A combination of treatments can effectively replace calcineurin inhibitors in preventing graft rejection when kidney transplants are performed on monkeys, scientists at the Emory Transplant Center have shown. The non-human primate research was conducted at the National Institutes of Health and Yerkes National Primate Research Center, Emory University.
The results are published in the July issue of Nature Medicine.
The finding opens the door to less-toxic post-transplant treatment that could be administered once a week rather than a dizzying mound of pills every day, says senior author Allan Kirk, MD, PhD, scientific director of the Emory Transplant Center and a Georgia Research Alliance Eminent Scholar.
"Both of the drugs used in this regimen are already used separately in humans, thus a clinical trial could be developed quickly," Kirk notes.
One key ingredient in the combination is an experimental therapy called a costimulation blocker, designed to interfere with the T cells that cause graft rejection without affecting other organs. Costimulation refers to one of two signals T cells need from other cells (antigen presenting cells) to become fully activated.
The other key ingredient -- a protein called alefacept -- subdues memory T cells, a variety of T cells that allow the immune system to respond faster and stronger to an infectious agent or vaccine upon second exposure.
Costimulation blockers are sufficient for allowing mice to tolerate a transplanted kidney, but not monkeys or people, Kirk says. Memory cells appear to prevent costimulation blockers from working as well in monkeys as they do in mice.
"One of the big differences we've found between mice and both monkeys and people is that we primates have more exposure to infections that require us to develop immunological memory," he says. "Memory cells are quicker to become activated and don't need costimulation as much, so blocking costimulation doesn't slow them down."
By themselves, neither costimulation blockers (in this case, a molecule called CTLA4-Ig) or alefacept could prevent rejection in monkeys after the eight week treatment period, Kirk and his colleagues found. They had more success by combining costimulation blockers, alefacept and the transplant drug sirolimus. Under this regimen, monkeys could last for months after treatment ended without developing rejection or self-reactive antibodies.
CTLA4-Ig mimics a molecule found on T cells (CTLA4) and acts as a decoy. CTLA4-Ig is now used as an FDA-approved therapy for rheumatoid arthritis.
A similar drug called belatacept is now in phase III kidney transplant clinical trials, but current studies use it in combination with conventional immunosuppressive drugs.
Alefacept targets memory T cells via a molecule on their surfaces called CD2, the authors found. Alefacept was approved by the FDA for treatment of psoriasis in 2003. It is also being tested in a kidney transplant clinical trial in combination with conventional drugs.
Both CTLA4-Ig and alefacept are proteins and must be administered intravenously or possibly subcutaneously. However, their stability means they don't need to be taken every day – once a week is enough, Kirk says.
The paper's first author is Tim A. Weaver, and other co-authors are Ali H. Charafeddine, Avinash Agarwal, Alexandra P. Turner, Maria Russel, Frank V. Leopardi, Robert L. Kampen, Linda Stempora, Mingging Song and Christian P. Larsen.
The research was supported by the National Institutes of Health.
Reference: T.A. Weaver et al. Alefacept promotes costimulation blockade-based allograft survival in primates. Nature Medicine. 15, 746-749 (2009)
The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Emory Winship Cancer Institute; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children's Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, Emory University Orthopaedics & Spine Hospital, the jointly owned Emory-Adventist Hospital, and EHCA, a limited liability company created with Hospital Corporation of America. EHCA includes two joint venture hospitals, Emory Eastside Medical Center and Emory Johns Creek Hospital. The Woodruff Health Sciences Center has a $2.3 billion budget, 18,000 employees, 2,500 full-time and 1,500 affiliated faculty, 4,300 students and trainees, and a $5.5 billion economic impact on metro Atlanta.
Holly Korschun | EurekAlert!
Polymers Based on Boron?
18.01.2018 | Julius-Maximilians-Universität Würzburg
Bioengineered soft microfibers improve T-cell production
18.01.2018 | Columbia University School of Engineering and Applied Science
What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.
Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...
The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...
08.01.2018 | Event News
11.12.2017 | Event News
08.12.2017 | Event News
18.01.2018 | Medical Engineering
18.01.2018 | Ecology, The Environment and Conservation
17.01.2018 | Ecology, The Environment and Conservation