BioWorld International Correspondent

LONDON - After trying for more than 20 years, researchers have finally succeeded in creating a mouse with a human immune system. The new mouse model produces B cells, T cells and dendritic cells and is capable of switching on the immune response when challenged with tetanus toxoid.

It will, researchers predict, be valuable for the study of how the human immune system develops, for testing new vaccines before going into human clinical trials, for evaluating the effects of drugs that boost or suppress the immune system, and for studying how best to stimulate the immune system with vaccines.

Provided the human cells are susceptible to infection with HIV - and there is no reason why they should not be - the model also will be useful as an aid to developing vaccines to protect against HIV and in the study of the natural history of HIV infection.

Markus Manz, group leader at the Institute for Research in Biomedicine, a nonprofit research foundation in Bellinzona, Switzerland, told BioWorld International: "This is very exciting. We know that this model has lots of potential. Nevertheless, its real significance in terms of improving knowledge and developing possible therapies still needs to be assessed."

Experiments with HIV have begun, he said, but he could not yet discuss what they have shown.

Manz, together with colleagues at the same institute and collaborators elsewhere in Switzerland, reported his findings in a paper in the April 2, 2004, issue of Science, titled "Development of a Human Adaptive Immune System in Cord Blood Cell-Transplanted Mice."

He and his colleagues had set out to develop a mouse that could produce a functional primary immune response after being grafted with human blood-forming stem cells taken from cord blood. Several models already were available in which some degree of human hemopoiesis took place, but all of those had problems and drawbacks.

For example, one model allowed human hemopoiesis to occur but was technically demanding and presented ethical problems because it used human fetal tissue. Another was simpler, and although immature B cells and T cells developed, those did not mature, so there was no immune response to vaccination and no production of antibodies.

"What we decided to do that was new," Manz said, "was to transplant the blood-forming cells into newborn animals that lack an immune system. We thought it would be good to use newborns, because after birth the immune system expands massively, so we speculated that incoming stem cells might find the right environment to similarly expand massively."

The group also decided to transplant the stem cells into an organ in which hemopoiesis normally takes place - directly into the liver.

"One important benefit of our model," Manz said, "is that it is very straightforward to make - the mice are readily obtainable, the cord blood is easy to get hold of and the injection itself is not difficult."

After three months, tests showed that the immune systems of the mice, which lacked their own immune systems, had been reconstituted with human cells.

Manz and his colleagues looked for the most important types of cells within the adaptive (as opposed to the innate) immune system. They found B cells, which they showed were capable of maturing and producing immunoglobulins; T cells, which were able to undergo the full spectrum of T-cell division and maturation; dendritic cells; and interferon-producing cells.

When the researchers challenged the mice with tetanus toxoid, the mice produced a typical human immune response by producing protective antibodies.

In their next experiment, the team infected the mice with Epstein-Barr virus, which targets cells of the human immune system but does not infect murine cells. "We saw that when we infected the animals, they made a T-cell response against this virus," Manz said.

He predicted that the mouse would prove an interesting tool for studying the development of the immune system.

"We can look at how the immune system is built up, and how stem cells differentiate into the different cell types of the adaptive immune system," he said. "It will also allow us to look at functional immune responses. We can find out the best ways of optimally vaccinating against diseases, including which adjuvants to use and so on," Manz added.

As a clinician who also works in the field of bone marrow transplantation, he also is keen to use the model to study the biology of hematopoietic stem cells, and the reconstitution of the immune system following transplantation.