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标题: HEPDART 2011:Novel dendritic cell receptor-targeted HBV therapeutic vaccine indu [打印本页]

作者: StephenW    时间: 2011-12-16 16:32     标题: HEPDART 2011:Novel dendritic cell receptor-targeted HBV therapeutic vaccine indu

本帖最后由 风雨不动 于 2012-4-14 15:03 编辑

ABSTRACT 72
Novel dendritic cell receptor-targeted
HBV therapeutic vaccine induces robust
immune responses in HBV chronic
carrier peripheral blood mononuclear
cells ex vivo
RE Déry1, A Ma1, D Wang1, Y Xia1, K Gutfreund2, and
R George1
1 Paladin Biosciences, a Division of Paladin Labs Inc.,
Edmonton, Alberta, Canada; 2 Department of Medicine,
University of Alberta, Edmonton, Alberta, Canada
BACKGROUND: Exposure to viral antigens during
chronic HBV infection leads to functional impairment
or deletion of virus-specific T cells. Therapeutic
vaccines that induce strong host immune responses
may therefore resolve chronic HBV infection. We
developed a therapeutic HBV vaccine which fuses
HBV S1, S2, Core and murine Fc fragment. We have
previously shown that this vaccine targets specific
receptors on dendritic cells (DCs) and elicits ex vivo
antigen-specific cytotoxic and humoral immune
responses in human peripheral blood mononuclear
cells (PBMCs). In addition, it has been shown that the
vaccine generates robust humoral and cell-mediated
immune responses in vivo in animals. The current
study evaluates the ability of the vaccine to elicit
antigen-specific T cell responses in PBMCs derived
from patients with chronic HBV infection.
METHODS: The vaccine was expressed in Sf9 insect
cells and purified by affinity chromatography. Whole
PBMCs or purified T cells from chronically HBV infected
donors were activated ex vivo by co-culturing
with vaccine-loaded mature DC (mDC). Activated
T-cells were re-stimulated using either HBV S1/S2/
Core overlapping peptides or fresh vaccine-loaded
mDC. Resulting T-cell proliferation and production of
IFN-γ, TNF-α, and Granzyme B were measured by flow
cytometry. The HBV-specific cytotoxic lymphocyte
(CTL) response was measured in chronically HBV infected
patient PBMC derived mDC and T-cells ex
vivo, using the real-time cell microelectronic sensor
(RT-CES) system. Vaccine-loaded mDCs were used as
antigen-presenting cells when co-cultured with naïve T
cells, or as target cells when co-cultured with vaccine primed
T cells.
RESULTS: Primary stimulation of chronically HBV infected
donor T cells with vaccine-loaded mDC
resulted in both CD4+ and CD8+ T cell proliferation.
Re-stimulation of vaccine-activated T cells with HBV
S1/S2/Core overlapping peptides induced IFN-g
production in both CD4+ and CD8+ T cells. Restimulation
of activated chronically HBV-infected T
cells with vaccine-loaded mDC significantly increased
IFN-g and TNF-a production. Interestingly, vaccine activation
of PBMCs from chronically HBV-infected
patients stimulated Granzyme B production by
CD4+CD25- cells (Tresp), accompanied by an increase
in Annexin V+ staining on CD4+CD25+ cells (Tregs). In
our dynamic CTL killing assay, co-culture of vaccine activated
HBV chronic carrier T cells with mDCs
resulted in a dose, time and T cell-dependent decrease
in DC viability.
CONCLUSION: The vaccine-dependent expansion
of IFN-g, TNF-a producing CD8+ and CD4+ T cells,
Tresp-induced apoptosis of Tregs in chronically HBVinfected
donor PBMCs as well as CTL killing of target
mDC by vaccine-activated HBV infected donor T cells
suggests that the vaccine can break HBV tolerance
in chronic HBV carriers by inducing strong immune
responses which include functional activation of
Tresp-dependent apoptosis of Tregs. Thus, our HBV
therapeutic vaccine may be a good candidate for the
treatment of chronic HBV infections.
(Financial support from NRC-IRAP Canada and Alberta
Innovates Technology Futures is gratefully acknowledged.)




