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
生物网5月10日报道，来自美国圣犹大儿童研究医院（St. Jude Children's Research Hospital）的科学家们联合其他研究人员共同制成了人类免疫系统的实验室模型。这一模型将协助科学家们研究如何有效改进造血干细胞移植(HSC)技术。研究人员指出，该模型还将是研究干细胞如何形成免疫系统的不同部分（包括T淋巴细胞）；免疫细胞如何杀死癌细胞；如何对放射和化疗起作用的有利工具。这一研究成果将发表在2005年5月15日的《免疫学》杂志上。
圣犹大儿童研究医院干细胞移植负责人Rupert Handgretinger指出，这一突破的重要性在于解决了人类免疫系统研究人员所面临的伦理困境。他说：“通过造血干细胞移植来替代患者自身的血液系统，可以治疗很多患有血癌或某种遗传、免疫类疾病的病人。但是由于人类干细胞移植研究面临的伦理界限，使得这一治疗方法未能完全发挥潜能。而发明的模型将让全世界的研究人员进行更多实验，提供更多免疫系统相关资料，并提高造血干细胞移植的成功率。”
美国杰克逊实验室的莱昂纳多·舒兹指出，这一模型将引发引导更多正常干细胞功能方面的研究，而且对再生医学的研究也极为重要。同时，还能促进对人类自身免疫性疾病的了解。
由于移植造血干细胞的成功率很低，或移入的细胞无法生成功能完善的免疫细胞，因此先前的人类免疫系统模型都不是很成功。干细胞移植就是将干细胞注入人体内，然后产生不同类型的正常血细胞。
现在，这一称为“NOD-scid IL2R-null”的新模型可以通过移植人类造血干细胞，生成T细胞、B细胞、骨髓细胞、自然杀伤细胞（natural killer cells）和树突状细胞（dentritic cells）。自然杀伤细胞是一种淋巴细胞，可以杀死被感染细胞；树突状细胞是一种白细胞，可以捕获外来物质（如细菌）并呈现给T细胞；T细胞随后开始活跃，做出免疫反应；骨髓细胞属于免疫细胞，包括颗粒球和淋巴球。
该模型能产生多种T细胞，会对大量不同潜在目标做出反应；T细胞表面携带有多种受体；免疫细胞受到刺激通常进行分化增殖；受体是能辨识细菌、病毒、癌细胞等特殊分子的蛋白质，这些都证明了模型的有效性。
“T细胞受体删除环” (TRECs)的发现有力地证明了这一模型通过将造血干细胞转换为胸腺T细胞来模拟人类免疫系统。
受体由蛋白质分子构成，每个都按照特定基因编码。TRECs是在这些基因进行“混搭”、重新整理期间形成的。每个T细胞利用“混搭”后的基因合并体生成一个受体，使细胞能记住某个特定的目标。一旦受到刺激需要增殖时，每个母T细胞就会针对特定目标生成一群相同的细胞。
该模型结合了其他模型的主要特点，因此可以成功移植造血干细胞，对人类免疫系统的研究是一个极为有效的工具。
