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标题: 《Nature》：iPSC引发自体免疫排斥反应 [打印本页]

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作者: tpwang    时间: 2011-5-15 20:45     标题: 《Nature》：iPSC引发自体免疫排斥反应

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Nature News：
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Reprogrammed cells trigger immune reactions in mice：Medical applications of induced pluripotent stem cells called into question.
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5 o& p% Y4 s$ S' L8 K$ H: _Erika Check Hayden - m( ^. t9 ?3 s: |6 h( e# ^! e

0 b( {9 `& y+ k' z3 CYang Xu, UC San DiegoCells that have been reprogrammed to grow into different types of tissue might be rejected by the body — even when they are transplanted into the individual from whom they are made, researchers report in a study published today in Nature1.
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: F; Y$ v. h# z8 I! l4 e& x) SThe study was led by Yang Xu, a molecular biologist at the University of California, San Diego. It will shake up the regenerative-medicine field, because until now, most scientists have assumed that reprogrammed cells made from an individual's own tissue could be safely transplanted back into the same person.
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"This is a surprise; it's going to put a spanner in the works for the whole field," says Paul Fairchild, an immunologist and stem-cell biologist at the University of Oxford, UK.% w, [, B4 W- M0 m) z+ r' U: l7 A* ^

9 x1 x5 T9 d5 A5 y) f& gThe latest study looked at mouse embryonic stem cells and mouse induced pluripotent stem (iPS) cells. Both types of cell are pluripotent, meaning that they can grow into many other cell varieties.
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0 y0 L; o- n. Y$ P: a4 K; zXu's team transplanted the cells into mice with the same genetic make-up as those that had donated the source cells. This mimics transplantation of cells from one human individual back into the same individual.! y9 s3 r: Q/ w; \# y( X. c  U

0 d  |8 f' P+ |9 D) QWhen transplanted, the embryonic stem cells gave rise to teratomas — tumours containing a chaotic jumble of cell types, which are used as a signifier of a cell's pluripotency. Most of the iPS cells, by contrast, were not able to form teratomas, or made teratomas that were attacked or rejected by the immune systems of the host mice.
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# o1 U9 l" ~# ^& C! I9 ?2 e"We expected that iPS cells generated from patients would be able to be transplanted back into patients," says Nissim Benvenisty, a stem-cell biologist at the Hebrew University of Jerusalem. "This paper indicates that that may not be the case."6 K- M. Y' w+ `

