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标题: High hopes of HIV cure by injection [& Hepatitis b?] [打印本页]
作者: StephenW 时间: 2011-2-3 23:20 标题: High hopes of HIV cure by injection [& Hepatitis b?]
本帖最后由 StephenW 于 2011-2-3 23:23 编辑
http://www.heraldsun.com.au/news/victoria/high-hopes-of-hiv-cure-by-injection-treatment-may-only-take-month/story-e6frf7kx-1225999810530
High hopes of HIV cure by injection, treatment may only take month - Marianne Betts, health reporter
- From: Herald Sun
- February 04, 2011 12:01AM
Experts believe the injection immune boost could lead to a cure for HIV within 15 years. Source: Supplied
MELBOURNE scientists have made a major breakthrough they believe will lead to a cure for HIV.
The scientists have cleared an HIV-like infection in mice by boosting their immune system with a synthetic version of a hormone that occurs naturally in the body.
"We are very optimistic that we should be able to find a cure for HIV in 10 to 15 years," said lead researcher Dr Marc Pellegrini, of the Walter and Eliza Hall Institute.
Dr Pellegrini said the cure would be in the form of an injection, given to HIV patients either every three days or once a week -- depending on its strength -- for about a month.
The breakthrough could cure other chronic viral infections, such as hepatitis B and C, and bacterial infections such as tuberculosis, he said.
There are 20,000 HIV+ Australians, while more than 7000 have died from HIV-related illnesses.
"Viruses such as HIV and hepatitis B and C overwhelm the immune system, leading to the establishment of chronic infections that are lifelong and incurable," Dr Pellegrini said.
The body became so overrun by the virus the immune system, in particular T-cells, gave up trying to battle the infection.
The breakthrough centres on a hormone that occurs in low levels in the body's immune system called interlukin-7 (IL-7).
Dr Pellegrini's team infected mice with a virus which mimics HIV. Some were then injected with IL-7 over three weeks, and the rest given an alternative.
The researchers found that the T cell numbers in the mice given IL-7 were boosted dramatically after 30 days -- and after 60 days they were clear of the virus.
Dr Pellegrini hopes to begin trials on newly infected HIV patients within two years
The research is published in the journal Cell.
[email protected]
作者: StephenW 时间: 2011-2-3 23:25
高治愈艾滋病希望通过注射，治疗可能只需要一个月
*玛丽安贝茨，健康记者
*来自：太阳先驱报
* 2011年2月4日上午12:01
专家认为，注射免疫刺激可能导致在15年的艾滋病毒治疗。来源：提供
墨尔本科学家已经取得了重大突破，他们认为这将导致对艾滋病毒治疗。
科学家们通过提高清除的和自然产生的激素在人体内合成的，他们的免疫系统在小鼠艾滋病病毒感染一样。
“我们非常乐观地认为，我们应该能够找到在10至15年的艾滋病毒治疗，说：”佩莱格里尼的首席研究员马克博士，沃尔特和伊丽莎的霍尔研究所。
佩莱格里尼博士表示，将在治疗的注射方式，给予艾滋病患者或每三天或每周一次 - 根据其强度 - 约一个月。
这一突破可以治疗其他慢性病毒感染，如B和C型肝炎，肺结核等细菌感染，他说。
有20000 HIV阳性澳大利亚人，而超过7000从艾滋病毒有关的疾病而死亡。
“如艾滋病毒和乙肝和丙肝病毒压倒免疫系统，导致其对终身无法治愈的慢性感染和建立”博士佩莱格里尼说。
身体变得如此侵占病毒的免疫系统，特别是T细胞，放弃了战斗的感染。
在激素水平低，在发生在人体的免疫系统的突破中心称为白细胞介素6（白细胞介素- 7）。
佩莱格里尼博士的研究小组与艾滋病毒感染小鼠的模仿。有些人则注射白细胞介素- 7三个多星期，其余给予选择。
研究人员发现，在给定的IL - 7的小鼠T细胞数目显着增强后30天 - 60天之后，他们的病毒清除。
医生佩莱格里尼希望两年内开始新感染艾滋病毒患者的审判
这项研究发表在Cell杂志。
[email protected]
作者: yolanda67 时间: 2011-2-4 00:36
作者: freshnail 时间: 2011-2-4 00:41
CELL 杂志，很NB的科学杂志啊！！
致少从科学上来说，实验室的数据可信度比较大吧
作者: StephenW 时间: 2011-2-4 00:53
回复 freshnail 的帖子
Walter and Eliza Hall Institute 在澳大利亚的墨尔本。非常有名.
