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!
Discovery of a Key Regulatory Gene in Cardiac Valve Formation
24.05.2017 | Universität Basel
Carcinogenic soot particles from GDI engines
24.05.2017 | Empa - Eidgenössische Materialprüfungs- und Forschungsanstalt
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.
In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
24.05.2017 | Physics and Astronomy
24.05.2017 | Physics and Astronomy
24.05.2017 | Event News