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作者: StephenW    时间: 2011-12-16 16:32

摘要:72
新型树突状细胞的受体靶向
乙肝治疗性疫苗诱导强劲
在慢性乙肝的免疫反应
承运人周边血液单核
细胞体外
重Déry1,MA1,D Wang1,Ÿ霞,K Gutfreund2,并
ř George1
1帕拉丁生物科学,帕拉丁Labs公司的一个部门,
加拿大艾伯塔省埃德蒙顿; 2医学系,
埃德蒙顿,阿尔伯塔省,加拿大阿尔伯塔大学
背景:暴露在病毒抗原
慢性乙肝病毒感染导致功能障碍
病毒特异性T细胞或删除。治疗
诱导较强的宿主的​​免疫反应的疫苗
可能因此解决慢性乙肝病毒感染。我们
开发出一种治疗性乙肝疫苗,其中保险丝
乙肝病毒S1,S2,核心和小鼠的Fc片段。我们有
曾表明,这种疫苗的目标,具体
对树突状细胞的受体(DCS)和引出体外
抗原特异性细胞毒性,免疫和体液免疫
人外周血单个核反应
细胞(PBMCs)。此外,它已被证明
疫苗产生强大的体液和细胞介导的
在动物体内的免疫反应。目前
研究评估疫苗的能力引起
派生外周血抗原特异性T细胞反应
慢性乙肝病毒感染患者。
方法:该疫苗表达的Sf9昆虫
细胞和亲和层析纯化。全
外周血单核细胞或纯化的T细胞,从长期HBVinfected
捐助者共培养体外激活
与疫苗装成熟DC(MDC)。激活
T细胞被重新使用无论是乙肝病毒的S1/S2 /刺激
核心重叠的肽或新鲜疫苗装
MDC。导致T细胞增殖和生产
干扰素-γ,肿瘤坏死因子-α和颗粒酶B流量测量
流式细胞仪。 HBV特异性细胞毒性淋巴细胞
(CTL)反应在长期HBVinfected
患者外周血单核细胞衍生MDC和T细胞前
体内,使用实时细胞微电子传感器
(RT - CES)上系统。被用作疫苗加载MDCS
抗原呈递与幼稚T细胞共同培养
细胞,或作为靶细胞共同培养与vaccineprimed
T细胞。
结果:小学刺激长期HBVinfected
捐助者的T细胞疫苗加载MDC
导致CD4 +和CD8 + T细胞增殖。
与乙肝疫苗刺激重新激活T细胞
S1/S2/Core重叠诱导IFN - G肽
在CD4 +和CD8 + T细胞的生产。 Restimulation
激活慢性乙肝病毒感染T
与疫苗装入MDC细胞显著增加
IFN - g和TNF - a的生产。有趣的是,vaccineactivati​​on
从慢性乙肝病毒感染的外周血
患者刺激颗粒酶B的生产
CD4 + CD25 -细胞(Tresp),伴随着增加
Annexin V的染色+在CD4 + CD25 +细胞(Treg细胞)。在
我们充满活力的CTL杀伤实验中,共同的文化vaccineactivated
HBV慢性携带者T细胞与MDCS
导致的剂量,时间和T细胞依赖性减少
在DC的可行性。
结论:该疫苗依赖扩张
IFN - G,TNF - a的生产CD8 +和CD4 + T细胞,
Tresp诱导的细胞凋亡调节性T细胞在长期HBVinfected
捐助者的外周血单核细胞以及CTL杀伤目标
MDC通过疫苗激活的乙肝病毒感染的供者T细胞
表明,该疫苗可以打破乙肝宽容
在慢性乙肝病毒载体诱导强烈的免疫
功能激活的反应,其中包括
Tresp依赖的调节性T细胞的凋亡。因此,我们的乙肝病毒
治疗性疫苗可能是一个很好的候选人
治疗慢性乙肝感染。
(NRC - IRAP加拿大和阿尔伯塔省的财政支持
创新科技期货表示感谢。)
作者: MP4    时间: 2011-12-16 17:18