作者: freshnail 时间: 2011-2-4 01:05
本帖最后由 freshnail 于 2011-2-4 01:11 编辑
http://www.cell.com/abstract/S0092-8674(11)00012-2
Cell, 03 February 2011
Copyright 2011 Elsevier Inc. All rights reserved.
10.1016/j.cell.2011.01.011
Authors
Marc Pellegrini, Thomas Calzascia, Jesse G. Toe, Simon P. Preston, Amy E. Lin, Alisha R. Elford, Arda Shahinian, Philipp A. Lang, Karl S. Lang, Michel Morre, Brigitte Assouline, Katharina Lahl, Tim Sparwasser, Thomas F. Tedder, Ji-hye Paik, Ronald A. DePinho, Sameh Basta, Pamela S. Ohashi, Tak W. MakSee AffiliationsHint: Rollover Authors and Affiliations The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne 3050, Australia Departments of Medical Biophysics and Immunology, Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada Cytheris Inc., 92130 Issy les Moulineaux, France Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA Institute for Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str.7, 30625 Hannover, Germany Department of Immunology, Duke University Medical Center, Durham, NC 27708, USA Belfer Institute for Applied Cancer Science, Department of Medical Oncology, Department of Medicine and Department of Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA Department of Microbiology and Immunology, Queen's University, Kingston, ON K7L 396, Canada Corresponding author These authors contributed equally to this work These authors contributed equally to this work
Highlights
•Socs3 is upregulated in T cells during chronic active viral infection in mice
•Deletion of socs3 in T cells prevents immune failure and promotes viral clearance
•In vivo IL-7 therapy represses Socs3 in T cells and clears chronic infection
•IL-7 promotes IL-22 production to mitigate immunopathology in chronic infection
Summary
Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases.
作者: freshnail 时间: 2011-2-4 01:05
不知道是不是这篇文章？
作者: StephenW 时间: 2011-2-4 14:00
回复 freshnail 的帖子
我想就是这篇文章. 非常好
. Professor Michel 在她的论文也提到IL-7(http://www.hbvhbv.com/forum/thread-1000391-2-1.html。
以下是澳大利亚的ABC广播电台关于这
发现.
Immune system boost cures HIV miceBy national medical reporter Sophie Scott
Posted February 4, 2011 11:16:00
A group of Australian scientists have been able to cure HIV in mice by boosting their immune systems.
Doctor Marc Pellegrini from Melbourne's Walter and Eliza Hall Institute found a hormone known as Interleukin 7 stimulates the body's response to an infection, causing it to clear the virus.
This process is called immune exhaustion.
"We found that Interleukin 7 boosted the immune response in a pretty profound fashion, such that animals were able to gradually clear the virus without too much collateral tissue damage," Dr Pellegrini said.
"The findings could lead to a cure for chronic viral infections like HIV, hepatitis B and C, and bacterial infections such as tuberculosis."
The aim of the research was to manipulate the immune system to fight off infection.
"Viruses such as HIV and hepatitis B and C overwhelm the immune system, leading to establishment of chronic infections that are lifelong and incurable," Dr Pellegrini said.
"Despite tremendous efforts, long-lived immune responses for some of these viruses are ineffective because the body is so overrun by virus that the immune system - in particular T cells - just give up trying to battle the infection."
The scientists also found that gene SOCS-3 was switched off, which boosted the immune system and allowed the animals to clear the HIV infection.
The findings have been published today in the medical journal, Cell.