( W2 a, n3 V( }6 Q8 z5 l8 sThe team found that certain genes were expressed at much higher levels in the teratomas formed by iPS cells than in those formed by embryonic stem cells. Two of the genes — Zg16 and Hormad1 — were specifically targeted in immune attacks. Xu suggests that these genes are normally turned off by the time a fetus begins the process of developing immune tolerance to its own tissues, so they are not recognized as 'self' by the host's body; the iPS reprogramming procedure might alter the normal expression of these genes.
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3 @# ?) _. u- m) mFacing rejection$ ^  h6 B" S! a
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But Xu's study is not necessarily the dire news for the iPS field that it might seem.
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- R# I' G+ ]% w% j. \Researchers working with iPS-derived cells that have matured to an adult fate — for instance, neurons or heart cells — have been able to transplant them into mice without rejection, but these experiments have mostly looked at mice without functional immune systems. And scientists designing therapies are mostly proposing to transplant only one type of differentiated cell at a time made from patients' own skin cells back into their bodies, rather than the jumble of differentiated cells found in a teratoma.
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Xu and other researchers don't yet know whether purified differentiated iPS-derived cells would be rejected, or whether the problem is specific to undifferentiated cells.0 V# d9 d, _2 [7 Q' ?7 N/ z, U
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Xu's study "doesn't really mirror the clinical situation at all", says Fairchild.
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Fairchild points out that the iPS cells in Xu's study were derived from embryonic skin cells, rather than from adult skin cells, as would be the case for human patients. Perhaps these immature skin cells are more likely than adult cells to trigger an immune reaction. And he adds that it is not clear which cells in the teratomas triggered the immune rejection, or whether human cells would behave in the same way. Until these questions are resolved, Fairchild says, Xu's paper "might cast a shadow over the whole field of regenerative medicine unnecessarily".
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Joseph Wu, a transplant biologist at Stanford University in Palo Alto, California, agrees that the paper "may trigger additional regulatory concerns" for iPS-cell derived patient-specific transplants.
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The finding comes on top of the publication of a spate of studies suggesting that iPS cells might contain more genetic abnormalities than embryonic stem cells2. The US Food and Drug Administration heard concerns about genetic mutations in iPS cells at a meeting in Bethesda, Maryland, in March. 0 h2 K) K" l4 `
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Fine-tuned therapies& e$ L& I2 o. r. G; M
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Wu does not think that companies would be interested in developing patient-specific iPS-derived therapies. They are more likely to focus on cell-derived therapies that can be used in many people, which would require suppression of the immune system anyway.
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"The overall significance of the finding is that more research [needs] to be done to examine whether iPS cells are immunoprivileged or not," says Wu.
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* {8 j2 ^7 Q6 K" ~% EXu agrees. His group's next steps will be to examine which specific cells in the teratomas trigger immune rejection, and under what conditions. The team used two different methods to make the iPS cells, and they showed slightly different propensities to trigger immune rejection, so it may be that reprogramming methods can be fine-tuned to avoid the problem altogether. 9 u$ ~0 v& s4 F) S: P

  W( q$ o& a' M; }9 U. ?: W"We propose that the technology to generate iPS cells needs to be improved in order to minimize the difference between iPS and embryonic stem cells, so that iPS cells can be more useful in human therapies," says Xu. * g+ Q9 H3 J7 L) T5 u+ H

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1.Zhao, T. , Zhang, Z.-N. , Rong, Z. & Xu, Y. Nature doi:10.1038/nature10135 (2011).
! J, B) M% {9 Z4 C2.Pera, M. F. Nature 471, 46-47 (2011).
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/ M1 t2 h7 }* ~/ Q8 JImmunogenicity of induced pluripotent stem cells) L6 P& b6 g- Z3 O  j1 j: m
Tongbiao Zhao,1 Zhen-Ning Zhang,1 Zhili Rong1 & Yang Xu1 ' u; a  e9 j, \3 U
AffiliationsContributionsCorresponding author Journal name:
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DOI:
8 _6 j) u. _" Cdoi:10.1038/nature10135
+ g' p7 g" R6 P* L& l8 [# `+ b3 WReceived07 July 2010Accepted19 April 2011Published online13 May 2011

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作者: tpwang    时间: 2011-5-15 20:51

回复 tpwang 的帖子% z+ V5 p- w8 w
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一些名人的反应（摘自kittybruce网友提供的干细胞新闻） ：3 J) A. a1 X9 l3 \: ]6 K& |# ]1 N
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Other scientists said the results, published online on Friday in the journal Nature, were surprising. “The path to the clinic has just gotten a lot murkier,” said Dr. Robert Lanza, chief scientific officer of
  v2 J+ I* G. X. |Advanced Cell Technology, a company trying to develop medical treatments using both embryonic stem cells and induced pluripotent stem cells. He said it was not clear that the results in mice would hold true for humans, though some other scientists said they assumed they would.) |6 Z! }4 V- v6 Y5 k0 D
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The new report is just the latest to take some of the shine off iPS cells. In recent months other researchers have reported that the cells are prone to various types of genetic abnormalities. “As with any new technology, there is always this initial phase of infatuation, and then the reality sets in,” said Dr. George Q. Daley, director of the stem cell transplantation program at Children’s Hospital
7 J( W' b& \" ]$ l; R0 g$ |Boston. “I think it goes to the heart of the issue of how ignorant we really are in understanding these cells.”
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Dr. Daley said the finding about the immune reactions “happened to be a particularly startling result that I wasn’t anticipating.” Still, he added, years of work lie ahead before iPS cells would be ready to use in treating people, so it is too early to be discouraged. Many scientists say iPS cells for now will be used to create cells — like brain cells from someone with Alzheimer’s disease — that can be used to study diseases in the laboratory.' C5 G' N7 A& ]

