《Nature》：iPSC引发自体免疫排斥反应

tpwang

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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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4 A5 t5 {6 D" [! `5 E' T1 N' \Erika Check Hayden " ]9 n$ D, n) D1 m# Q

  ~7 [. k# f3 ]1 nYang 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 Nature1.2 r. l* N' J7 W9 H. q: Y6 ]; A

; }$ P2 t! _: O2 [+ O6 mThe 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.5 R: K7 c  R; Y" s3 I

& {" x' R2 X1 }" O0 @0 z* M"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.
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. l- f# J+ k# O' 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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Potential for change
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/ O4 _( O0 Q- j8 B& h0 wXu'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.4 h3 n) x0 h- m. d4 [

; I- ^& o: C5 r; G# ZWhen 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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8 ~  ~- ?8 M6 P0 N3 h"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."4 o8 B( M' X9 r% z& m3 c
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The 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. , d& {/ b8 |# v2 d1 K/ R
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Facing rejection
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0 O& ]+ X. |3 b" X0 i6 eBut Xu's study is not necessarily the dire news for the iPS field that it might seem.
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- U2 y6 h  u' b' |5 H% rResearchers 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. % g) V  r$ y* ?" G# E
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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.5 @# D! D: v; ~+ R, `: B

1 ~. P! y& X- Q0 M& \2 v2 r' R3 nXu's study "doesn't really mirror the clinical situation at all", says Fairchild. , \4 M! E+ e: }1 H. k& J. T' f
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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.
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' Q3 E! r6 w. V7 [Fine-tuned therapies
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, \+ U8 C5 k: Y9 jWu 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. 0 B* g& w$ {2 N$ g) c) y/ ^
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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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Xu 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. / ?( z0 [5 _( ?7 |  w/ K
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"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.   v& ?+ O9 O+ v6 x! R( F2 s8 Y  D5 ?' H
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References! U* H' W" Q- Y0 p$ ?. Y
1.Zhao, T. , Zhang, Z.-N. , Rong, Z. & Xu, Y. Nature doi:10.1038/nature10135 (2011).
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% D+ Q7 |, u2 l- _) g, A1 kImmunogenicity of induced pluripotent stem cells
" O8 G6 H: L% M0 f: v$ TTongbiao Zhao,1 Zhen-Ning Zhang,1 Zhili Rong1 & Yang Xu1
; U# D1 U! }! w" CAffiliationsContributionsCorresponding author Journal name:
. w/ Y5 \, Q% a8 U5 l+ p7 P1 TNature
7 _/ C( I# t' y( ?# p2 O$ p: X1 BYear published:
+ T) w: n% e* x( W. C(2011)* A, f' e$ K$ Z: U. k7 R
DOI:( e8 }' L3 a* X
doi:10.1038/nature10135; ?8 n, Y* r& J
Received07 July 2010Accepted19 April 2011Published online13 May 2011

tpwang

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一些名人的反应（摘自kittybruce网友提供的干细胞新闻） ：1 M$ `) P3 ?. k0 \: k  M* K0 a' T
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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% @" b, Y5 y; T9 N; C
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.
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- U5 [3 W0 m7 b/ kThe 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/ j- @6 G: o9 H8 r- _
Boston. “I think it goes to the heart of the issue of how ignorant we really are in understanding these cells.”& r/ l. E' ^. n: I, ^
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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./ t. Z4 |6 p4 L0 \" w" i; Q

+ ~, h# Y$ y5 WDr. 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.( `8 r) C) C7 I! q' K
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Dr. 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! I. |+ X" ^  `4 U! A
implanted 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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Jeanne 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.  s  n4 v- G; W; @# l: a

$ `! a$ j  D+ r1 p“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.$ s7 F9 T. ?. \1 N" r
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SCNT再次被提及。

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full text

tpwang

回复 tpwang 的帖子  H  y  z, f2 y% j  W4 ]
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Immunogenicity of induced pluripotent stem cells# }8 Y1 W$ K& }' K
Tongbiao Zhao,1 Zhen-Ning Zhang,1 Zhili Rong1 & Yang Xu1 1 r& l; Z$ A8 W% w/ w4 ^
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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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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。+ i; U/ @) J! J+ o; F- x

6 J' [3 g  t5 E0 [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。2 d: q! r& R: J3 N$ h+ m6 I
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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 S7 b+ J0 J1 A- A* ~

1 V4 k7 ]+ y& J8 i4 h! P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.”+ j3 ^( u+ P* r  O

mcherry.f

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

hygene

“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。

jhu132llh

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IPS还是伤不起呀
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tpwang

mcherry.f 发表于 2011-5-15 22:46 8 i* |& n( B) K7 S
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。; X* c* r2 r/ e7 J5 ^! f; ^
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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。: \: h( Z: Z2 T8 ?2 L3 {" L9 c

' @; e0 {% @3 U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。. W; V1 B) I7 D& h) u

& [: i) U. k* ]& o' U, Z% y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。6 \# r+ k7 e6 Z# e$ ?/ ^5 ?

! h* [. z& \" r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。
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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。

sunsong7

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。

sajiemeian

极度需要恶补英语