提高艾滋病治疗免疫系统小鼠
由国家医疗记者索菲斯科特
于2011年2月4日11时16分00秒
澳大利亚一组科学家已经能够治愈小鼠提高他们的免疫系统艾滋病毒。
医生马克佩莱格里尼从墨尔本的沃尔特和伊丽莎霍尔研究所发现的白细胞介素7已知的激素刺激身体的反应，感染，导致它以清除病毒。
这个过程被称为免疫用尽。
“我们发现，白细胞介素7推动在一个漂亮的深刻时尚的免疫反应，使得动物能够逐渐清晰，没有太多的抵押品组织损伤的病毒，”博士佩莱格里尼说。
“调查结果可能会导致慢性病毒感染艾滋病毒一样，B和C型肝炎，肺结核等细菌感染的治疗。”
本研究的目的是为了操纵免疫系统抵御感染。
“如艾滋病毒和乙肝和丙肝病毒压倒免疫系统，导致被终身无法治愈的慢性感染和建立”博士佩莱格里尼说。
“尽管巨大的努力，对这些病毒的一些长期存在的免疫反应是无效的，因为身体是如此溢出，病毒，免疫系统 - 特别是在细胞笔 - 。干脆放弃努力战斗的感染”
科学家们还发现，基因SOCS - 3已关机，这促进了免疫系统，使动物感染艾滋病毒的清除。
研究结果已发表在医学杂志，细胞。
作者: StephenW 时间: 2011-2-4 14:07
Professor Michel的论文也提到 IL7 ,并有一个临床试验!!! A clinical trial combining antiviral treatment
with a classical preventive vaccine and multiple IL-7 injections is currently underway in HBenegative
chronic hepatitis B patients with no detectable HBV DNA during at least three
months of anti-viral treatment (www.ClinicalTrials.gov, Identifier: NCT01027065).
Can combination therapy be improved further?
The use of strong Th1-inducing adjuvants or cytokines might increase the efficacy of
therapeutic vaccination. Several trials have evaluated the use of a therapeutic vaccine
combined with IL-2 to treat human immunodeficiency virus of HBV infection [44, 45]. The
withdrawal of antiviral treatment at the end of vaccination had almost no effect on the risk of
viremia relapse. However, one potential drawback of IL-2 treatment is that it induces Tregs,
which constitutively express IL-2Rα. Other cytokines, such as IL-7 and IL-15, are essential
for the homeostatic proliferation of T cells in vivo, the survival of effector cells and the
maintenance of memory T cells during viral infection. These cytokines may increase the pool
of naïve T cells available for vaccine-mediated stimulation and the survival of activated T
cells. Studies on animals have shown that IL-7 improves anti-tumor responses and survival
after a vaccine-induced immune response [46]. A clinical trial combining antiviral treatment
with a classical preventive vaccine and multiple IL-7 injections is currently underway in HBenegative
chronic hepatitis B patients with no detectable HBV DNA during at least three
months of anti-viral treatment (www.ClinicalTrials.gov, Identifier: NCT01027065).
联合治疗可以进一步改善？
强有力的Th1型细胞因子诱导佐剂或使用可能增加疗效
治疗性疫苗。几个试验评估了治疗性疫苗的使用
与IL- 2联合治疗乙型肝炎病毒感染人体免疫缺陷病毒[44，45]。该
抗病毒治疗撤出在结束对接种疫苗的风险几乎没有影响
病毒血症复发。然而，一对IL -2治疗潜在的缺点是，它诱导调节性T细胞，
其中组成表达IL-2Rα的。其他细胞因子如IL-7和IL- 15，是必要的
对于T细胞稳态增殖的体内，效应细胞的生存和
记忆性T细胞病毒感染的维修养护。这些细胞因子可能增加池
天真的T细胞疫苗可用于介导的刺激和活化T生存
细胞。动物研究表明，白细胞介素- 7提高抗肿瘤反应和生存
后一种疫苗引起的免疫反应[46]。一个临床试验相结合的抗病毒治疗
有古典的预防疫苗和多发性白细胞介素- 7针，目前正在进行中HBenegative
慢性乙型肝炎患者乙肝病毒DNA的检测，没有在至少三
个月的抗病毒治疗（www.ClinicalTrials.gov，标识符：NCT01027065）。
作者: nick27 时间: 2011-2-4 16:03
但愿能为我们在新的一年里带来了新的希望--不久将来会有治愈的药
作者: freshnail 时间: 2011-2-5 00:36
不久的将来，到底还有多久，唉。。。。。。。。。。
作者: freshnail 时间: 2011-2-6 10:52
今天可以下载全文了
作者: StephenW 时间: 2011-2-6 13:41
回复 freshnail 的帖子
IL-7 blocks SOCS-3 in T cells, allowing them to proliferate and attack the virus-infected cells. (Image: WEHI)
Chronicviral infections can sometimes overwhelm the immune system, leading toa phenomenon some call "immune exhaustion." When this happens, theimmune system is no longer able to fight back effectively against theinfection.