HepaVaxx B,ViRexx,Paladin Labs Inc
http://www.thestar.com/Business/article/557772
http://www.hbvhbv.com/forum/thread-638049-1-1.html

Chimigen,ViRexx,Lorne Tyrrell,University of Alberta李嘉诚医学院
http://www.hbvhbv.com/forum/thread-972180-1-1.html
作者: StephenW    时间: 2011-12-16 17:42

回复 MP4 的帖子

It does seem to be a vaccine developed from the Chimigen Platform. But what is the connection to Lorne Tyrrell?
作者: MP4    时间: 2011-12-16 17:53

http://www.hbvhbv.com/forum/thread-638049-1-1.html
据ViRexx公司首席执行官及首席科学家Lorne Tyrrell介绍
作者: StephenW    时间: 2011-12-16 18:13

回复 MP4 的帖子

I wonder whether this vaccine is their old Hepavaxx vaccine. What happens to their Phase I clinical trial? Why report what seems to be old findings in HEPDART 2011?

作者: MP4    时间: 2011-12-16 18:41

http://biospectrumindia.ciol.com/content/biotalk/11005052.asp
Chimigen HBV Therapeutic Vaccine is currently in late stage preclinical development and there are plans to initiate a phase-I clinical trial soon.

1期临床试验通常是找正常人做安全性试验,不需要HBVer。

2期,一需要合作投资商(需要很多钱),二需要市场(需要HBVer试验场,印度,中国。。。)

N年前Chimigen有个FLASH,很直观。



作者: StephenW    时间: 2011-12-16 19:16

回复 MP4 的帖子

The phase 1 trial finished in 2006!

August 09, 2006 09:17 ET

ViRexx Completes Treatment in HepaVaxx B Vaccine Phase I Study
EDMONTON, ALBERTA--(CCNMatthews - Aug. 9, 2006) - ViRexx Medical Corp. (TSX:VIR) (AMEX:REX) a company focused on immunotherapy treatments for certain cancers, chronic hepatitis B & C and embolotherapy treatments for tumors, announced today that enrolment and treatment has been completed in the Phase I trial for HepaVaxx B Vaccine, the lead candidate from ViRexx's novel Chimigen™ vaccine platform. The trial has enrolled and vaccinated its target of 15 healthy volunteers with a subcutaneous injection of HepaVaxx B Vaccine. There were no significant adverse events associated with the treatment.

"Establishing a strong safety profile for this novel therapeutic vaccine is critical to the advancement of our Chimigen™ platform. We intend to continue to monitor volunteers in order to complete the safety assessment for this study." commented Dr. Lorne Tyrrell, Chief Executive Officer and Chief Scientific Officer of ViRexx Medical Corp. "Existing hepatitis B antiviral therapies are effective in only approximately 20 to 30 percent of chronic carriers. The therapeutic potential of HepaVaxx B Vaccine, used alone or in combination with existing anti-viral therapies could have an enormous impact for these chronic carriers."

HepaVaxx B

HepaVaxx B Vaccine consists of a recombinant chimeric molecule containing a hepatitis B viral antigen and a portion of a murine monoclonal antibody. The molecule is designed to target dendritic cells, which play a significant role in antigen presentation and initiation of an immune response. In preclinical testing, HepaVaxx B Vaccine has produced both cellular and humoral immune responses. ViRexx believes that the development of humoral and cellular responses may be effective in clearing the virus from patients with chronic hepatitis B infection.

作者: 咬牙硬挺    时间: 2011-12-16 20:50

感谢楼主一直以来的辛勤耕耘
作者: MP4    时间: 2012-6-26 19:13

chimigen治疗性乙肝疫苗重生-新名NU500
http://www.hbvhbv.com/forum/foru ... fromuid-320872.html
chimigen平台的动画介绍,非常直观,有声音
http://www.hbvhbv.com/forum/foru ... fromuid-320872.html





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