A mouse model that can support a human immune system was developed by The Jackson Laboratory's Dr. Leonard Shultz and collaborators at St. Jude Children's Research Hospital and the University of Tennessee, both in Memphis, the EMD Lexigen Research Center, Billerica, Mass., and the University of Massachusetts, Worcester. The mouse allows scientists to 1) perform the critical studies necessary to improve hematopoietic stem cell (HSC) transplants for treating leukemia, sickle cell disease and other blood disorders (all without putting patients at risk), and 2) study the HIV(AIDS) virus in a model that mimics the human immune system better than any previously constructed.
The model, NOD.Cg-Prkdcscid Il2rgtm1Wjl/Sz, combines the features of the NOD/LtJ (Stock Number 001976) background, the severe combined immune deficiency mutation (scid, which is caused by a spontaneous mutation of the Prkdc gene), and Il2rg-deficiency. It is deficient in mature lymphocytes and natural killer (NK) cells. Il2rg is indispensable for IL2, IL4, IL7, IL9, IL15, and IL21 high-affinity binding and signaling. In mice, it is also thought to play a key role in mediating susceptibility to thymic lymphomas. In humans, IL2RG-chain deficiency causes X-linked SCID, blocks NK cell development, and results in additional defects in innate immunity.1
NOD.Cg-Prkdcscid Il2rgtm1Wjl/Sz has two major advantages over previous immunodeficient mouse models. First, because it is resistant to lymphomas (even after sublethal irradiation), it lives for over 16 months. Its longevity is particularly important because it will enable researchers to conduct long-term experiments not possible with previous immunodeficient mice. Second, although the scid, B2m-deficient, Rag1-deficient, and Rag1-Pfr-deficient mice on the NOD/LtJ background we compare2 in a previous issue of JAX Notes™ have been successively better in their ability to engraft human HSCs, they fail to differentiate those HSCs into mature human lymphoid and myeloid cells. In contrast, the bone marrow of HSC-engrafted Il2rg-deficient mice generates six times more human CD45+ cells (B cells, NK cells, myeloid cells, plasmacytoid dendritic cells, and HSC) than does the bone marrow of similarly treated NOD.CB17-Prkdcscid/J mice. Their spleens contain functioning human Ig+ B and T cells (CD3+). Co-administering human Fc-IL7 fusion protein along with HSCs results in high percentages of human CD4+CD8+ thymocytes and human CD4+CD8- and CD4-CD8+ peripheral blood and splenic T cells.
Because the Prkdcscid Il2rgtm1Wjl model has such a superior ability to engraft human hematopoietic stem cells (HSCs) and differentiate them into the various cell subsets of the human immune system, it is capable of acting as a surrogate for the human immune system and thus enable researchers to avoid the complex ethical issues of conducting research directly in humans. Essentially, researchers will be able to produce a human immune system in a mouse.
As Dr. Rupert Handgretinger, director of stem cell transplantation at St. Jude and co-leader of the Transplantation and Gene Therapy Program, said: "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. 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."3
The model will be a valuable tool for studying how stem cells give rise to the various cells of the immune system, how immune cells kill cancer cells and fight infections, and how immune cells respond to radiation and chemotherapy, two major treatments for many cancers. Dr. Shultz of The Jackson Laboratory is very enthusiastic about the model's potential: "Because this novel humanized mouse model permits studies of normal stem cell function, it will be a very important tool in research on regenerative medicine. 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."3
The new model should also firmly establish the inbred mouse's niche in HIV(AIDS) research. Although mice are biologically similar to humans, the native mouse immune system is not susceptible to HIV. The ability of this mouse model to support a fully functional human immune system will solve that problem.
References
(Authors in bold are Jackson Laboratory scientists)
1Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R. 2005. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rgnull mice engrafted with mobilized human hemopoietic stem cells. J Immunol 15:6477-89.
2JAX Notes™. 2005. NOD.Cg-Rag1tm1Mom Prf1tm1Sdz/SzJ, a new immunodeficient mouse strain supporting enhanced human hematolymphoid cell engraftment. JAX Notes™ 496:10.
3St. Jude Children's Research Hospital. 2005. Laboratory model of immune system overcomes ethical constraints on studies of hematopoietic stem cells in humans. St. Jude Children's Research Hospital news release May 9, 2005 (www.stjude.org/news).