Now researchers led by Dr MarcPellegrini from the Walter and Eliza Hall Institute in Melbourne haveshown that boosting the immune system in mice can rid them of a chronicinfection by an HIV-like virus.
The findingopens up the possibility of using this immune boosting technique tocombat chronic infections like HIV, hepatitis and tuberculosis.
The researchers set out to investigate the mechanisms responsible for immune exhaustion, and to see if they might be reversed.
Itwas believed that some system was acting to suppress the immune systemin cases of chronic infection in order to prevent the immune systemoverreacting and possibly damaging other tissue.
Theyhypothesised that a cell signalling hormone called interleukin-7(IL-7), which is known for overcoming inhibitory mechanisms, might beable to prevent this suppression of the immune system.
Theinfected mice with a virus, Lymphocytic chorimeningitis virus (LCMV)variant clone 13, which establishes a chronic infection similar to thatproduced by HIV.
They then injected the micewith human IL-7 and found the mice experienced a "profound" boost toimmune response and were able to eliminate the infection entirely.
Themice experienced increased thymic output and saw an increase in T cellnumbers, both T cells that targeted LCMV and other types of T cells aswell.
According to Pellegrini, the mechanism atwork behind the scenes was that IL-7 was able to downregulate anotherprotein, SOCS-3, in T cells.
It was SOCS-3that was putting the breaks on the immune system in cases of chronicinfection and preventing the body from potentially attacking itself.
“Inan overwhelming infection, SOCS-3 becomes highly activated andsuppresses the immune response, probably as a natural precaution toprevent ‘out-of-control’ responses that cause collateral damage to bodytissue,” said Pellegrini.
“In the case ofthese overwhelming infections, the immune system effectively slams onthe brakes too early, and the infection persists.”
Bydownregulating Soc3, the immune system was able to bounce back andclear the infection, although not without some collateral damage toother tissue caused by the highly active immune system.
“Thekey for us was figuring out that turning off SOCS-3 only really workedwhen it was within T cells,” said Simon Preston, a co-author on thepaper.
“It allowed the immune response toboost the number of virus-specific T cells and have an immune responsegood enough to eliminate the virus without initiating an immuneresponse that was too large and would make the animal sick.”
Thisfinding could have tremendous significance in the field of combatingchronic infection, and could lead to new therapies that might even leadto a cure for HIV.
“The findings could help todevelop drugs that target some of these host molecules, such as SOCS-3,and turn them off for very short, defined periods of time toreinvigorate the T cells, allowing them to regroup to fight infection,”said Pellegrini.
The researchers suggest thatIL-7 treatment might produce a potent antiviral response while thepatient is undergoing antiretroviral treatment to reduce the viralload. In this situation, it's possible the body might be able toeradicate the infection.
The study was published in the journal, Cell,and was supported by the National Health and Medical Research Council,the Canadian Institute for Health and the Cancer Research Institute.
作者: freshnail 时间: 2011-2-6 19:29
说老实话，文章下载了，不过没有看懂，呵呵
作者: StephenW 时间: 2011-2-6 19:39
本帖最后由 StephenW 于 2011-2-6 19:39 编辑
回复 freshnail 的帖子
即使专家也不明白其他专家发表的论文。我们不是专家，我们越不明白.我相信下面的语句总结了发表论文:
"IL-7 blocks SOCS-3 in T cells, allowing them to proliferate and attack the virus-infected cells."
