Stem cell news: Science转化医学: 干细胞使免疫系统默认异体移植器官

kittybruce

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8 O, d! Q5 ?* c( e3 \5 j% I: T芝加哥Northwestern Memorial Hospital研究者利用供者血液动员获取造血干细胞并富集另一种“facilitating cells”，在HLA配型不全相合的肾移植术后一天将上述细胞注入经过预先清髓的受者，8名受者中5人达到良好的免疫耐受，不需要服用免疫抑制药物。但因未设无“facilitating cells”对照组，这种细胞的具体作用仍不明了。0 _% y( j  g. r7 I6 D4 H
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National Post
% m' _: b! u* H( a* AStem cell treatment tricks immune system into accepting donor organs, study shows
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Reuters  Mar 8, 2012 – 6:26 PM ET
* z4 G1 {' ~' z. D) _CHICAGO — Scientists have found a way to trick the immune system into accepting organs from a mismatched, unrelated organ donor, a finding that could help patients avoid a lifetime of drugs to prevent rejection of the donated organ.
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Of eight kidney transplant patients who have been treated with this new approach, five have managed to avoid taking anti-rejection drugs a year after their surgery, according to the study published on Wednesday in Science Translational Medicine.  T: H" r* l" U: G4 \0 Z3 c
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And one patient, 47-year-old Lindsay Porter of Chicago, is completely free of anti-rejection drugs nearly two years after her kidney transplant.# y$ Z5 y+ B2 a
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“I hear about the challenges recipients have to face with their medications and it is significant. It’s almost surreal when I think about it because I feel so healthy and normal,” she said in a statement.
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With conventional organ transplants, recipients need to take pills to suppress their immune systems for the rest of their lives. These drugs can cause serious side effects, including high blood pressure, diabetes, infection, heart disease and cancer.* ~5 N3 p: c7 v3 @' d; i  r
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“This new approach would potentially offer a better quality of life and fewer health risks for transplant recipients,” Dr. Suzanne Ildstad, director of the Institute of Cellular Therapeutics at the University of Louisville in Kentucky, who developed the new approach, said in a statement.
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7 X2 R7 [- b8 V! oBut some experts say the procedure, in which patients undergo a bone marrow transplant from an unmatched organ donor, is too risky, especially given the relative safety of kidney transplants.
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' q& k8 f; J4 h- o' wWe have to think about the risks and benefits. Since the current treatment is so stable, it really has to be safe,” said Dr. Tatsuo Kawai, a transplant surgeon at Harvard Medical School, who wrote a commentary on the new approach in the journal., z' ~+ l8 K6 |" R) W
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PATENTED TECHNOLOGY
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7 U9 {% r' i" w! y2 W; ^) c6 bThe new technique draws on research by Australian immunologist Sir Frank Macfarlane Burnet and Brazilian-born British zoologist Peter Medawar, who won the 1960 Nobel Prize for discovering that the immune system in animals can be trained to acquire tolerance of foreign tissue.7 o7 ?4 R( g& a( e2 p

$ D* I: e2 I, k" h' O; NBut it has been a long road to bring this about in people, says Dr. Joseph Leventhal, a transplant surgeon at Northwestern Memorial Hospital in Chicago, where the transplants took place.  P! Z$ ?- c9 A
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To get transplant recipients to accept the donor organ, the team needs to condition” them by suppressing their body’s bone marrow with chemotherapy and radiation before transplanting the donor’s bone marrow, the soft fatty tissue inside bones. Bone marrow contains immature blood-forming stem cells that give rise to all blood cells, including immune system cells.
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( r* J0 h- l4 w$ ]" n. \' w“The idea here is to try to use donor-derived stem cells to achieve engraftment, a state we call chimerism,” Leventhal, a co-author of the study, said in a telephone interview. “Here what we are trying to do is get donor and recipient cells to peacefully coexist in the transplant recipient.”
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3 X5 Q1 o8 D. \' p2 u+ U# EAbout a month before transplant surgery, kidney donors must inject themselves with a medication for several days that forces stem cells and other key cells called “facilitating cells” into their bloodstream, from where they can be collected and sent off to the University of Louisville for processing.
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* A6 x, r3 j9 Q* MLeventhal said these “facilitating cells” are naturally occurring cells that help create a more favorable environment for the stem cells and allow engraftment to occur safely.
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% m  I' j8 ^5 `8 d5 h6 rIldstad has developed a process for enriching these cells and formed a company called Regenerex LLC, which is developing the patented technology.
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Meanwhile, the transplant recipient is given radiation and chemotherapy to suppress the immune system, a process intended to prepare them for accepting the donor’s stem cells.: \3 N3 T# ~8 b! w4 R

% c) a8 m* n, @: x! Y" D2 @5 X! MThe patient then undergoes a kidney transplant, and a day later gets transplanted with the enriched mix of the donor’s stem cells and facilitating cells with the hope of forming two bone marrow systems that can exist and function in one person.8 o7 E8 q  A! u2 _2 @/ _1 z

* V2 N1 i9 h: v% p7 zFollowing those procedures, the recipient starts off taking anti-rejection drugs but is gradually weaned off them with the goal of stopping entirely a year after the transplant.7 t# X- `) n( |6 [% w& ]

. {1 p5 S, ^7 t) jIn the study, five out of eight patients reached this one-year goal. Two patients had a partial response and have been placed on a reduced dose of immunosuppressive drugs.5 z8 ~0 D  K+ z0 j3 e8 E6 |
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One patient developed sepsis and lost the new kidney, but has since received a conventional kidney transplant.
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The study is the first to try to create chimeric tolerance in patients using the facilitating cells created by Regenerex.0 {, Y  r( j- Y2 {: P2 d. [" x) N6 F5 C
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“By use of this stem cell product, we have been able to show we can safely achieve engraftment of donor stem cells,” Leventhal said.8 O- `0 h4 R2 Q

8 ?& l8 t4 d+ E7 h6 K+ VHe said patients developed tolerance to the graft, eliminating the need for anti-rejection drugs, even when donors and recipients were mismatched and unrelated.
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, m3 J1 h) f) l7 H5 \Kawai of Harvard called the results “amazing,” but he said it is hard to tell from the study how much of a difference the facilitating cells made because there was no control arm, in which patients underwent the procedure without getting the enriched facilitating cells.7 k! `$ _. Y+ ^+ M3 z5 r. ]- R

$ n# M2 p; }) Z! M: B# c' V3 aAnd because these cells are not fully described in the paper, he said it is impossible for other labs to replicate the results.
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At Harvard, Kawai and colleagues achieved temporary chimeric tolerance — in which two immune systems coexisted in one body — in a separate study published in 2008 in the New England Journal of Medicine.
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Patients in that study did not have their immune systems suppressed by chemotherapy and radiation, and the donor immune system cells died off after a few weeks. But at least one patient still has a working donor organ 10 years after the procedure and does not need to take anti-rejection medications.8 |& d# h' Q- C: S- C3 X% d

; g4 X$ X+ _3 _Kawai worries that patients in the recent trial are taking too much risk. “Their approach is to totally destroy the host immune system by medication and radiation,” he said.$ D- R$ b6 f! n# M3 M
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Kawai said he would like to see the approach tested first in patients with blood cancers or other disorders who would need a bone marrow transplant — patients for whom there are no other options, and therefore in whom this harsh treatment is justified.
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Leventhal said the team is still enrolling patients in the clinical trial, which aims to include as many as 40 subjects.
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To qualify, donors and recipients need to have compatible blood types and a negative cross-match, which means the recipient does not have antibodies in the blood that could cause rejection of the kidney.2 W$ w4 F6 d! f1 }# M0 A

+ g9 v- Y0 F, F' ?" B6 \& ?3 s# ?. q? Thomson Reuters 2012! U- T2 N2 Q: F; H( O
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   Sci Transl Med  7 March 2012:
2 p- a* I8 R/ c( S1 H+ y8 m# {Vol. 4, Issue 124, p. 124ra28
" V$ V" _% v$ K; q; G- e; RSci. Transl. Med. DOI: 10.1126/scitranslmed.30035096 y# i; _2 k; X2 R4 X

4 L2 n+ S( N' f% D" K( {& ]    * Research Article
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/ r; i% P$ K& P0 D7 IKidney transplant6 ]& j" f' m- h& D
Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoietic Stem Cell Transplantation9 }- b5 t/ i3 Y" \2 [2 I+ Y

5 O& T) `+ r5 U& z) O* H   1. Joseph Leventhal1,
$ ~9 [+ f" ^8 h0 ^- l   2. Michael Abecassis1,2 M7 R9 S& c4 D+ `, E
   3. Joshua Miller1,
* N; V0 x' K& y8 \   4. Lorenzo Gallon1,) Q$ S) s  Y* y5 W: D9 A; X/ }
   5. Kadiyala Ravindra2,
, Q3 Q0 n, ?, J4 V9 L; L% ]   6. David J. Tollerud2,3,, [2 o. M5 w1 x: h! m# F. X. n
   7. Bradley King2,3,
* _' T# @1 v$ G. H- y* M& L   8. Mary Jane Elliott2,
9 A/ E( \! ?) _+ k' }0 y$ h   9. Geoffrey Herzig4,2 o5 @+ a5 [" ~
  10. Roger Herzig4 and; q/ o2 d- n- `0 l$ a2 L: n
  11. Suzanne T. Ildstad2,3,*8 J  H3 A+ E( t2 z2 T& p
Author Affiliations
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      1Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, IL 60611, USA.
3 |" U6 E# C9 L, W   2.
" T, p! i3 X; S1 e/ g      2Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202, USA.
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      3Regenerex, LLC, Louisville, KY 40202, USA.- E( _$ ^6 c" ]" @+ _. U
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. I" E4 a: p4 [4 z$ G0 X+ j# e      4James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
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: A$ s- h- E$ E) H5 k  a- v& A1 j   1. ?*To whom correspondence should be addressed. E-mail: stilds01@exchange.louisville.edu
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9 u1 z5 o; V. n6 g! O. `$ {AbstractBack to Top( W/ G1 A1 M, i. E$ h

" ^6 g( z6 w& @" i3 m* [The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft facilitating cells (FCs) combined with nonmyeloablative conditioning; this approach resulted in engraftment, durable chimerism, and tolerance induction in recipients with highly mismatched related and unrelated donors. Eight recipients of human leukocyte antigen (HLA)–mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200-centigray total body irradiation, and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from five of six loci with related donors to one of six loci with unrelated donors. The absolute neutrophil counts reached a nadir about 1 week after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month ranged from 6 to 100%. The conditioning was well tolerated, with outpatient management after postoperative day 2. Two subjects exhibited transient chimerism and were maintained on low-dose tacrolimus monotherapy. One subject developed viral sepsis 2 months after transplant and experienced renal artery thrombosis. Five subjects experienced durable chimerism, demonstrated immunocompetence and donor-specific tolerance by in vitro proliferative assays, and were successfully weaned off all immunosuppression 1 year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.
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$ Z/ C% D/ ?9 J7 m% J- T: S, g: |( s    * Copyright ? 2012, American Association for the Advancement of Science