Featured Research

from universities, journals, and other organizations

Post-transplant Combo Can Replace Toxic Immune-suppressing Drugs In Monkeys

Date:
July 31, 2009
Source:
Emory University
Summary:
A combination of costimulation blockers and alefacept can replace calcineurin inhibitors, the mainstay drugs given to transplant patients, in preventing graft rejection after kidney transplants in monkeys. The finding opens the door to less-toxic post-transplant treatment for humans that could be administered once a week. Costimulation blockers target immune cells without the predominant side effects of conventional transplant drugs. Alefacept subdues T cells responsible for immunological memory.

Transplant patients rely on drugs to prevent graft rejection, but at the cost of serious side effects. The class of immunosuppressive drugs known as calcineurin inhibitors (examples are cyclosporine and tacrolimus) can damage patients' kidneys and lead to high blood pressure, among other problems.

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.


Story Source:

The above story is based on materials provided by Emory University. Note: Materials may be edited for content and length.


Journal Reference:

  1. T.A. Weaver et al. Alefacept promotes costimulation blockade-based allograft survival in primates. Nature Medicine, 2009; 15, 746-749

Cite This Page:

Emory University. "Post-transplant Combo Can Replace Toxic Immune-suppressing Drugs In Monkeys." ScienceDaily. ScienceDaily, 31 July 2009. <www.sciencedaily.com/releases/2009/07/090708132816.htm>.
Emory University. (2009, July 31). Post-transplant Combo Can Replace Toxic Immune-suppressing Drugs In Monkeys. ScienceDaily. Retrieved October 2, 2014 from www.sciencedaily.com/releases/2009/07/090708132816.htm
Emory University. "Post-transplant Combo Can Replace Toxic Immune-suppressing Drugs In Monkeys." ScienceDaily. www.sciencedaily.com/releases/2009/07/090708132816.htm (accessed October 2, 2014).

Share This



More Health & Medicine News

Thursday, October 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Ebola Might Not Be Out Of Control In U.S., But Coverage Is

Ebola Might Not Be Out Of Control In U.S., But Coverage Is

Newsy (Oct. 2, 2014) Coverage of the lone Ebola patient discovered in Texas has U.S. media in a frenzy — but does the coverage match the reality? Video provided by Newsy
Powered by NewsLook.com
US Hunts Contacts of Ebola Patient, Including Children

US Hunts Contacts of Ebola Patient, Including Children

AFP (Oct. 2, 2014) Health officials in Texas on Wednesday scoured the Dallas area for people, including schoolchildren, who came in contact with a Liberian man who was diagnosed with Ebola in the United States. Duration: 00:55 Video provided by AFP
Powered by NewsLook.com
Study Says Losing Sense Of Smell Can Indicate Death

Study Says Losing Sense Of Smell Can Indicate Death

Newsy (Oct. 2, 2014) Researchers found elderly adults with a poor sense of smell are more likely to die within five years. Video provided by Newsy
Powered by NewsLook.com
Pregnancy Spacing Could Have Big Impact On Autism Risks

Pregnancy Spacing Could Have Big Impact On Autism Risks

Newsy (Oct. 1, 2014) A new study says children born less than one year and more than five years after a sibling can have an increased risk for autism. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins