Immune System Lab Model Overcomes Ethical Limits On Human Hematopoietic Stem Cells Studies

05/09/05 -- Scientists at St. Jude Children's Research Hospital have joined with colleagues at several other institutions to develop a laboratory model of the human immune system. This model will allow scientists to study ways for improving the results of hematopoietic stem cell (HSC) transplantation without putting patients at risk.

Researchers say the model will also be a valuable tool for studying how stem cells give rise to various parts of the immune system, including T lymphocytes; how immune cells kill cancer cells and fight infections; and how immune cells respond to radiation and chemotherapy, two major treatments for many cancers. A report on this work appears in the May 15 issue of Journal of Immunology. The study was done in cooperation with The Jackson Laboratory (Bar Harbor, ME), the University of Tennessee (Memphis), EMD Lexigen Research Center (Billerica, MA) and the University of Massachusetts (Worcester, MA).

The breakthrough is particularly important because it solves an ethical dilemma facing researchers who study the human immune system, according to Rupert Handgretinger, M.D., Ph.D., director of Stem Cell Transplantation at St. Jude and co-leader of the Transplantation and Gene Therapy Program.

"Hematopoietic stem cell transplantation to replace a patient's own blood system could cure many more people who have blood cancers and certain genetic and immune disorders," Handgretinger said. "Unfortunately, this treatment has not reached its full potential, in part because of ethical limitations on studying stem cell transplantations in humans. Our new laboratory model will now let researchers around the world do many important experiments that will provide valuable insights into how the immune system works and how to increase the success rate of HSC transplantation."

"Because this new humanized mouse model will permit studies of normal stem cell function, it will be an important tool in research on regenerative medicine," said Leonard D. Schultz, Ph.D., a senior staff scientist at The Jackson Laboratory and first author of the paper. "The ability of these mice to support development of a functional human immune system should also facilitate the testing of experimental human vaccines and help us understand the mechanisms underlying human autoimmune diseases."

Previous models of the human immune system were limited by relatively low levels of success in engraftment of HSCs and the failure of the engrafted cells to produce fully functional immune cells. Engraftment is the process in which stem cells infused into the body are accepted, after which they produce the various types of blood cells normally found in the body.

The model, called NOD-scid IL2R-null, can be readily engrafted with human HSCs, which then develop into T cells, B cells, myeloid cells, natural killer (NK) cells and dentritic cells (DCs), Handgretinger said. NK cells are a type of large white blood cells called lymphocytes, which kill both infected cells and tumor cells DCs are white blood cells that trap foreign matter, such as bacteria, and present it to T cells, which then become activated and orchestrate an immune response. Myeloid cells are immune cells that include granulocytes and monocytes.

The investigators demonstrated the model's effectiveness by showing that it could produce the wide variety of T cells needed to respond to a large number of different potential targets; that the T cells carry a wide diversity of receptors on their surfaces; and that the immune cells respond normally stimulation by multiplying. Receptors are proteins that recognize specific molecules on bacteria, viruses, cancer cells and other potential targets that stimulate the immune system.

A key piece of evidence showing that the model mimics the human immune system by efficiently turning HSCs into T cells in the thymus gland was the finding of so-called "T cell receptor excision circles" (TRECs).

Receptors are made up of protein building blocks, each of which is coded for by a specific gene. TRECs form during a "mix-and-match" rearrangement of these genes into any one of countless combinations. The rings represent sections of DNA cut out of chromosomes during the mixing and matching of genes that are chosen to build a particular receptor. Each T cell uses the resulting combination of genes to make a receptor that lets the cell recognize a specific target. When stimulated to multiply, each parent T cell produces an army of identical cells against a designated target.

Previously, a team led by Handgretinger showed that a high level of TRECs in the blood of children means that the thymus has converted a large number of stem cells into parent T cells--each of which targets a specific foreign substance.

The NOD-scid IL2R-null model combines the crucial characteristics of other models that, by themselves, were inadequate to study HSC engraftment and the different functions of an intact human immune system, according to Stanley Chaleff, M.D., a postdoctoral fellow who did much of the work on the project. "This combination of characteristics permits the successful engraftment of HSCs," Chaleff said. "Because our models don't develop cancer like other models do, they are more efficient tools for studying the human immune system."

Other authors of the study include Leonard D. Shultz, Bonnie L. Lyons, Lisa M. Burzenski and Bruce Gott (The Jackson Laboratory, Bar Harbor, ME); Xiaohua Chen and Stanley Chaleff (St. Jude); Malak Kotb (University of Tennessee, Memphis); Stephen D. Gillies (EMD Lexigen Research Center, Billerica, MA); and Marie King, Julie Mangada and Dale L. Greiner (University of Massachusetts, Worcester, MA).

