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Dr. Fadi Lakkis, the Frank & Athena Sarris Chair in Transplantation Biology and scientific director of Pitt’s Thomas E. Starzl Transplantation Institute.
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Pitt-based study discovers a way to block transplanted organ rejection

Pitt-based study discovers a way to block transplanted organ rejection

For nearly six decades, organ transplantation has saved many thousands of lives, but the struggle continues to reduce organ failures over the long term. 

Now comes a “game-changing” study, led by University of Pittsburgh researchers and published recently in Science. The research describes a newly discovered immune pathway that could be responsible for eventual rejection of transplanted organs.

That rejection pathway, it says, involves the more primitive “innate” immune system that was previously thought to carry no memory nor have no long-term impact on transplanted organs.

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“The rate of acute rejection within one year after a transplant has decreased significantly, but many people who get an organ transplant are likely to need a second one in their lifetime due to chronic rejection,” stated Dr. Fadi Lakkis, the study’s senior author who serves as scientific director of Pitt’s Thomas E. Starzl Transplantation Institute.

Chronic rejection of transplanted organs typically results in scarring that can lead to organ failure. The study also describes a process to block that immune response as a way to help extend the lifespan of transplanted organs.

The missing link in the field of organ transplantation has been “a specific way to prevent rejection,” especially over the long term, “and this finding moves us one step closer to that goal,” Dr. Lakkis said.

However, the study involved mice and not humans, which means step-by-step research will be necessary before a method to stop the process is developed and successfully tested in humans.

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Dr. Daniel Kreisel, surgical director of  lung transplantation at Washington University in St. Louis, who wasn’t involved in the study, said chronic rejection has been the Achilles heel in organ transplantation. 

“This new pathway was not previously thought of nor identified as a pathway that can potentially be targeted,” he said. “This represents a paradigm shift in the research and introduces an addition to the pathways that have been traditionally targeted, with this new one to be targeted for ideal outcomes.”

The immune system features two branches — the innate and the adaptive — with the innate system being first to identify the presence of foreign agents and to activate the adaptive immune system (including T-cells) to attack foreign invaders.

That adaptive branch of the immune system long has been known to carry memory of invaders as proved by vaccines and long-term protection against such infections as the measles.

Dr. Thomas Starzl, the late, famed Pitt transplant surgeon, developed the drug Prograf (tacrolimus) that proved to be safer and initially more successful than traditional anti-rejection drugs, including steroids, in preventing the adaptive immune system from destroying transplanted organ tissue.

But in time, research showed that Prograf most notably reduced rejection in the first year after transplantation but only equaled the success of traditional medications over the long run.

That has long suggested that another type of immune response was responsible for eventual destruction of transplanted organs, but that pathway had remained a mystery until the Pitt study was published.

One early step in discovering this pathway occurred in 2017, when a Pitt-based study, also led by Dr. Lakkis, described how innate immune cells known as monocytes initiated the immune response against foreign cells in transplanted organs.

The current study builds on that foundation by describing how those monocytes also carry memory and continue the attack indefinitely.

“We found that their capacity to remember foreign tissues is as specific as adaptive immune cells, such as T-cells, which is incredible,” said Dr. Martin Oberbarnscheidt, a Pitt assistant professor of surgery and one of the study’s senior co-authors.

Discovering pathways of diseases often is key to figuring out ways to blocking them. 

For that reason, the study holds promise, Dr. Lakkis said, in testing a method of adding a protein specific to monocytes to block them from attacking transplanted organ tissue without hampering the monocytes’ ability to attack other foreign invaders.

Dr. Lakkis and Dr. Oberbarnscheidt said the immune system has many redundant pathways to protect the body from foreign threats, so blocking the newly discovered pathway likely will not completely eliminate long-term rejection. But it could notably extend the lifespan of such organs.

“Knowing exactly how the innate immune system plays a role opens the door to developing very specific drugs, which allows us to move away from broadly immuno-suppressive drugs that have significant side effects,” Dr. Lakkis said.

The finding also has implications beyond transplantation, according to Dr. Oberbarnscheidt.

“A broad range of diseases, including cancer and autoimmune conditions, could benefit from this insight. It changes the way we think about the innate immune system,” he said.

Dr. Jerzy Kupiec-Weglinski, director of the Dumont-UCLA Transplantation Research Centers in Los Angeles, also wasn’t involved in the study but described it as “a game-changing report with far-reaching ramifications for the organ transplant field as well as cancer and autoimmune diseases.”

“What it means,” he said, “is that we may envision novel, highly specific therapeutics that may be developed to control host chronic rejection response, the principal cause of transplant loss nowadays.” 

David Templeton: dtempleton@post-gazette.com or 724-809-4999.

 

 

First Published: May 18, 2020, 10:06 a.m.

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Dr. Fadi Lakkis, the Frank & Athena Sarris Chair in Transplantation Biology and scientific director of Pitt’s Thomas E. Starzl Transplantation Institute.
Dr. Martin Oberbarnscheidt, a Pitt assistant professor of surgery and one of the study’s senior co-authors.
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