/ A4 t7 k4 [% ?8 vDr. Xu, whose research was paid for by the National Institutes of Health and by California’s stem cell program, created both embryonic stem cells and iPS cells from an inbred strain of mice and implanted those stem cells into other mice of the same strain. The mice did not have an immune response to the implanted embryonic stem cells. But their immune systems attacked the implanted iPS cells. Further experiments suggested that the reaction was caused by the abnormal activation of certain genes in the iPS cells, resulting in the production of proteins that seemed foreign to the immune systems of the mice.The degree of immune response depended on how the iPS cells were made. The strongest response was to cells made by incorporating genes for certain growth factors into the DNA of the skin cells. Cells made that way are not likely to be used for medical treatments anyway because at least one of the inserted genes can cause cancer.
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2 D  m( Q" U% g) M' f( t1 kDr. Rudolf Jaenisch, a professor of biology at the Massachusetts Institute of Technology and a founding member of the Whitehead Institute, said that in practice, iPS cells themselves would not be
* w& ^/ ]' ~" E. u+ s% iimplanted into people. Rather, the stem cells would first be turned into specific types of cells, like brain cells or heart cells. He said it was unclear whether such differentiated cells would elicit the same
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* U. e' L8 }& P7 TJeanne F. Loring, director of the center for regenerative medicine at the Scripps Research Institute, said the new findings would not preclude use of the iPS cells for therapy because immune-suppressing drugs could always be used. But the potential problem with iPS cells might make some scientists take another look at making patient-specific tissues by creating an embryo from a patient’s cell through so-called therapeutic cloning. That approach, which is not known to have been accomplished using human cells, is controversial because the same technique might also be used to create a baby.
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2 X& |/ A' Q7 W3 r) {“This reopens the whole need for S.C.N.T, which will be controversial,” said Dr. Lanza of Advanced Cell Technology, referring to somatic cell nuclear transfer, the scientific term for cloning.
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SCNT再次被提及。

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作者: maxiaorongqp    时间: 2011-5-15 21:46

full text

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作者: tpwang    时间: 2011-5-15 22:02

回复 tpwang 的帖子
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/ s/ y" _' K+ w" X/ y' I. g( DImmunogenicity of induced pluripotent stem cells
3 H9 I2 o( u, i9 c; B' Z0 h# gTongbiao Zhao,1 Zhen-Ning Zhang,1 Zhili Rong1 & Yang Xu1
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, D/ o: y0 |3 zInduced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, hold great promise for regenerative medicine as the renewable source of autologous cells1, 2, 3, 4, 5. Whereas it has been generally assumed that these autologous cells should be immune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not been vigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbred C57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, the allogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients. B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach (ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration. In contrast to B6 ESCs, teratomas formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, the majority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, and apparent tissue damage and regression were observed in a small fraction of teratomas. Global gene expression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequently overexpressed in teratomas derived from EiPSCs, and several such gene products were shown to contribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice. These findings indicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiated from iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients.' L) a" U3 V! P) I6 x# F( q
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胚胎成纤维细胞，逆转录病毒和episomal诱导iPSCs，形成的畸胎瘤受到免疫排斥，包括T细胞浸润，组织损伤和畸胎瘤衰退。一些基因在畸胎瘤中过表达，并直接参与上述免疫反应。这些结果表明iPSC分化细胞中的一些异常基因表达可以诱发T细胞相关免疫反应。提示即使自体来源的iPSCs临床应用也需要进行免疫反应检验。; v8 Y9 g2 N- F

