Anatomy of Tolerance

Understanding T Cell Migration and Immune Response for Optimal Organ Transplantation

Every day a stranger offers the greatest gift of all, the gift of life. In the U.S. alone, more than 100 million people have signed up to be organ donors. Yet, the need for transplantation is so great that nearly 75,000 people are currently waitlisted to receive an organ. Medical researchers are working to better understand immunosuppression and the role of T cell migration in preventing acute and chronic organ rejection.

Much has been learned since the first successful organ transplant in 1954 when an identical twin donated a kidney to his brother suffering from kidney disease. Since then, there have been tremendous advances in organ transplantation, including techniques to better match donors and recipients and the development of new immunosuppressive drugs. Discoveries in these areas have helped reduce acute organ rejection and improve transplant outcomes.

However, even healthy organs transplanted between appropriately matched patients may be inadvertently rejected by the donor’s immune system. Immunosuppression, while helpful, can also offer some disadvantages.

“The problem with immunosuppression drugs is that patients need to take them for life. The drugs have side effects and can at times lead to adverse medical reactions,” says Jonathan Bromberg, M.D., Ph.D., chief of the Division of Transplantation at the University of Maryland Medical Center.

Dr. Bromberg’s background is unique because he is both a surgeon and an immunologist. “I was told follow your heart and your brain, so I did both,” says Dr. Bromberg, who obtained both a Ph.D. in immunology and his medical degree from Harvard University. Dr. Bromberg is a professor of surgery and microbiology and immunology at the University of Maryland School of Medicine.

Interdisciplinary research led by Dr. Bromberg between the University of Maryland’s School of Medicine and Department of Microbiology and Immunology may help to better understand the immune system at a more fundamental level.

Dr. Bromberg’s work focuses on trying to determine how modulating immune system response can help support — rather than reject — organ transplants. The benefits to the patient would include fewer transplantation complications, the need for less medication and possibly even fewer doctor visits once the organ is transplanted.

Traveling T Cells

In the area of immunosuppression, the general approach has been to develop drugs that focus on a single molecule or cell. However, a broader approach may also be important because molecules, cells and organs don’t always interact in a linear fashion. In fact, they act more as a complex network with multiple interacting pathways.

“We haven’t yet discovered all the guiding principles surrounding basic immunology and therefore haven’t yet determined how to best modulate the immune system for optimal organ transplantation,” says Dr. Bromberg.

Although it hasn’t yet been achieved, the holy grail would be to perfectly regulate immune suppression to achieve complete tolerance of the transplanted organ. Dr. Bromberg’s research suggests that tolerance may have a lot to do with how, when and where specific white blood cells travel.

One of the questions he is trying to answer is how certain cells, such as regulatory T cells, travel from the blood to the donated organ and then back into the blood and lymph nodes. Understanding regulatory T cell migration is crucial because research by various groups has shown that these cells can be involved in shutting off an immune response.

Deciphering signals and pathways

Regulatory T cell migration can be compared to a person taking a long road trip. The driver may decide to take a winding back road or a speedy highway. While traveling, the driver may also decide to stop somewhere to eat or even take a detour into a scenic road. With every trip, the person gains experiences and learns new things.

“Signals tell regulatory T cells when to leave one place and go somewhere else,” says Dr. Bromberg. “And when it reaches its destination, another set of signals can tell it to do other things such as to mature, differentiate or proliferate.”

Dr. Bromberg believes that understanding signaling that drives these and other cells is key. “Getting regulatory T cells to travel at the right time to the right place and in the right numbers may be important in helping suppress an immune response,” he says.

Determining the signals that cause these cells to move into and out of the organ and lymph nodes — sites of immune reactivity — is therefore pivotal. This may not be achieved by hitting a single cell or molecule, but by better understanding the pathways that underlie cell migration and the complex interactive immune network.

“It’s a different way to look at the immune system, because we still don’t have drugs that take this traveling into account,” says Dr. Bromberg. “However, understanding these interactions may also help develop better immunosuppressive drug targets.”

In his research in mice, Dr. Bromberg is studying how a combination of monoclonal antibodies, timing and transfusion of certain white blood cells and molecules can impact immune suppression.

Results have shown that administering this combination as early as seven days prior to organ transplantation can play an important role in the immune response by establishing a more tolerant environment for organ transplantation which may eventually lead to better acceptance of the transplanted organ.

Developing a better understanding of the basic aspects of the immune system could even lead to improvements in other areas.

Today, one of the most successful transplantations involves kidney transplants. On average, the chance of rejection in the first year after kidney transplantation is about 10% to 15%. However, as patients get further along — 5 to 15 years after transplant — they may develop something called chronic rejection, which involves chronic scarring.

“We believe this chronic scarring is due to ongoing, low-level rejection of the organ by the immune system. This happens with various transplants over time, and right now it can be difficult to diagnose or control,” says Dr. Bromberg.

“However, if we understood the immune response to a point where we could achieve perfect immunosuppression, then we would be able to completely prevent both acute and chronic organ rejection in the first place,” he adds. “This would help us achieve complete tolerance.” 

JONATHAN BROMBERG, M.D., Ph.D., studies immunosuppression and the migratory patterns of T cells with the hope of understanding what causes organ rejection. To schedule an appointment, please call 1-866-408-6885.