Models with complete human immune system derived from hematopoietic stem cells produce functional white blood cells for studies of immune responses against cancer and infection with help from St. Jude
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 IL2Rănull, 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 IL2Rănull 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).
-- Helen Lawrenson