) G4 t3 q0 I  [8 P! `一些意见包括：来源细胞不是成熟细胞，不清楚畸胎瘤中哪些细胞导致了免疫排斥反应，实验条件与临床现实相关不大等。有人担心这一结果会对iPSC研究以致整个干细胞研究带来负面影响，尤其是政策与伦理争议的不良影响。; S) V6 G4 g9 @6 U' ^5 d& V9 |

$ ~( b1 M8 @, B题外话，Sean Morrison从密执安大学跳槽到德克萨斯西南医学中心，一方面是提供了诱人的条件（大笔癌症研究经费，老婆跟着获利），另一方面是密执安州对待干细胞研究的政治态度一致不够积极。Morrison是干细胞研究的最大鼓吹者之一，密执安州的政治形势一定使得他不满意。而各种干细胞的负面新闻，尤其是iPSC这类号称没有任何伦理问题的新技术也有肿瘤和免疫问题，整体上对这些干细胞文化与政治环境“不友好”的地区更不利。4 T  }' u: `3 z; q

& C) P& K; r- {这个初步研究的另一个微妙结果是不同方法获得的iPSC似乎免疫反应程度不同。如果这是确实的，那么小分子、RNA以及半路转换（丁盛）方法是否也有这类问题，值得关注。反正是越搞越复杂了，正如 George Daley 说的，“我认为这一结果直指我们对这些细胞的了解是如何的肤浅的核心事实”I think it goes to the heart of the issue of how ignorant we really are in understanding these cells.”+ u$ S+ m  m7 l$ |' h& H

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作者: mcherry.f    时间: 2011-5-15 22:46

It seems that there is immunogenecity shifting during the reprogramming of somatic cells.

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作者: hygene    时间: 2011-5-16 08:40

“I think it goes to the heart of the issue of how ignorant we really are in understanding these cells”，在大自然面前，人类总是显得非常幼稚，未知的领域随着人类认识的提高将会越来越多。

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作者: jhu132llh    时间: 2011-5-16 09:04

哎
! ~+ K3 W3 p/ ?- I1 h7 m* `IPS还是伤不起呀
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作者: tpwang    时间: 2011-5-16 10:00

mcherry.f 发表于 2011-5-15 22:46 " S; r  D1 r5 p+ i6 g. w
It seems that there is immunogenecity shifting during the reprogramming of somatic cells.

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如果这个iPSC的immunogenecity shifting现象确实被证实，带来几个额外的问题。- z% |8 s4 E" W$ k) N5 h) ?

+ K' [0 q/ `6 C" }' O$ `" A! L8 v首先，这个免疫性改变的机制是什么，是表观遗传还是coding sequences的变异，这两者都已经被证实存在于iPSC。具体哪些基因的异常表达导致和参与了免疫反应，程度，条件等，例如是否与Oct4有关（已有研究表明存在类似的免疫反应）。本研究鉴别出两个基因，已知与T细胞免疫有关。更深一步，还需要找出特定的peptides等。4 Y  S3 @/ o7 p0 o6 B) C; k9 A

7 b( U2 J7 Y. b其次，这些变异发生在iPSC过程的哪个阶段，比如是发生在表观遗传解除的过程，还是完全多潜能状态的形成过程。如果是后者，那么诸如半路转化（丁盛的途径）是否有可能避免这个多潜能转化带来的免疫性改变。如果是前者，那么直接转分化可能就更具有吸引力了。: L: C7 z: F+ t% c$ j

