using IL-7 were dramatic and these could have great translational potential (HIV and hepatitis C are candidates) provided, of course, the approach does not come with a Faustian price to pay. References:
{1} Barber et al. Nature 2006, 439:682-7 [PMID:16382236].
{2} Blackburn et al. Nat Immunol 2009, 10:29-37 [PMID:19043418]. Competing interests: None declared
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楼主: StephenW
发表于 2011-3-3 19:12