白细胞介素-7阻止SOCS-3在T细胞，使他们能够增殖和攻击被病毒感染的细胞。“
作者: freshnail 时间: 2011-2-6 20:01
作者: 幸福来临 时间: 2011-3-2 15:50
作者: lin12345 时间: 2011-3-2 21:33
作者: 特深沉 时间: 2011-3-3 09:24
HIV只有人和高级灵长类会携带病毒。小鼠不能携带HIV病毒。
那么，可能这不是真正的HIV病毒，而是类似的病毒在小鼠上试验。
或者，不是普通小鼠，基因改造小鼠，使小鼠能带HIV病毒。
过去的经验表明这两种方式都不能很好模拟真正HIV在人体的免疫情形。
作者: StephenW 时间: 2011-3-3 10:03
本帖最后由 StephenW 于 2011-3-3 10:03 编辑
特深沉 发表于 2011-3-3 09:24 
HIV只有人和高级灵长类会携带病毒。小鼠不能携带HIV病毒。
那么，可能这不是真正的HIV病毒，而是类似的病毒 ...
你是对的. 在英语文章中说:"HIV-like infection" 类似HIV的感染.
其他报告没有提及这重要的一点.谢谢你.
但我认为这不会改变文章的结论.
"生物通报道：来自澳大利亚墨尔本大学医学生物学系，霍尔医学研究所，加拿大大学健康网络医院，美国斯坦福大学医学院等处的研究人员利用免疫系统中的一个早已发现的因子：IL-7，来清除小鼠体内的艾滋病病毒，抑制感染，增强小鼠的免疫反应，从而有可能治愈艾滋病。这一研究成果公布在Cell杂志上，并被作为头条推荐"
作者: 20140 时间: 2011-3-3 19:12
特深沉版主可就是不一样~~~~
作者: 20140 时间: 2011-3-3 19:12
又让我们看到了多一点的希望
作者: StephenW 时间: 2011-3-9 17:26
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
作者: StephenW 时间: 2011-3-9 17:42
评价Dhaya Seshasayee和弗拉菲乌斯马丁新的评价| Raphaelle帕克和Irini Sereti |托比亚斯Boettler和马提亚冯Herrath |巴里劳斯
在这项研究中，作者报告说，外源性白细胞介素（IL）-7可以帮助通过抑制细胞因子信号涉及3（SOCS3的）镇压机制清除小鼠慢性淋巴细胞性脉络丛脑膜炎病毒（下LCMV）感染。这篇文章的最有趣的方面是观察，白细胞介素- 7增加的IL - 22的生产在肝脏（肝脏病理可能会限制），这表明在促进炎症的IL - 7的双重作用，同时采取行动，限制主机的组织损伤。
中IL - 7代和T -细胞反应维修的重要性已被记录在无数的研究。重组白细胞介素- 7人类当局已证实导致的T -细胞数量的增加与T细胞剧目的多样性。类似的效果已经观察到的病毒感染小鼠模型的影响，这已被认为是有助于提高病毒清除。然而，确切机制，白细胞介素- 7发挥其影响尚未阐明。在本研究中，作者提出的IL - 7细胞因子的表达增加行政结果（白细胞介素-6，干扰素[干扰素]γ，白介素- 17），通过减轻SOCS3的，这些细胞因子介导的抑制可能。作者还观察到，这白介素- 7 -诱导的炎性细胞因子的产生增加不是由肝脏病理的陪同下，通常观察下LCMV，这可能是由于当地的大幅升高的IL - 22在肝脏中的CD4 T细胞的生产。这一观察增加了越来越多的证据上的IL - 22的保护作用，如身体内脏器官。精密机制，白细胞介素- 7诱导肝脏的IL - 22诱导不明确，需要进一步研究。
竞争的利益：无申报
*引用这一评价