8 C% `+ [( _- d再次，这些表观遗传改变或其他因素导致的免疫性改变是否可控或可逆，即控制那些导致免疫反应的基因表达会不会影响iPSC的诱导等。再后，iPSC分化为靶细胞的过程是否会消除这些免疫反应因素，从可塑性的逻辑角度来说，倒回到多潜能状态带来不少潜在的变异，而再次分化为靶细胞有可能去除这些变异，这在其他一些方面得到了证实。亚内斯持这个观点。
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6 v% ~, S  x) ?- U4 |. p- f更实用一些，这些免疫反应即使存在，是否会严重影响iPSC及其终端产品的应用。其一，临床上不大可能直接移植iPSC用于治疗，所以，iPSC直接移植形成畸胎瘤然后观察免疫排斥反应的平台，对终端分化细胞移植的临床前景到底具有什么实际意义，不好说。即使终极分化细胞也保有一定的免疫性状变异，这些变异引起的反应能否用有效的方法合理控制，如现在所用的控制免疫排斥反应手段一样。- g" k6 V% ^& {- H! V
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在这之前，这个结果还需要很多验证，首先可以检验一下各种诱导手段在免疫源变异方面的情况，确认这是一个一般的规律还是某些方法和条件的特例。

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作者: sunsong7    时间: 2011-5-17 12:06

iPS仅仅对细胞遗传物质进行重编程是没有前途的。遗传物质只是重编程信息的保管文库，发育过程基因表达的时空顺序不但取决于某些基因开启或闭合，细胞质才是基因信息的加工“工场”。结构决定功能，iPS的细胞质“工场”是为制造某些定型产品设计的，现在强令其转型加工标准的通用部件，出现一些“记忆”、“免疫排斥”、“表观差异”在所难免，可怕的进行iPS移植后这些“工场”转为地下，变成“黑工场”就不是小麻烦了。

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作者: sajiemeian    时间: 2011-5-17 16:00

极度需要恶补英语

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作者: sajiemeian    时间: 2011-5-17 16:33

为什么我附件下载了打不开？浪费包包了。。。。

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作者: 细胞海洋    时间: 2011-5-17 17:10

回复 sajiemeian 的帖子
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不要使用迅雷下载 使用浏览器默认下载

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作者: 细胞海洋    时间: 2011-5-18 08:30

科学网
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, A' ~4 F0 Q+ j5 U% V  l! c! u4 j来自加州大学圣地亚哥分校的研究人员在5月13日《自然》（Nature）杂志上发表的一篇文章中称他们在小鼠中证实将诱导多能干细胞（iPSCs）分化生成的多种组织移植至动物体内会产生快速的免疫排斥反应，即便iPSCs的起源细胞来自于移植小鼠本身。一直以来，大多数科学家们都认为来自于个人自身组织的重编程细胞能够被安全地移植到同一个体体内并能避免排斥反应。这一研究结果或将对再生医学领域造成巨大的震动。
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0 N7 e- S! Z/ g( m领导这一研究的是加州大学圣地亚哥分校的徐洋（Yang Xu）教授，其1989年毕业于武汉大学，之后赴美求学，获得哈佛大学的博士学位，并在麻省理工学院完成博士后的研究工作，目前任加州大学圣地亚哥分校生物系终身正教授，以及国家自然科学基金海外评委。
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/ r* |- E% R7 w“这是一个令人惊讶的研究发现，它或将扭转整个再生医学领域的研究工作，”英国牛津大学的免疫学家和干细胞生物学家Paul Fairchild发表评论说。
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在这篇文章中，徐洋的研究团队将小鼠的胚胎干细胞和小鼠iPS细胞移植到了提供起源细胞的小鼠体内。研究人员发现移植的胚胎干细胞在小鼠体内形成了畸胎瘤。然而相比之下，由于受到宿主免疫系统的免疫攻击或免疫排斥，大部分的iPS细胞未能在小鼠体内形成畸胎瘤。
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7 |* C, }+ ^. \“科学家们原本期望能将来源患者自身的iPS细胞移植到患者体内，这一研究论文的结果表明一切可能并非如此。”耶路撒冷希伯来大学的干细胞生物学家Nissim Benvenisty说。" F& b2 R6 y- N- N

