Future in Transplant - 4 Elimination of Corticosteroids From Transplant Immunosuppression -Corticosteroid withdrawal remains an attractive protocol. Minimization of immunosuppression is important to reduce morbidity and perhaps mortality. Newer immunosuppressive agents have increased investigators' and clinicians' enthusiasm about this pathway. Corticosteroid avoidance is successful in selected centers. This strategy has been studied as a single-center approach by multiple investigators, but many of the studies are not adequately powered and have not been evaluated for short-term endpoints such as silent acute rejection and/or early CAN. A selection bias toward enrolling low-risk patients remains a problem in analyzing these results, and absence of a control group in certain studies makes it difficult evaluate the final results. Results from a multicenter study will be critical to evaluate the efficacy of this protocol. In conclusion, alternative end points are needed to evaluate minimization protocols. In addition to acute rejection and graft failure, additional markers such as early CAN should be used to test the efficacy of corticosteroid elimination. Are we harming patients with corticosteroid administration or avoidance? This question has been debated for the past 2 decades and, it is hoped, will be answered in the near future.
CP-690,550 -HealthDay Reporter THURSDAY, Oct. 31 (HealthDayNews) -- Using a clue from children with severely defective immune systems, researchers say they have developed a compound that promises to prevent the rejection of organ transplants with few of the dangerous side effects of existing drugs. The compound, called CP-690,550, is designed to suppress the activity of immune cells that attack foreign tissue, but not the cells that protect the body against infection. The Pfizer researchers prepared a pure version of JAK3 and began a long search for a compound that would inactivate it without affecting other protective immune system cells.".When they find the right mix, human transplant studies probably will start by adding the new medication to existing rejection-preventing therapies,Changelian says."It will be a pretty long-term thing, to convince transplant surgeons to trade our drug for their current drugs," he says. "Until we do a large number of such studies, no self-respecting transplant surgeon would make the change."
A WORLD-FIRST breakthrough in stem-cell research promises a cure for lung diseases that kill tens of thousands of Australians -- and millions more around the world.Melbourne scientists at the prestigious National Stem Cell Centre have turned human embryonic stem cells into lung cells. The revolutionary development is a step towards coaxing damaged lungs to repair themselves. The technique could yield cures for cystic fibrosis, mesothelioma, emphysema, chronic bronchitis and, eventually, lung cancer. Research leader Dr Richard Mollard said the discovery was a "big step forward". He said this was the first time lung cells had been successfully grown. Dr Mollard, 37, said although it was too soon to start human clinical trails, early results were promising. "It certainly looks like we are heading in the right direction," he said. "What I can say is that this is an exciting step forward and the potential has been realised." Lung diseases cost Australia more than $2 billion a year to treat and kill tens of thousands of Australians every year. The US spends $24 billion a year treating the diseases. "Lung disease is highly under-estimated as a killer," Dr Mollard said. There is no cure for cystic fibrosis. Nationally it costs $500 million a year to treat. Dr Mollard said the breakthrough meant people with lung diseases may be offered pioneering stem-cell therapy as a treatment and potential cure within a few years. But he said a cure for lung cancer would take longer. "Lung cancer is a very different disease," Dr Mollard said. "However, eventually we may even be able to replace cells damaged by cancer." Melbourne-born Dr Mollard was brought home two years ago by Australia's stem-cell pioneer Professor Alan Trounson to work at the Monash University-based centre. He had been working in France and was about to accept a research position in New York when Professor Trounson recruited him. He said Victoria was now one of the world leaders in stem-cell science. "The potential for stem-cell research to be an effective treatment is huge. People have done experiments and have shown you can re-activate spinal columns," he said. There was also some hope, he said, with pancreatic cells and also cells introduced into hearts that have suffered a heart attack. Dr Mollard said he has had calls from Germany, Singapore, France and the US from scientists wanting to know more about his discovery. "In the last three weeks there has been a real momentum," he said. "We are all excited. This is a big first step." Kerryn McIver, from Cystic Fibrosis Victoria, said the discovery offers promise. Cystic fibrosis sufferer Geoff Brown, 19, whose younger brother Murray, 10, also has the condition, said the breakthrough was very exciting. "I think it's fantastic. I'm extremely impressed and hope this can be used in the near future for my sake, my brother's sake and all the other sick people," he said. "I live my life in hope that one day there will be a cure." Mr Brown, whose brother has been treated at Monash Medical Centre for the past week, said the possibilities from stem-cell research were endless. "Stem-cell research is just great. I really think we will see more progress and more breakthroughs in the next few years," he said.
