《Nature》：iPSC引发自体免疫排斥反应

tpwang

5 M& F, U* S  ?; n- X, ANature News：
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Reprogrammed cells trigger immune reactions in mice：Medical applications of induced pluripotent stem cells called into question.1 V6 R& m. _  E# T4 x. D) A

1 Q& V9 U8 R6 e7 |; eErika Check Hayden
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0 c3 u; V* x7 Y5 Z7 ~2 K. \6 v* Q( YYang 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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The 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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; f7 v4 x2 E' B/ ?& p$ Q"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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6 L5 y* @4 S/ XThe 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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Xu'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.& x3 ?" R5 _- @9 m. p( K

) n  h' u4 g3 x1 w& }/ ~When 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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( W9 O6 q! f& e! c3 X6 \$ c"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."! B; N2 [% P8 N% p. s9 Y1 r- `3 ~

1 ^+ L' z; g# k( K4 c& ZThe 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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Facing rejection
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8 P. s5 I" F2 L. ?3 b2 YBut Xu's study is not necessarily the dire news for the iPS field that it might seem.
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7 p, }4 c+ c( B# HResearchers 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. 5 R1 r/ r+ k1 x- }! Z. u3 _
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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.8 z6 x! r6 ?' i& ~

# q  d8 `% i& B( f  G/ {( EXu's study "doesn't really mirror the clinical situation at all", says Fairchild. 3 Z, t6 r- J, 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".( ?& z& r/ G! m- ?5 Z! r
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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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) ^, j7 Q6 U  R" f% f% m. UFine-tuned therapies! _6 k1 k3 U& U
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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. / p* U* y0 D2 S$ R* J

4 M: e" T! h" g# n" X3 f "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.7 q4 Y  ~9 C  D. u. z5 h5 B' c5 l- V
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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.
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4 V' t8 ~* m: V3 \) L( r3 n. P0 |9 \"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.
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References
" K, Y1 {- J3 {2 l, x1.Zhao, T. , Zhang, Z.-N. , Rong, Z. & Xu, Y. Nature doi:10.1038/nature10135 (2011).
8 ]9 |, W! W  b8 B2.Pera, M. F. Nature 471, 46-47 (2011).2 m% c- T% l/ p8 n! n. q$ j

. C' M' R3 N1 R, KImmunogenicity of induced pluripotent stem cells
1 V3 g% P) `- x! N. P$ q+ yTongbiao Zhao,1 Zhen-Ning Zhang,1 Zhili Rong1 & Yang Xu1 * q3 I6 Q) |4 V( H* r: Y
AffiliationsContributionsCorresponding author Journal name:7 p& F4 F: c# G
Nature3 {( b( T( U6 \* I- o1 E4 @
Year published:3 b$ K1 k( S% c8 c* M
(2011)
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doi:10.1038/nature101354 f: R$ A. F# \  E
Received07 July 2010Accepted19 April 2011Published online13 May 2011

JOEL

回复 tpwang 的帖子
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7 V# V( U( }1 L& Z8 r% O) k5 A------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.”# i( M' ^& @" n: m/ D3 J
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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.

JOEL

回复 hygene 的帖子
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- j1 S& U. `" C. _. OYou are absolutely right!
3 T7 M" H" v# q# z- CComparing 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.% R. u! j1 e( X/ X
人类的科學探索精神總是崇高的。
" y, |+ b2 t+ W5 l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！

JOEL

回复 sunsong7 的帖子0 `* p4 C" i8 p
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Agree with your commnet.6 ~2 y( b2 Z& 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.

tpwang

quduck 发表于 2011-5-25 11:34 8 z, t/ W7 T/ l- b  s
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。
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此话有理。8 A* V% c# C# ]2 r' f$ C
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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。6 \* v; A% ]# g# C' B

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quduck

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。
2 d) a: Q9 x/ @) `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。

starlj

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。
0 o. _; J3 v( }, `个人感觉有几个问题需要关注：
$ y5 r* z) n! o9 C7 @6 s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。
; n' C7 Q$ I, {! A- i- o9 @6 Q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。
, s9 L: x3 U0 ?) W5 D) B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？( c& g0 t; p6 T; G) S( F4 H* [" n) Y
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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sunsong7

干细胞狂想 发表于 2011-5-20 18:36 / ?/ s# X% u1 s! i, G) a0 }9 v' S
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
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干细胞狂想

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？

chips100

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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