Seshasayee研发，马丁女：“在这项研究中，作者报告说，外源性白细胞介素（IL）-7能帮助老鼠...”评价：[佩莱格里尼M等人。白细胞介素- 7从事多种机制，克服慢性病毒感染和极限器官病理学。细胞。 2011年2月18日; 144（4）:601 - 13;分类号：10.1016/j.cell.2011.01.011]。学院1000年，2011年3月4日。 F1000.com/8506956
缩写形式
Seshasayee研发，马丁传真：2011。 F1000.com/8506956
评价：
Dhaya Seshasayee和弗拉菲乌斯马丁
基因技术公司，美国
免疫学
2011年3月4日
等级6
推荐
在过去的几年中，白细胞介素- 7素（IL - 7）已成为在由淋巴细胞或免疫缺陷病的特点与免疫细胞因子疗法极大的兴趣。我们发现这篇文章有趣，因为它研究了在体内白细胞介素- 7总局关于通路的影响慢性病毒感染的控制的影响。笔者描述了白介素- 7对小鼠慢性淋巴细胞性脉络丛脑膜炎管理病毒（下LCMV）导致通过下调细胞因子抑制病毒清除感染的信号通过增强IL - 6的生产3（SOCS3的）。
笔者研究了重组人白细胞介素- 7与克隆- 13下LCMV，诱使慢性感染小鼠注射感染的影响。感染后八天，老鼠收到的IL - 7或磷酸盐缓冲三周液（PBS）或10g的每日注射。白细胞介素- 7处理允许在一至两个月后感染中的脾，肝，脑，肾病毒清除。
如前所示，白细胞介素- 7注射引起一过性升高，尽管在CD4和CD8 T细胞，包括急剧扩张，抗原特异性T细胞。值得注意的是，白细胞介素- 7处理允许将NP396 - T的具体过程中，通常引起急性（阿姆斯特朗株），而不是慢性LCMV感染以及天真的，非下LCMV特异性T细胞细胞的发育。此外，类似以前的工作（见文献{1}，上Raphaelle Parker是作为一个作家上市），白细胞介素- 7治疗功能效应诱导的CD8 T表达的PD - 1和CD69的细胞增加的比率较低水平。白细胞介素- 7 -治疗动物表现出的IL - 6水平较高，IL - 17和干扰素（IFN）γ的抑制与转化生长因子（TGF）细胞因子水平较低一起对照组相比，测试版。尽管亲炎症环境诱导的T低百分之监管（调节性T细胞），肝有没有证据，这是归因于增加IL - 22的生产细胞保护作用。
这项研究的重点是示范中IL - 7调制的免疫反应，允许通过SOCS3的镇压病毒清除。 SOCS3的表达过程中的T细胞克隆- 13而不是阿姆斯特朗感染，表明其表达的抑制可能在病毒血症控制牵连。事实上，成功地模仿的IL - 7治疗的效果由SOCS3的克隆过程中删除- 13感染的T细胞的作者。 SOCS3表达下调（可能通过FoxO转录因子）的要求对IL - 6的增强生产。
这将有必要扩大这一工作，并阐明这些途径，特别是在人类的人，以淋巴细胞在白细胞介素- 7信号可能不完整，以便更好地了解，如慢性肝炎和艾滋病毒其在慢性病毒感染的清除作用。除了对可能出现的反病毒的IL - 7的影响乐观，这项研究还揭示了在建立或慢性病毒感染的既定战略，旨在清除预防可能出现的新的目标光。
参考文献：
{1}帕克等人。血2010，116:5589-99 [结论：20841508]。
竞争的利益：无申报
*引用这一评价
帕克001 Sereti我：“在过去几年中，白细胞介素- 7素（IL - 7）已成为细胞因子...”评价：[佩莱格里尼M等人。白细胞介素- 7从事多种机制，克服慢性病毒感染和极限器官病理学。细胞。 2011年2月18日; 144（4）:601 - 13;分类号：10.1016/j.cell.2011.01.011]。学院1000年，2011年2月25日。 F1000.com/8506956
缩写形式
帕克001 Sereti余：2011。 F1000.com/8506956
评价：
Raphaelle帕克和Irini Sereti
国家过敏和传染病，美国
免疫学