7 H. m' n4 Y2 W& ?6 N研究人员发现相对于胚胎干细胞形成的畸胎瘤，由iPS形成的畸胎瘤中的某些基因呈高水平表达。其中的Zg16及 Hormad1两个基因的异常表达可直接导致遭受特异的免疫攻击。徐洋表示这些基因在正常情况下处于关闭状态直至胚胎开始对自身组织形成免疫耐受为止，如此就能确保它们不会被宿主所识别。而iPS的重编程程序有可能改变了这些基因的正常表达。) |$ x- X& t) F9 ]( j4 j

2 M' b4 \. g) Y* Z6 `+ ~% C然而徐洋的研究发现对于iPS研究领域的科研人员而言未必是悲惨的消息。1 \9 r" }: ]+ V5 @8 g0 W

- B5 [$ i4 h+ n% O1 z长久以来，科学家们在开展iPS研究的过程中把iPS衍生获得的终末分化细胞例如神经细胞或心肌细胞移植到小鼠体内，证实它们不会引起免疫排斥（但事实上其中的大部分实验都是在缺乏功能性免疫系统的小鼠上开展的）。并且科学家们在设计治疗方案时大多是提出每次将一种由患者自身皮肤细胞生成的分化细胞移植回患者体内，而非畸胎瘤中混杂的多种分化细胞。; L3 U* Q5 u4 M0 S: q. B

. D+ W4 T% W2 p5 t徐洋及其他的研究人员并不清楚纯化的iPS衍生分化细胞是否会受到免疫排斥，或是这一类问题是否仅特异地存在于未分化细胞中。
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“徐洋的研究还并不能完全地反映临床情况，”Fairchild说。
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+ P& B7 b8 X' u4 o# i+ gFairchild指出在徐洋的研究中采用的iPS细胞来源于胚胎皮肤细胞，而非成人皮肤细胞。或许相对于成体细胞，不成熟的皮肤细胞更有可能启动免疫反应。此外他还补充道目前尚不清楚畸胎瘤中哪种细胞引起了免疫排斥，以及人类细胞是否会以相同的方式产生反应。Fairchild认为徐洋的论文有可能使整个再生医学领域蒙上不必要的阴影。. j8 M% j0 \; J( D
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斯坦福大学的移植生物学家Joseph Wu也认为这一论文或有可能引发科学界对于iPS细胞源性患者特异性移植产生更多的监管忧虑。8 L' E) M3 {! {/ J2 b/ z# V! b
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近期在这一顶级期刊上接二连三地发表了一系列的研究论文指出相对于胚胎干细胞，iPS细胞或许包含着更多的遗传缺陷。美国食品和药物管理局(FDA)在今年三月马里兰州贝塞斯达的会议上聆听了科学家们对于iPS细胞中遗传变异的关注。1 O" m! ^8 t& h* O

6 U) e7 s* a7 C7 i' I' E徐洋认为公司并不会对开发患者特异性iPS治疗产生兴趣，而他们更有可能将焦点关注在可在大多数人中运用的细胞治疗上，因为这种疗法均需要抑制患者的免疫系统即可。
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“这些研究发现的整体意义在于促使人们开展更多的研究工作去检测iPS细胞是否具有免疫豁免特性，”徐洋说。$ @5 k- @2 @( A& R

% t: {9 A3 e, |( v- w: e徐洋表示在接下来的研究中他的研究团队将进一步检测确定畸胎瘤中的哪一类特异细胞在何种条件下启动了免疫排斥。研究人员利用两种不同的方法来生成iPS细胞，他们证实这两种细胞在启动免疫排斥上只显示了轻微的差异，这或许表明重编程的方法对于避免免疫排斥可起到微调的作用。. R/ D% j/ z- ^( T, o) L

2 w0 f0 E9 v2 C% A6 P1 {“我们认为iPS技术还需要进一步地改良以尽量减小iPS细胞与胚胎干细胞之间的差异，从而确保iPS细胞能够运用到人类疾病治疗中去，”徐洋说。（生物谷Bioon.com）
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生物谷推荐原文：
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' r$ D; c/ A: t! N' R: c( zNature   DOI:10.1038/nature101357 L: k& @: x. m; d0 X

