Designer antibodies may help transplanted organs sneak by the body's defenses. The molecules, reported in the March Nature Biotechnology, prevent mouse immune cells from recognizing some foreign molecules, but leave most of the immune system intact. If the molecules work in humans, they might reduce the need for immune-suppressing drugs--which can leave transplant patients vulnerable to infections, cancer, and nerve damage.
When patients receive transplant organs, host immune cells called antigen-presenting cells enter the transplanted tissue and adorn the membrane with molecules from the foreign cells, called an MHC. These molecules act as a call to arms for the host's T cells, which kill cells that bear those particular MHCs. "If you disturb any of these events, the T cell doesn't work," says Uwe Staerz, an immunologist at the National Jewish Medical and Research Center in Denver, Colorado. That would be a boon for preventing organ rejection, but it's difficult to disarm some T cells without disrupting the entire immune system, he says.
Staerz thought he could keep one kind of T cell, called the CD4 cell, from attacking cells with certain MHCs. Following success with other kinds of T cells, Staerz and his colleagues patched together an antibody that would grab a specific MHC with one arm, while the other clogs the CD4 receptor on the antigen-presenting cell. Once a T cell bumps into a presented MHC, it must also bind with the presenter's CD4 receptor; if it doesn't, there's no immune response. This mongrel molecule, he thought, would tie up the CD4 receptor only on antigen-presenting cells that carry the targeted MHC, leaving the rest free to combat true pathogens.
To test his molecule, Staerz mixed mouse antigen-presenting cells and T cells in a dish with his designer antibody. It worked: T cell activation fell to less than 10% of its normal level, and the stalled T cells produced no immune-stimulating hormones. Staerz says that a cocktail of targeted antibodies could dull the immune response to transplanted tissues or help treat autoimmune diseases, which involve T cells accidentally responding to the body's own MHC.
Gunther Dennert, an immunologist at the University of Southern California in Los Angeles, calls Staerz's work "impeccable," but cautions that there is a big difference between mouse cells in culture and cells of the human body. "The question is whether the technique will work in animals," he says.