'Stimulated' stem cells stop donor organ rejection
(Medical Xpress) -- Johns Hopkins researchers have developed a way to stimulate a rats stem cells after a liver transplant as a means of preventing rejection of the new organ without the need for lifelong immunosuppressant drugs. The need for anti-rejection medicines, which carry serious side effects, is a major obstacle to successful long-term transplant survival in people.
With a combination of a very low, short-term dose of an immunosuppressive drug to prevent immediate rejection and four doses of a medication that frees the recipients stem cells from the bone marrow to seek out and populate the donor organ, the rats lived more than 180 days with good liver function despite stopping both drugs after one week. The researchers are also testing the method on other transplanted organs, including kidneys, in rats and other larger animals.
Essentially, the Hopkins scientists transformed the donor liver from a foreign object under attack by the rats immune system into an organ tolerated by the recipients immune system all in a matter of three months from the date of transplant, they report.
The technique, if replicated in humans, could mark a major shift in the process of organ transplantation, the researchers say. An article describing the experiment appears in the current issue of the American Journal of Transplantation.
It is the dream for all scientists in the transplant field to erase the need for lifelong immunosuppressant drugs, says study leader Zhaoli Sun, M.D., Ph.D., an associate professor of surgery at the Johns Hopkins University School of Medicine. Currently, if a patient survives for 10 or 20 years with a new liver, that organ is still seen as foreign inside its new body because immunosuppression puts blinders on the immune system that must stay on to prevent rejection. Our idea was to find a way to turn that organ into something that belongs and is never at risk of rejection.
Although thousands of people with end-stage liver disease have gotten lifesaving liver transplants in recent years, rejection remains a chronic risk. And the expensive immunosuppressant drugs they need increase the chance of developing severe infections and many kinds of cancers. Some patients have difficulty sticking to the cocktail of drugs, which must be taken every day.
For their study, researchers transplanted portions of the livers of one kind of rat (dark agouti, or DA) into another (Lewis-type). For seven days after transplantation, the Lewis rats were treated with low-dose tacrolimus (an immunosuppressant), plerifaxor (a stem-cell stimulator) or a combination of the two. Twelve of the 13 rats that received a combination of the two drugs had long-term liver function and survived more than 180 days, while nearly all of the remaining rats rejected their new livers after 12 days.
This short-term treatment had long-term results, says Sun, who also is director of Hopkins Transplant Biology Research Center.
Typically, organ transplant recipients receive full doses of immunosuppressant drugs, such as tacrolimus, immediately after they receive new livers. Otherwise, rejection quickly results and patients may die.
Sun and his colleagues gave the Lewis rats in their experiment the equivalent of one-tenth the standard dose of tacrolimus. The goal was to have the new liver experience some mild rejection, but not enough to kill it. This controlled rejection, Sun says, appears to create injury signals in the body that cry out for stem cells to come and repair the damage being done to the new liver. It also prevents the new liver from regenerating itself with cells from the donor because it is under immunologic attack, leaving an opening for the recipients stem cells to jump in and play that role.
Sun and his colleagues used plerifaxor, a relatively new drug, known to free stem cells from the bone marrow and release them to circulate in the bloodstream. The drug is currently approved for patients about to undergo chemotherapy whose stem cells are harvested frozen and then returned to the body after cancer treatment.
Sun says that, in his experiment, many of these stem cells travel to the damaged liver to repopulate it with cells from the recipient, slowly taking over for the donor cells. Sun says the mechanism that brings the stem cells into the liver is becoming better understood, while the mechanisms by which stem cells become liver cells remain elusive. Equally interesting, Sun says, the stem cells also appear to modulate the immune response, increasing the number of regulatory T-cells and helping to reduce the chances of rejection.
In our study, the risk of organ rejection is eventually eliminated because the liver is no longer a foreign object, but comprised of many of the recipients own cells, Sun says. Once the recipients stem cells take over, the body sees the regenerated liver as its own and works to protect it, not attack it.
Within three months, Sun and his colleagues found that the majority of the liver cells in the transplanted organ belonged to the recipient, not the donor. When they used whole livers instead of partial livers, the process took a year. This suggests that the transformation process is jumpstarted by using partial livers for transplant, because the organ already needs to regenerate itself to most effectively function, he says.
Sun cautions that clinical trials with human organ transplant patients might be years away, but only if further research in animals confirms the methods safety and value. The technique might prove useful not only at the time of a new transplant, but even after years of immunosuppressant drug use.
Provided by Johns Hopkins University
- Adult stem cells take root in livers and repair damage May 11, 2011 | not rated yet | 0
- How liver kills 'killer cells' Sep 19, 2011 | not rated yet | 0
- Embryonic stem cells might help reduce transplantation rejection Sep 15, 2008 | not rated yet | 0
- Stem cell breakthrough: Bone marrow cells are the answer Jan 28, 2010 | not rated yet | 0
- Stem cell study seeks to wean non-related transplant recipients from anti-rejection drugs May 28, 2009 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
By discovering the new mechanism by which estrogen suppresses lipid synthesis in the liver, UC Irvine endocrinologists have revealed a potential new approach toward treating certain liver diseases.
Medical research May 23, 2013 | 5 / 5 (1) | 0 |
Aortic arch pulse wave velocity, a measure of arterial stiffness, is a strong independent predictor of disease of the vessels that supply blood to the brain, according to a new study published in the June issue the journal ...
Medical research May 23, 2013 | not rated yet | 0
Since the discovery of Prontosil in 1932, sulfonamide antibiotics have been used to combat a wide spectrum of bacterial infections, from acne to chlamydia and pneumonia. However, their side effects can include serious neurological ...
Medical research May 23, 2013 | not rated yet | 0 |
Scientists at the National Institutes of Health report they have discovered in mouse studies that a small molecule released in the spinal cord triggers a process that is later experienced in the brain as ...
Medical research May 23, 2013 | 5 / 5 (3) | 0 |
Spanish researchers have discovered that the daily clearance of neutrophils from the body stimulates the release of hematopoietic stem cells from the bone marrow into the bloodstream, according to a report published today ...
Medical research May 23, 2013 | 5 / 5 (2) | 0
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
18 hours ago | 5 / 5 (3) | 0 |
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
12 hours ago | 3 / 5 (2) | 0 |
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
15 hours ago | 3.7 / 5 (3) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
15 hours ago | 5 / 5 (4) | 0 |
How can healthy people who hear voices help schizophrenics? Finding the answer for this is at the centre of research conducted at the University of Bergen.
18 hours ago | 4 / 5 (2) | 2
(Medical Xpress)—The way Alzheimer's disease is portrayed by advocacy groups and the media is having undue influence on the euthanasia debate, according to a Deakin University nursing ethics professor.
19 hours ago | not rated yet | 2