August 05, 2014

$17 million multi-institutional grant to maximize kidney transplant survival
Immune system cells and a drug used for treating rheumatoid arthritis will be studied in an effort to reduce inflammation in kidney transplants and improve long-term function.

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bannonwebThe University of Alabama at Birmingham is participating in a new seven-year, $17 million multicenter study funded by the National Institutes of Health to determine whether certain immune system cells and/or a drug used for treating rheumatoid arthritis can improve and maintain the long-term health of kidney transplant recipients.

The goal of the study is to reduce or eliminate inflammation in kidney transplants and prevent the associated decline in graft function, thereby maximizing long-term organ survival. It will involve two clinical trials in parallel by researchers at four sites around the country.

Roslyn Mannon, M.D., professor in the School of Medicine in the Division of Nephrology and professor of surgery in the Division of Transplantation, is the principal investigator for the grant at UAB. University of California, San Francisco is the lead institution for the study.

Mannon, director of research for the Comprehensive Transplant Institute and immediate past president of the American Society of Transplantation, says the newly funded series of trials to take place at UAB will involve the use of regulatory T cells, or Tregs, and the use of an anti-IL6 receptor antibody. The programs are expected to begin this fall.

“We have been a site for NIH and Clinical Trials in Organ Transplantation studies since 2009,” said Mannon, also a member of the NIH steering committee for the CTOT and a member of the mechanistic studies committee. “In the current funded projects, we collaborate with other institutions on three clinical trials devoted to kidney transplant patients. We have 27 UAB patients enrolled to study a novel combination of immunosuppression with a total of 65 enrolled in all three sites. Additionally, one study is specifically for kidney and pancreas transplant recipients, and is one of the first studies in this patient population to be performed in the past 15 years. To be a part of this new multicenter study is great news. We will continue to participate in these cutting-edge national research efforts.”

Despite advances in transplantation — reducing early acute rejection rates to less than 15 percent and improving one-year graft survival to more than 90 percent — long-term graft success rates have remained unchanged at 4 percent loss annually. A major contributor is the progression of interstitial fibrosis and tubular atrophy in the kidney.

The Comprehensive Transplant Institute provides a means to expand patient options, including incompatible transplantation and kidney-paired donation and new access to transplants for patients with HIV or hepatitis C infection. Every gift will help expand UAB’s expertise in transplant immunology, transplant pathology, and outcomes research, which will have a direct impact on patient care.  
The cells that the researchers are focused on are Tregs, a small population of lymphocytes that suppress the activity of other immune cells. They maintain normal immune system homeostasis and safeguard against autoimmune diseases, and their immunosuppressive properties also can be harnessed to control transplant rejection.Tregs have the potential to induce long-term donor-specific tolerance without impeding desired immune responses to pathogens and tumors in transplant patients.

The principal investigator of the study is Flavio Vincenti, M.D., UCSF professor of medicine and a kidney and pancreas transplant specialist at UCSF Medical Center. Other participating institutions are Emory University and Cedars-Sinai Medical Center.

“This grant allows us to work toward achieving two important advances in the transplant field,” said Vincenti. “We can introduce personalized medicine by treating patients based on molecular profiling of their kidney. We also can allow control of the response to the transplant by the patients’ own immune systems by regulatory T cells, either through infusions or pharmacologically.”

Researchers believe inflammation can be controlled in kidney transplant recipients by increasing the number or activity of Tregs, either by infusing them into the body or by blocking interleukin 6 (IL6) with the drug tocilizumab.

To do so, they will conduct two clinical trials — Treg Adaptive therapy in Subclinical inflammation in Kidney transplantation, or TASK, and Therapy to Reduce Allograft Inflammation with IL6 inhibition, called TRAIL.

The trials will involve expert clinical investigators, translational Treg biologists and mechanistic core researchers. The four selected transplant centers are noted for high-quality patient care, high patient volume and the necessary translational infrastructure to ensure successful recruitment. In fact, there already are pre-existing, productive working relationships among the transplant centers and investigators.

Learn more on UAB’s research efforts to help transplanted patients keep their organ permanently and listen to Mannon’s podcast on kidney research at UAB’s The Mix.
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