Fig. 1: Micrograph of a regulatory T cell. These cells keep the inflammatory immune response under control and offer a promising tool for preventing graft-versus-host disease and various autoimmune disorders.
© 2009 Kim Hasenkrug, Ronald Messer and David Dorward
The immune system is finely tuned to detect and eliminate potentially harmful foreign entities within the body, where regulatory T (Treg) cells (Fig. 1) prevent immune cells from attacking healthy tissue. Now, patients undergoing tissue grafts or suffering from autoimmune disease are a step closer to receiving transplants of purified Treg cells to fight inflammation.
Every cell type in the body carries a distinct set of surface proteins that represent a potential ‘fingerprint’ for sorting in the laboratory. Previous research in mice has shown that Treg cells can be isolated based on expression of the CD25 protein; in humans, however, this marker is expressed not only in Treg cells but also in the effector cells that promote inflammatory response, making it ill-suited for sorting. “Quite a lot of money has been ‘burned’ in failed attempts to copy therapeutic strategies that have been successful in animal models,” says Olaf Rötzschke of A*STAR’s Singapore Immunology Network, “[and] the lack of suitable markers for the isolation of human Treg cells has largely prevented the translation of these promising results into human therapies.”
The basic strategy is sound, however, so Rötzschke partnered with Kirsten Falk at the Max-Delbrück-Center for Molecular Medicine in Berlin and colleagues at the Fondazione Santa Lucia in Rome and identified alternative markers for human Treg sorting. One promising target that caught their attention was CD49d, an adhesion molecule that facilitates the inflammatory response.
“CD49d-blocking antibodies are already the most effective treatment for multiple sclerosis and Crohn’s disease,” explains Rötzschke. He and Falk noted that CD49d expression is essentially absent from human Treg cells, and developed a sorting strategy that selectively eliminates human immune cells that express CD49d or CD127—a second marker typically absent from human Treg cells.
The resulting pools of cells are highly enriched with Treg cells and virtually free of contaminating pro-inflammatory cells. Importantly, these cells have not been tagged with any antibodies or other factors that might modulate their function—an important consideration for transplantation applications. Experiments in a mouse model of graft-versus-host disease confirmed the effectiveness of these cells, with minimal inflammatory response observed in Treg-recipient mice.
Rötzschke believes that the high purity and ‘untouched’ state of these cells bodes well for human applications. “A clinical Phase I trial is already in preparation. In cooperation with the Singapore General Hospital, Treg cell transfer will be employed to treat graft-versus-host-disease,” he says. “It will be one of the first clinical trials of this type worldwide.”
The A*STAR-affiliated authors in this highlight are from the Singapore Immunology Network.