Source: St. Jude Children's Research Hospital

    生物網(wǎng)5月10日?qǐng)?bào)道，來自美國(guó)圣猶大兒童研究醫(yī)院（St. Jude Children's Research Hospital）的科學(xué)家們聯(lián)合其他研究人員共同制成了人類免疫系統(tǒng)的實(shí)驗(yàn)室模型,。這一模型將協(xié)助科學(xué)家們研究如何有效改進(jìn)造血干細(xì)胞移植(HSC)技術(shù)。研究人員指出,，該模型還將是研究干細(xì)胞如何形成免疫系統(tǒng)的不同部分（包括T淋巴細(xì)胞）；免疫細(xì)胞如何殺死癌細(xì)胞,；如何對(duì)放射和化療起作用的有利工具,。這一研究成果將發(fā)表在2005年5月15日的《免疫學(xué)》雜志上。

    圣猶大兒童研究醫(yī)院干細(xì)胞移植負(fù)責(zé)人Rupert Handgretinger指出,，這一突破的重要性在于解決了人類免疫系統(tǒng)研究人員所面臨的倫理困境,。他說：“通過造血干細(xì)胞移植來替代患者自身的血液系統(tǒng)，可以治療很多患有血癌或某種遺傳,、免疫類疾病的病人,。但是由于人類干細(xì)胞移植研究面臨的倫理界限，使得這一治療方法未能完全發(fā)揮潛能,。而發(fā)明的模型將讓全世界的研究人員進(jìn)行更多實(shí)驗(yàn),，提供更多免疫系統(tǒng)相關(guān)資料，并提高造血干細(xì)胞移植的成功率,。”

    美國(guó)杰克遜實(shí)驗(yàn)室的萊昂納多·舒茲指出,，這一模型將引發(fā)引導(dǎo)更多正常干細(xì)胞功能方面的研究，而且對(duì)再生醫(yī)學(xué)的研究也極為重要,。同時(shí),，還能促進(jìn)對(duì)人類自身免疫性疾病的了解。

    由于移植造血干細(xì)胞的成功率很低,，或移入的細(xì)胞無法生成功能完善的免疫細(xì)胞,，因此先前的人類免疫系統(tǒng)模型都不是很成功。干細(xì)胞移植就是將干細(xì)胞注入人體內(nèi),，然后產(chǎn)生不同類型的正常血細(xì)胞,。

    現(xiàn)在，這一稱為“NOD-scid IL2R-null”的新模型可以通過移植人類造血干細(xì)胞,，生成T細(xì)胞,、B細(xì)胞、骨髓細(xì)胞,、自然殺傷細(xì)胞（natural killer cells）和樹突狀細(xì)胞（dentritic cells）,。自然殺傷細(xì)胞是一種淋巴細(xì)胞，可以殺死被感染細(xì)胞,；樹突狀細(xì)胞是一種白細(xì)胞，可以捕獲外來物質(zhì)（如細(xì)菌）并呈現(xiàn)給T細(xì)胞；T細(xì)胞隨后開始活躍,，做出免疫反應(yīng),；骨髓細(xì)胞屬于免疫細(xì)胞，包括顆粒球和淋巴球,。

    該模型能產(chǎn)生多種T細(xì)胞,，會(huì)對(duì)大量不同潛在目標(biāo)做出反應(yīng)；T細(xì)胞表面攜帶有多種受體,；免疫細(xì)胞受到刺激通常進(jìn)行分化增殖,；受體是能辨識(shí)細(xì)菌、病毒,、癌細(xì)胞等特殊分子的蛋白質(zhì),，這些都證明了模型的有效性。

     “T細(xì)胞受體刪除環(huán)” (TRECs)的發(fā)現(xiàn)有力地證明了這一模型通過將造血干細(xì)胞轉(zhuǎn)換為胸腺T細(xì)胞來模擬人類免疫系統(tǒng),。

    受體由蛋白質(zhì)分子構(gòu)成,，每個(gè)都按照特定基因編碼。TRECs是在這些基因進(jìn)行“混搭”,、重新整理期間形成的,。每個(gè)T細(xì)胞利用“混搭”后的基因合并體生成一個(gè)受體，使細(xì)胞能記住某個(gè)特定的目標(biāo),。一旦受到刺激需要增殖時(shí),，每個(gè)母T細(xì)胞就會(huì)針對(duì)特定目標(biāo)生成一群相同的細(xì)胞。

    該模型結(jié)合了其他模型的主要特點(diǎn),，因此可以成功移植造血干細(xì)胞,，對(duì)人類免疫系統(tǒng)的研究是一個(gè)極為有效的工具。