$ H  t0 q8 d$ V( u$ j* F- XImmunogenicity of induced pluripotent stem cells
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$ N- j4 q. u0 K. [& P+ Z; e% eTongbiao Zhao; Zhen-Ning Zhang; Zhili Rong; Yang Xu% d1 i; j9 R( I( r
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Induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, hold great promise for regenerative medicine as the renewable source of autologous cells1, 2, 3, 4, 5. Whereas it has been generally assumed that these autologous cells should be immune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not been vigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbred C57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, the allogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients. B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach (ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration. In contrast to B6 ESCs, teratomas formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, the majority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, and apparent tissue damage and regression were observed in a small fraction of teratomas. Global gene expression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequently overexpressed in teratomas derived from EiPSCs, and several such gene products were shown to contribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice. These findings indicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiated from iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients.
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作者: chips100    时间: 2011-5-19 11:17

ESC是没有或免疫原性很低，分化后免疫原性升高。如果这样的话 ，iPS在干性阶段不能用，那分化后就更可能被排异。转分化看来有点市场了，毕竟保存的，记忆的多，但是会不会抹掉，需要验证一下。相对而言，iPS回到干性，虽然有点表观记忆，是否还需要阳性阴性的选择。如果是，那走的路可能就有点长了。是否需要在体外模拟豁免过程？免疫界发展到现在一直没什么大进展，可能要有个革命了
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作者: 干细胞狂想    时间: 2011-5-20 18:36

iPSC挑战上帝之手，不知道未来会发展成如何，有没有将iPS 与ES基因表达谱做个比较分析啊？

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作者: sunsong7    时间: 2011-5-21 10:53

干细胞狂想 发表于 2011-5-20 18:36 2 K! ]! l8 b/ J. n" q: B$ o
iPSC挑战上帝之手，不知道未来会发展成如何，有没有将iPS 与ES基因表达谱做个比较分析啊？

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hES和iPS细胞的基因图谱比较（大略）http://www.stemcell8.cn/thread-35995-1-1.html# a( H  ~2 z- J; Q9 r

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作者: starlj    时间: 2011-5-22 14:01

这个实验结果比较有意思，虽然会加大iPS走向临床应用的难度，但总体上讲还是加深了对iPS细胞的认识。同时也为iPS技术或者自体细胞移植治疗设立了以前没有想到过的鉴定指标。
2 Q7 u2 f) z3 b! m" h8 M8 x7 [* `个人感觉有几个问题需要关注：. e6 e3 g+ _5 o# Q8 [, n( H$ q8 f
其一：文章中提到的同种品系ES细胞并没有出现免疫排斥，而自体iPS细胞居然出现排斥。这说明了iPS细胞与ES细胞还是存在差别。但这种差别，可能是人为因素。比如iPS细胞的质量问题。文中采用的iPS细胞系，并未告诉是否可以出现生殖系嵌合。重编程是一个漫长的过程，此间产生的不同的iPS克隆之间特征都可能不一样，所以才需要一系列的鉴定手段来判断一株iPS细胞是否是与ES相似。文中的鉴定仅仅到了嵌合鼠。如果有生殖系传递或者四倍体互补的鉴定，将更能说明问题。作者应该加大样本量，采用高质量的iPS细胞系来做免疫试验，才能更有说服力。
: F) f* k6 _! T; P+ T0 |( X8 R% L其二：文章中的iPS细胞系来源是B6小鼠的MEF细胞。MEF制备过程决定了不可能有相应的小鼠出生，也就是说iPS细胞与最终做免疫试验的小鼠并不是真正的一样，只能说是同一个品系来源。最严格的实验应该采用B6小鼠的成体细胞，比如鼠尾间成纤维细胞TTF来进行重编程。然后将得到的高质量的iPS细胞（经过生殖系传递或四倍体互补鉴定）在TTF来源小鼠身上做免疫试验。如果在这样的条件下仍然能发生免疫排斥，则说明了重编程过程的发生免疫原性改变的问题。
% e) z: l! B6 C) l其三：不排除的确是因为文章中所说的部分基因的异常表达导致immunogenecity shifting。如果说这些基因真的与immunogenecity shifting有关，倒也可以看做是免疫学的重要进展。说明某些基因的异常表达式可以导致个体免疫原性的变化。但这种变化是由于重编程的不完全、记忆还是分化过程中的其他因素引起的呢？8 S2 h: f9 K3 L$ J$ }' O8 x& w- B' N& Z
总之，该实验存在一定的背景上的干扰。但发现的现象需要重视，机制需要阐明，才能为iPS走向临床，或者说细胞治疗走向临床提供指导。
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作者: quduck    时间: 2011-5-25 11:34