Leflunomide: is there a place for its use in transplantation? -Leflunomide is a disease-modifying agent approved for use in rheumatoid arthritis and used off label for other conditions such as systemic lupus erythematosus. It has several properties that generate significant interest for potential use as an immunosuppressive agent in transplantation. This article reviews some of the properties stimulating this appeal and the initial reports on the use of leflunomide in transplantation, ending with a discussion of similar agents in development.Recent findings Reported use of leflunomide in human transplantation is limited, but two recent reports, one prospective and one retrospective, describe the successful use of this agent in solid organ transplantation.Summary Leflunomide has several properties that make it an excellent candidate for use in transplantation, but concerns about the prolonged half-life and potential for hepatotoxicity temper the enthusiasm. As it will likely be several years before similar, shorter acting agents are available, continued study is warranted to discern the appropriate use in human transplantation of this currently available agent. (Source: Current Opinion in Organ Transplantation 2003)
Experimental Pill May Block Transplanted Organ Rejection With Fewer Side Effects
WASHINGTON Oct. 31 — Scientists have created a pill that may prevent the rejection of transplanted organs without as many of the side effects patients now face. The pill, which mimics a powerful immune-system disease, protects monkeys given kidney transplants, the researchers report in Friday's edition of the journal Science. Although much more study is needed, human safety experiments are beginning.If it works, the drug, created by Pfizer Inc., could be a more sophisticated way to prevent transplant rejection. Unlike today's anti-rejection drugs, it was specially engineered to inhibit a molecule called JAK3 that is key to marshaling the immune cells that attack and destroy newly implanted organs. Ironically, the new compound was inspired by the deadly "bubble boy disease," in which children are born without a functioning immune system. A complete lack of JAK3 is at the root of the genetic disease, also called severe combined immunodeficiency or SCID. With the new compound, Pfizer scientists hope to harness JAK3's immune suppression powers enough to help transplant recipients without overwhelming the body's defenses."It's a brand new concept," said Dr. Dominic Borie, transplant immunology chief at Stanford University School of Medicine, who tested Pfizer's drug in 12 monkeys given varying doses for three months.While it completely protected only a third, "it works, and does as well as other immunosuppressive drugs" with fewer side effects, he said.The big question is how well the drug will work in people who are already sick instead of monkeys who start off healthy, said Dr. John Fung, transplant chief at the University of Pittsburgh Medical Center, who was not involved with the research.Still, he said he was intrigued."It looks like a very promising approach," Fung said. "It ushers in a new era of drugs that are targeted at specific pathways" of organ rejection.The body's reaction to a new organ is thousands of times more aggressive than its fight against a routine infection, so transplant recipients take powerful immune-suppressing drugs, sometimes for the rest of their lives.Despite the obvious benefits, today's anti-rejection drugs can cause debilitating or even deadly side effects. Some raise blood pressure and cholesterol levels, increasing the risk of heart disease. Some cause anemia. And some gradually destroy the kidneys, eventually forcing many transplant recipients onto dialysis.Those side effects arise because the older drugs' molecular targets are found in cells throughout the body. Because the new compound's target, JAK3, is an enzyme found only in immune cells, it shouldn't cause kidney, heart and other problems, said Paul Changelian, Pfizer's lead researcher.The hunt for the drug so far known by the unwieldy code name CP-690,550 began almost a decade ago, when the National Institutes of Health discovered JAK3 and found it was crucial in activating infection-fighting white blood cells. Working with NIH, Pfizer then designed a pill to curb white blood cells' attack on donated organs by inhibiting JAK3's action.It worked in mice given heart transplants. Stanford then tested 12 monkeys. Four had no signs of kidney problems after three months, and others had varying degrees of rejection earlier, suggesting the drug was comparable to other medications, Borie said. The monkeys' only side effect was anemia from the highest dose.No problems arose in first-stage safety tests, in which healthy people volunteer to take a dose, Changelian said. Pfizer now is testing various doses in people with the autoimmune disease psoriasis before attempting studies in more fragile kidney transplant recipients.Copyright 2003 The Associated Press.
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