2011年2月25日
等级：8
必读
新型药物靶点
这一全面的报告表明，与细胞因子白细胞介素（IL）-7提高免疫介导的病毒复制过程中一个持久的控制病毒感染的治疗。增强内源性抗病毒免疫反应，以实现一种慢性病原体清除已被证明是非常困难的，特别是在建立持久性。在这里，作者提出的重组IL - 7的处理能填补这一空白。
它们表明，长期淋巴细胞性脉络丛脑膜炎病毒（下LCMV）感染与IL - 7更迅速地清除病毒治疗的老鼠相比，控制动物。治疗主要是增加了组织浸润淋巴细胞，下LCMV特异性和非特异性的数量，并在血清细胞因子水平，如干扰素，干扰素（IFN）-γ和IL - 6和IL - 17，IL12p70和IL - 1有力而引起的，同时降低转化生长因子（TGF）-β的水平。机械地，这是由于白细胞介素- 7 -介导的细胞因子信号抑制SOCS3的镇压。有趣的是，作者并没有观察免疫病理损害的重要迹象。他们表明，这可能是的IL - 22介导的细胞因子损伤的保护，从结果，因为肝脏炎症与一中和的IL - 22抗体治疗白细胞介素- 7 -对待动物增加。观察了IL - 7能potently提高非特异性和特异性免疫反应，并在同一时间阻止免疫病理损害，是迷人的，令人咋舌。不幸的是，一个即时翻译的诊所主要需要注意的是，这一发现的IL - 7治疗也potently促进自身反应性T两年前发表的同一组{1}细胞，发育。
参考文献：
{1} Calzascia等。进程内Natl中山科学美国2008，105:2999-3004 [结论：18287017]。
竞争的利益：无申报
*引用这一评价
Boettler笔，冯Herrath男：“这一全面的报告显示，随着细胞因子白细胞介素（IL）-7提高免疫介导的治疗...”评价：[佩莱格里尼M等人。白细胞介素- 7从事多种机制，克服慢性病毒感染和极限器官病理学。细胞。 2011年2月18日; 144（4）:601 - 13;分类号：10.1016/j.cell.2011.01.011]。学院1000年，2011年2月22日。 F1000.com/8506956
缩写形式
Boettler笔，冯Herrath男：2011。 F1000.com/8506956
评价：
托比亚斯Boettler和马提亚冯Herrath
香格里拉过敏与免疫学研究所美国拉霍亚
免疫学
2011年2月22日
等级：8
必读
新型药物靶点
我发现这个由德麦和他的同事十分惊人的报告。这个概念，我们无法控制，因为我们的一些持续感染的免疫细胞功能失调，但目前已成为公认的免疫范例。我们也知道有，为了这个所谓的'免疫疲惫的帐户多个事件，并阻止这些事件只是一个充其量只是部分有效。我们需要的是什么灵丹妙药逆转的影响，有助于所有功能。可以想象一个这样的灵丹妙药就在眼前，它的名字是白细胞介素（IL）的-7。
这些由德麦和同事的意见，采用免疫淋巴细胞性脉络丛脑膜炎13用尽克隆病毒（下LCMV）的经典模式，现在表明，T细胞SOCS3的诱导是一种内在的主要因素，有助于免疫功能障碍。此外，白细胞介素- 7以抵消政府行为SOCS3的影响，恢复免疫功能的慢性感染的小鼠。事实上，受感染的小鼠能够摆脱他们的慢性感染，在被用尽的奇异大逆转远远超过报告的中介作用影响病毒滴度{1}，甚至用尽时，奇异的组合被用来影响{2}。结果使用IL - 7是戏剧性的这些可能有很大的潜力转化（艾滋病毒和丙型肝炎的考生）提供的，当然，这种方法并不与浮士德的代价来。
参考文献：
{1}理发等。 2006年自然，439:682-7 [结论：16382236]。
{2}布莱克等人。纳特免疫学杂志2009 10:29-37 [结论：19043418]。
竞争的利益：无申报
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