干细胞从发现到现在走了多少年才被批准用于临床？而且现在还在无尽的研究。
. c* B; v( o! d0 i而iPS 才几岁，过程总是漫长曲折的，没有足够的时间和工作是无法下结论的。

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作者: tpwang    时间: 2011-5-25 11:46

quduck 发表于 2011-5-25 11:34
  {# J2 C+ |0 `0 r干细胞从发现到现在走了多少年才被批准用于临床？而且现在还在无尽的研究。* j. {3 g2 d& ]9 K% P- L- Z
而iPS 才几岁，过程总是漫长曲 ...

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此话有理。& S2 }9 Z) e% K2 U  E# F0 T

( [5 C8 E  \' s; W: C不过，这里的情况是iPSC毕竟与其他干细胞类别不一样，期待高，也就影响大。所谓爱之甚切，责之甚严。也是情理之中的事情。
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作者: JOEL    时间: 2012-5-3 18:57

回复 sunsong7 的帖子
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9 H1 r# ~, U( b: x5 [  v6 `3 q. Y8 ?Agree with your commnet.8 v) ~8 x+ y  U/ l% N, X
In the the theory of "99% vs. 1%" in the genetic expressions of iPS, the reality that the 1% seems to have become the dominant force. It is really a significant negative message. The worrying in the field is reasonable obviously.

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作者: JOEL    时间: 2012-5-3 19:16

回复 hygene 的帖子
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% _# ]- a$ W' a0 iYou are absolutely right!
8 q# P7 D% z, aComparing with the mysteries, which has been set in "the great nature," the totality of human knowledge in the scientific exploration on the nature is just a sand of the seashore.1 e! u5 `* B" ]/ J9 E" l
人类的科學探索精神總是崇高的。. F! |/ l7 x( l  h! A0 W
但在伟大的造化之前人类最好應懐有一颗谦卑的心。仍需知道，全部的人类知識与尚未知的大自然的奥秘相比，诚如我所學得精辟中文成语所言乃是：九十牛一毛！

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作者: JOEL    时间: 2012-5-3 20:53

回复 tpwang 的帖子
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1 V0 y, d" o" ~, v+ M" c------这个初步研究的另一个微妙结果是不同方法获得的iPSC似乎免疫反应程度不同。如果这是确实的，那么小分子、RNA以及半路转换（丁盛）方法是否也有这类问题，值得关注。反正是越搞越复杂了，正如 George Daley 说的，“我认为这一结果直指我们对这些细胞的了解是如何的肤浅的核心事实”I think it goes to the heart of the issue of how ignorant we really are in understanding these cells.”, \+ r, Z8 S1 N+ b* z) L- Q) T) ?7 a
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------Appreciate the analysis, objective, and to the very point. Yes considering that the differences of the immunization rejection in various levels while observing the transplantation of the iPSs made in different methods, it shows that we still have hope on the track of iPS. So far, hard to foresee the fate of iPSs.

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