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本帖最后由 wf78365421 于 2012-12-14 11:21 编辑 0 y) d5 | q, k
. Y8 y* N- e# Y( y% T3 }; a间充质干细胞移植不需要配型。
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' L, D6 }/ `& A' T 1、间充质干细胞免疫原性低,不表达HLA-DR、CD80/CD86等免疫相关抗原,这个可以通过流式表面标记来验证。MSC低免疫原性与MSC不表达或表达可忽略水平的MHC-Ⅱ分子和T细胞共同刺激分子B 7-1,B7-2,CD40或CD40L相关。Krampera等研究发现,无论同基因或异基因的MSC都能抑制混合淋巴细胞反应, 包括刺激细胞和非特异性丝裂原刺激的T细胞增殖反应。实验证明将大量MSC加入由刀豆蛋白A(ConA)刺激的增殖期T细胞中,MSC对T细胞增 殖的抑制率可达56%,其抑制作用与MHC无关。 Sun等研究发现老鼠骨髓MSC不表达MHC-Ⅱ类分子和T细胞共同刺激分子CD80,CD86,也不引起异基因淋巴细胞增殖反应。将同种异基因MSC加入非特异性丝裂原刺激的T细胞中,发现T细胞增殖显著受抑。有趣的是,江小霞等在成骨诱导时发现,源于MSC的成骨细胞仍具有免疫调节作用,而且随着成骨细胞数量的增多,对T细胞增殖的抑制作用也增强。上述研究表明,MSC不仅免疫原性,而且具有免疫抑制作用。虽已发现这种免疫抑制作用系MHC非限制性的,CD4+CD25调节性T淋巴细胞亦不参与,但确切机制有待进一步研究。* {/ b0 s4 q8 e
2、间充质干细胞具有免疫调剂作用:Bartholomew等应用狒狒皮肤移植模型表明,在受体内输入经体外扩增的供者(狒狒)MSC(20×10^6/kg)延长了组织不相容的皮肤移植物的存活时间,甚至应用“第三者”的MSC即既不是来源于供者,也不是来源于受者,在活体中MSC表现为对同 种异体排斥反应的抑制,并且在受者体内不引起作为抗原特异性的细胞和体液免疫应答。 " q4 R: O1 E1 d
3、从临床应用来看:美国Osiris Therapeutics公司开发的干细胞治疗药物Prochymal已经经过加拿大卫生部批准上市, Prochymal是一种人异基因骨髓间充质干细胞,用于治疗儿童GVHD(移植物抗宿主病),也不用配型。Prochymal由来自于健康的青年捐献者骨髓中的间质干细胞制备而成,从一个供源的骨髓中分离出干细胞并进行扩大培养,即可获得多达1万个剂量的Prochymal。Prochymal取材于成体干细胞,因而并不涉及胚胎干细胞相关的伦理问题。GVHD致死率高,多发于移植时配型不完全匹配的受者,由骨髓移植后的免疫排异反应引起,常对皮肤、肝脏和消化道等造成严重损伤。现多用激素类药物治疗,但疗效甚微。Prochymal在加拿大获批用于治疗那些对激素类药物无反应的GVHD儿童患者。在一个小规模临床试验中,约60%的GVHD儿童患者使用此药后症状得到改善。, O5 O" {7 I! S, g8 ]" U
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) G! b9 a6 }% Z3 M* z$ b# o w- [A Stem-Cell-Based Drug Gets Approval in Canada$ b1 q" U9 I1 ^0 q- a
In a boost for the field of regenerative medicine, a small biotechnology company has received regulatory approval in Canada for what it says is the first manufactured drug based on stem cells.* k$ N! \; j& y ?: W
The company, Osiris Therapeutics of Columbia, Md., said Thursday that Canadian regulators had approved its drug Prochymal, to treat children suffering from graft-versus-host disease, a potentially deadly complication of bone marrow transplantation.
$ V) [# F) K- [0 q7 o; W7 R( V“It’s really a good day for the concept and the hope behind stem cell therapies becoming a reality,” C. Randal Mills, the chief executive of Osiris, said in an interview.) R5 j$ h& D, h( u0 d
Prochymal is a preparation of mesenchymal stem cells, which are obtained from the bone marrow of healthy young adult donors. The stem cells are separated out from the marrow and expanded in culture, so that one donation is enough to make as many as 10,000 doses.
# D. P- C' }# @& @( O' ]Because these are adult stem cells, they do not raise the ethical concerns of embryonic stem cells, whose creation usually involves the destruction of human embryos.: A) o9 d, \( a9 ]( b* B
Graft-versus-host disease occurs when the immune cells in a bone-marrow transplant see the recipient’s organs as foreign and attack them, causing potentially severe damage to the skin, liver and digestive tract. This happens most often when the donor is not an exact match for the recipient.
, h5 G) {5 B5 s) Z9 YDoctors try using steroids or other drugs to damp the immune attack, but in many cases those don’t work, and the patient may die.1 Z1 i+ j, y9 a5 b( ^0 R0 L& `
Prochymal is approved in Canada for children whose condition is not controlled by steroids. In a small trial, about 60 percent of such children had a clinically meaningful response to the drug, Osiris said.- v, `1 K: k i
“Any drug or a cell that has activity in the patients with severe disease is exciting and important,” said Dr. Joanne Kurtzberg, director of the pediatric blood and marrow transplant program at Duke University Medical Center.( v% D1 ?3 ?, Y! U; |
Dr. Kurtzberg, who helped Osiris present its case to Canadian regulators, said the drug has saved some children’s lives from graft-versus-host disease and could lead to more successful bone marrow transplants.3 u# r! |+ y& b0 Q1 p! h
Osiris is not expected to gain much revenue from patients with a rare disease in Canada. But it is a welcome success for a 20-year-old company that has had its share of failures.9 d. w0 L& Z/ q
In 2009, Prochymal failed in two late-stage clinical trials, showing little to no advantage over placebo in treating graft-versus-host disease. The company is also trying to develop Prochymal as a treatment for Crohn’s disease, diabetes, heart attacks and other illnesses, but has had some failures there as well.
1 C3 t, t. W4 |' N, x7 O, QSanofi, the big French company that had the rights to sell Prochymal outside North America, said in February that it had discontinued its work on the drug.
! h! l( z& ?8 R0 z4 hDr. Mills, Osiris’s chief executive, said the company realized the drug was most effective in the most severe cases of graft-versus-host-disease that did not respond to steroids, leading it to do the small trial in children.; b! p. F8 a m
Dr. Mills said that the Food and Drug Administration indicated that it would require more data before approval, prompting Osiris to seek approval in Canada first. He said the company would apply to the F.D.A. later this year., |9 ~& `% ~/ m- w8 E
Stem cells are already used in medicine. Bone marrow or stem cell transplants are used to treat various cancers and genetic diseases. But those transplants are medical procedures, not products sold by a drug company.6 R8 q1 u2 R+ a, s1 a
There are cell therapies that have been approved by regulators, such as Carticel, a Genzyme product that uses a patient’s own cells to repair cartilage in injuries. Last year the F.D.A. approved a cord blood product for use in transplantation. Those products are not manufactured for off-the-shelf use like Prochymal is, Dr. Mills said.
( O( ]! V( M3 k* D3 U9 POsiris announced the approval after regular stock trading ended. After hours, the stock rose 14 percent to $6.00.
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