New Lab Mice Pave Way For Novel Studies Of Human Infection

Normal mice are not susceptible to human-specific viruses, such as Epstein Barr virus and HIV, making it hard to study and craft drugs to target the viruses. Epstein Barr is a virus that causes mononucleosis.

So UT Southwestern researchers, working with University of Minnesota collaborators, generated human-mice "chimeras" -- mice implanted with human tissues and human stem cells -- that developed fully functional human immune systems and infection-fighting cells, such as T cells, throughout their bodies, according to a study published online today in Nature Medicine.

The T cells in the mice even mounted a potent immune response to toxic shock syndrome and infection by Epstein Barr.

"These human-mice 'chimeras' are susceptible to a variety of human-specific viruses that couldn't be easily studied in the past, giving scientists a new way to study, develop and implement novel vaccines and therapeutics to fight human disease like cancer and AIDS," said Dr. J. Victor Garcia, professor of internal medicine at UT Southwestern and the study's senior author.

Investigators have long used mouse models to study human physiology and to test new drugs, but differences in mouse and human immune systems -- and the fact that normal mice can't be infected with human-specific pathogens or produce human immune cells needed to fight them -- have severely limited this line of research.

To allow these studies, researchers have developed chimeras.

In immune-deficient mice that are unable to reject human cells or tissues, researchers first implant the rodents with human tissues necessary to develop human T cells. Human blood stem cells, known as CD34+ cells, then are transplanted into the mice. CD34+ cells, which give rise to human T cells, B cells and other types of human cells that protect the body against foreign organisms and pathogens, are typically used to treat human cancer and blood and heart disorders.

In this latest study, UT Southwestern researchers and their Minnesota colleagues used this combination approach -- human tissues and stem cells -- to try to generate a new type of chimera that can develop T cells the same way as humans.

The resulting mice, known as Bone Marrow Liver Thymic mice (BLT mice), developed a human immune system with dramatically high human T cell and other cell counts in virtually all of their tissues, including the gut and lungs, sites of important immune response to diseases.

"The fact that virtually all human immune cells are adequately distributed in all the different mouse tissues has resulted in what is probably the most human-like immune system ever developed in mice," Dr. Garcia said.

UT Southwestern researchers tested the immune system by inducing toxic shock syndrome in the mice or infecting them with Epstein Barr virus, both deadly diseases that are known to cause a proliferation of T cells in humans. The mice produced ample human T cells to respond to each disease.

This finding highlights the potential of BLT mice to be used to study the interactions between the human immune system and viruses that target human immune cells. These viruses include HIV, dengue hemorrhagic fever and other highly pathogenic agents such as influenza, SARS, anthrax and others that are hard to study in humans. Dr. Garcia said the availability of this mouse model should pave the way for the evaluation and testing of novel drugs and approaches to treat these diseases.

Other UT Southwestern researchers involved in the study were lead author and student research assistant Michael Melkus, postdoctoral researcher Dr. Anja Wege, research associate Angela Padgett-Thomas, student research assistant Paul Denton, research assistant Florence Othieno and former instructor Joel Gatlin, currently of Arena Pharmaceuticals, Inc.

The National Institutes of Health supported the study.