Immune System Taught to Play Nice With Unrecognized Protein

Vaccines are a staple of modern health care. Though each one is complex, the idea behind them is simple: immunity is achieved through exposure to a weak or fragmented bug. The bug rouses the immune system, which, in turn, defeats the invader and fortifies itself in preparation for a later, more vigorous assault.

More recently, however, medical science has increasingly aimed at tweaking the immune system in the opposite direction, toward tolerance. This need stems from efforts to control autoimmune diseases and allergic reactions as well as from transplant medicine, in which physicians want patients to tolerate foreign tissue.

New research led by Irina Apostolou, HMS instructor in pathology at the Dana–Farber Cancer Institute, has moved immune tolerance research one step forward through the in vivo creation of regulatory T cells (Tregs) that suppress immune reactions to specific transplantation antigens.

To create the Tregs and induce tolerance, Apostolou, first author and former DFCI postdoctoral fellow Panayotis Verginis, and colleagues infused wild-type mice with low doses of a fragment of one particular HY-antigen, found normally on the tissue of male mice, but considered an invader in females. The work is described in the March 4 Proceedings of the National Academy of Sciences.

Induced immune tolerance research, however, is still in its early stages. “Studies of transplantation tolerance and autoimmunity using mouse models provide great advances in our understanding of … potential therapeutic approaches,” said Apostolou. “It is now necessary to determine whether our procedure of induction of antigen-specific tolerance can be generalized to other self or non-self antigens. This will take at least three to four years.”

“We are slowly approaching clinical relevance,” said Harald von Boehmer, HMS professor of pathology at DFCI, another author on the paper and former mentor of Apostolou during her postdoctoral research.

Apostolou devised the technique for converting T cells into Tregs in 2004. The procedure uses tiny pumps implanted under the skin that infuse low levels of a peptide derived from a given antigen. The immune system responds to the peptide, but not by mounting an attack. Instead, because a peptide is poorly immunogenic, the helper T cells responsible for immune defense against that peptide’s antigen transition into antigen-specific Tregs.

Apostolou first demonstrated this transition to Tregs in transgenic mice that have high frequencies of antigen-specific T cells. But in wild-type mice, as few as 1 in 100,000 T cells recognize any given antigen, so the resulting set of induced antigen-specific Tregs is also very small. The fact that mice treated with a single HY peptide tolerated the graft showed that antigen-specific Tregs, even when created in very small numbers, can still provide immune tolerance.

The mice gained tolerance because the creation of these antigen-specific Tregs prior to transplantation shifts the balance between effector and regulatory T cells in favor of the Tregs. This balance determines how the immune system responds to the transplant. In untreated mice, male antigens of the skin graft activate the immune system’s effector T cells, which attack the graft and reject it. In treated mice, the graft also activates the small population of antigen-specific Tregs, which expand to a force large enough to suppress tissue rejection and give the mice tolerance to the HY antigens.

Digging deeper, the researchers found that the induced tolerance was both broad and lasting. The treated mice tolerated male transplants other than skin. Even after a male bone marrow transfusion, the treated female mice maintained their tolerance.

Moreover, even though these antigen-specific Tregs recognize only one peptide from one HY antigen, they are able to suppress the immune response mounted by T cells that recognize other peptides from different HY antigens. This all-for-one ability, called “bystander suppression,” is the beauty of this adoptive immunotherapy, said von Boehmer.

This technique of inducing immune tolerance has the potential to dampen any unwanted immune response, with possible clinical applications in transplant medicine, autoimmune disease, and allergies. But the procedure may not work for all antigens, and each clinical application will likely have its own complexities.

In transplant medicine, for instance, Treg-based tolerance alone will not likely eliminate rejection of transplants because of “the kind of potpourri of incompatibilities from person to person in the clinic,” said Terry Strom, HMS professor of medicine and chief of immunology at Beth Israel Deaconess Medical Center.

Apostolou agreed, speculating that induced tolerance may someday work in combination with other therapies and may help reduce the duration or extent of the use of immunosuppressive drugs.

Despite these challenges, said Strom, the principle is “terribly important,” and the protocol is a practical and inexpensive way to induce antigen-specific tolerance.

In the case of autoimmunity, Von Boehmer and Apostolou are investigating whether their technique might work for the insulin antigens that trigger the onset of type 1 diabetes (see Focus, May 20, 2005). New evidence has emerged suggesting that the antigen specificity of a Treg is not the only key to its immune-suppressing power. Its “lifestyle” also matters, said von Boehmer, meaning that Tregs do not necessarily behave the same or have the same life span in normal and diseased organs.

“There are complexities here that we have to be aware of,” said Emil Unanue, professor of pathology and immunology at Washington University, noting that diabetes involves several antigens, intricate immune cell dynamics, and multiple stages of disease. According to Unanue, the data emerging in the last few years suggest that controlling autoimmunity is within the reach of medical science. The jump to clinical applications will take time, he cautioned, but this is “a very good step forward. I would say it’s a step vertically up.”