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Mice Developed at CCR Could Aid Disease Research

Scientists at the Center for Cancer Research have created mice with severely limited immune systems that could serve as recipients for human bone marrow cells, which could in turn produce a functional human immune system in the mice.

Such mice could serve as small, convenient animal models in studies of human disease, most obviously AIDS.

The scientists, led by biology graduate student Dr. Peter Mombaerts, MD, in Professor Susumu Tonegawa's lab, created the mice during work to determine whether a certain gene is critical to the development of the immune system in mice.

Their findings were published in the March 6 issue of the journal Cell.

After "knocking out," or inactivating, the recombination activation gene (RAG-1) in special, cultured embryo-derived cells, the scientists injected the mutated cells into mouse embryos that were implanted into foster mothers. The resulting mice were then bred.

The researchers found that offspring containing two mutated copies of RAG-1 (mice homozygous for the trait) were severely immunodeficient, thus proving that RAG-1 is essential to the development of the mouse immune system.

Specifically, the mutant mice lacked any mature lymphocytes, a class of white blood cells, and did not have IgM, one type of antibody, in their blood. Furthermore, they did not show any V(D)J rearrangements, a process critical to the normal functioning of the immune system and explained as follows in the Center for Cancer Research Newsletter:

"The two major classes of cells in the immune system . . . recognize antigens [foreign substances] via specific cell surface receptors. The genes for [these] receptors are assembled in combinatorial fashion from several segments, including so-called V (variable), D (diversity), and J (joining) segments.

"This combinatorial rearrangement of many different V, D and J segments allows for the great diversity of antigen specificity."

Professor Tonegawa, a coauthor of the Cell paper, earned the 1987 Nobel Prize in medicine for describing the V(D)J recombination process.

Mice that are naturally immunodeficient, or exhibit severe combined immunodeficiency (SCID), have been used as animal models for human disease. However, such mice "do show some limited immune competence of their own, thus compromising their utility," according to the CCR Newsletter. The mutant mice created by Dr. Mombaerts and colleagues "should be much more effective recipients [of human cells]."

The scientists' work also casts doubts on an hypothesis by Dr. David Baltimore that RAG-1 plays a central role in the development of the brain. Dr. Mombaerts and colleagues have found that except for a deficient immune system, so far the mutant mice look normal. Their brains and basic behavioral properties appear to be healthy, and they are fertile.

RAG-1 was discovered three years ago "in an elegant piece of work," said Dr. Mombaerts, by David Schatz, then an MIT graduate student in Dr. Baltimore's lab and now an assistant professor at Yale (Dr. Baltimore is now a professor at Rockefeller University).

A year later, Dr. Schatz and Marjorie Oettinger, another former MIT graduate student and now an assistant professor at Massachusetts General Hospital, isolated a second gene, RAG-2, in the immediate vicinity of RAG-1. The two scientists found that RAG-1 and RAG-2 "together were capable of activating V(D)J recombination in a test system," according to the CCR Newsletter.

In another paper in the March 6 Cell that accompanies that of Dr. Mombaerts and colleagues, a team of researchers led by Dr. Frederick W. Alt of Harvard Medical School report that they have created mice with inactivated RAG-2. These mice, like those with inactivated RAG-1, are also immunodeficient. "Taken together, [the data from both papers] suggest that RAG-1 and RAG-2 are both necessary in vivo either to activate or to catalyze the V(D)J recombination reaction," write Dr. Mombaerts and colleagues in Cell.

In addition to Dr. Mombaerts and Professor Tonegawa, authors of the RAG-1 Cell paper are Postdoctoral Fellow John Iacomini of the CCR, Randall S. Johnson of the Dana-Farber Cancer Institute and Harvard Medical School, Karl Herrup of the Shriver Center for Mental Retardation, and Virginia E. Papaioannou of Tufts University School of Medicine and Veterinary Medicine.

A version of this article appeared in the April 15, 1992 issue of MIT Tech Talk (Volume 36, Number 27).

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