Researchers discover reasons for organ rejection

Following up on yesterday's post this is a report published by the Daily Bruin, University of California, Los Angeles

In this vasculopathic heart vessel, interaction between two specific molecules narrows blood vessels, causing a reduction of oxygen flow.

Results of study reveal that two molecules are interacting to create negative immune response

By Sarah Khan UCLA Daily Bruin

For patients whose organs have failed, an organ transplant often means another shot at a healthy life.

But more than 40 percent of organ transplants fail within one year. A patient’s antibodies will sometimes attack the foreign organ, a phenomenon that has been little understood by researchers up to this point, said Elaine Reed, director of the UCLA Immunogenetics Center.

On Tuesday, UCLA researchers published the results of a five-year study that uncovers previously unknown reasons for why organs are rejected by their host body, said Reed, a co-author of the study.

The key lies with two molecules, human leukocyte antigen and integrin beta-4, which depend on each other to incite the organ rejection, she said.

The interaction of human leukocyte antigen and integrin ignites a negative immune response in a patient with an organ transplant, Reed said. The patient’s body then produces antibodies to shut down the functioning organ, often by overgrowing blood vessel cells and restricting the organ’s access to oxygen and other nutrients.

This mechanism may explain why organ rejection is difficult to reverse, Reed said.

“Once the patients start making the antibodies, you can’t stop it,” she said. “Chronic rejection is the major problem.”

Although it is possible to live without an organ like a kidney, there are not many options for a patient whose body rejects a heart, liver or lung. In these cases, retransplant is often the choice for survival, Reed said.

Waiting periods to receive organs can be so long that patients sometimes die on the wait list, said Murray Kwon, a heart transplant surgeon at Ronald Reagan UCLA Medical Center.

The study doesn’t stop at solving the mystery of organ rejection.

The team is also looking at applying the research to cancer prevention and treatment, said Xiaohai Zhang, lead author of the study and a postgraduate researcher in pathology and lab medicine at UCLA.

In the lab, Zhang prevented integrin from combining with human leukocyte antigen and, as a result, noticed that blood cells did not grow as much, he said.

It may be possible to do the same thing to tumors to keep blood vessels from sprouting inside them, he said.

Although the findings are not ready to be developed into drugs or therapies, the findings provide hope for organ transplant and cancer patients who otherwise have few options for a healthy life, Reed said.

“We have to understand the mechanism before we develop the therapy,” she said.

Published November 24, 2010 in News, Science & Health

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Has your life been saved by an organ transplant? "Pay it forward" and help spread the word about the need for organ donation - In the U.S. another person is added to the national transplant waiting list every 11 minutes and 18 people die each day waiting for an organ or tissue transplant. Organs can save lives, corneas renew vision, and tissue may help to restore someone's ability to walk, run or move freely without pain. Life Begins with You

Palliative Care Referrals After Lung Transplantation

Palliative Care Referrals After Lung Transplantation in Major Transplant Centers in the United States

This article in Medscape Pulmonary Medicine notes that lung transplantation improves survival and quality of life for patients with end-stage lung disease. However, long-term success in achieving these outcomes is limited due to the development of chronic rejection and the adverse effects of the requisite immunosuppression

By 5 years after transplantation, 43% of lung transplant recipients (LTR) develop chronic rejection. Compared with a survival rate of >80% at 4 years in LTR without chronic rejection, the overall mortality rate following the onset of chronic rejection is 40% within 2 years of diagnosis. Even recipients with chronic rejection who opt for retransplant experience higher morbidity and mortality compared with their initial transplant procedure.

The authors also note that from the onset of chronic rejection until death, LTR experience frequent hospitalizations (up to 14 readmissions) and exacerbations (up to 17 visits to the emergency department). In addition, LTR commonly experience higher levels of psychological distress (e.g., anxiety and depression) than other organ recipients, manage an average of 17 physical symptoms and report a low sense of mastery for managing their illness. Although both LTR and their families are typically satisfied with medical care during the early recovery phase after lung transplant, they are critical about the lack of continuity of care as their health condition deteriorates. Family caregivers report high levels of subjective burden, symptoms of depression and anxiety, stress related to tackling organizational difficulties, and financial burdens. They also express the need for more information, better communication, and better access to psychosocial support.

The authors also say that future research should include developing and testing interventions and strategies to integrate palliative care into lung transplant care to better meet the needs of LTR and their families as health declines.

Read the Full article for study methods, results, discussion and the author's conclusions.

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ISHLT 2009: Azithromycin for Bronchiolitis Obliterans Prophylaxis in Lung Graft Patients Gets Mixed Reviews

From Medscape Medical News

Neil Osterwell

April 24, 2009 (Paris, France) — In the never-ending search for therapies to prevent chronic lung allograft rejection, macrolide antibiotics, such as azithromycin, show promise, but only in about half of patients, report the authors of 2 European studies here at the International Society for Heart and Lung Transplantation 29th Annual Meeting and Scientific Sessions.

The first interim analysis from a randomized, double-blind trial comparing azithromycin and placebo showed that about half of patients with established bronchiolitis obliterans syndrome (BOS) had a response to azithromycin, reported Robin Vos, MD, a fellow in pathophysiology at Katholieke Universiteit and University Hospital Gasthuisberg, in Leuven, Belgium.

In addition, the efficacy of the drug appears to be related to grade of BOS, with close to half of patients with BOS grade 0p responding compared with only about 7% of patients with BOS grades 1 to 3, reported Federica Meloni, PhD, MD, from the Department of Hematological, Pneumological, and Cardiovascular Sciences, Respiratory Disease Section, at the University of Pavia, in Italy.

The results from the Belgian study support evidence of both an inflammatory and a fibroproliferative component to BOS, with the former likely to respond to azithromycin (Zithromax, Pfizer) and the latter unlikely to respond, the Belgian researchers suggested.

"We found an inflammatory phenotype with mainly neutrophils in the airways, and we found a phenotype with a more rapid decline in lung function later on, after transplantation, without cellular inflammation. We could clearly demonstrate that only those patients who have a high neutrophilia, without being infected, will respond to azithromycin, whereas the patients who don't have BAL [bronchoalveolar lavage] evidence of neutrophilia do not respond. So neutrophilia is really the driving force for an effect of azithromycin," said senior author Geert Verleden, MD, professor of immunology at Katholieke Universiteit, in an interview with Medscape Transplantation.

In the study, lung-transplant patients treated from September 2005 through December 2007 were randomized at discharge to receive either placebo or azithromycin 250 mg per day 3 times a week in addition to conventional therapies.

The primary study end points were BOS-free survival and overall survival at 2 and 3 years after lung transplantation. Under the protocol, patients who develop grade 1 or higher BOS are withdrawn from the study, started on open-label azithromycin, and are followed with forced expiratory volume at 1 second (FEV1) and airway inflammation studies.

At the most recent follow-up (2.3 years), 23 of the 83 enrolled patients discontinued because of the development of grade 1 or higher BOS, 5 had died (not from obliterative bronchiolitis), and 7 had dropped out because of adverse gastrointestinal events, suture problems, malignancy, or sepsis; 3 of these patients have since died.

Of the 23 who withdrew from the study as a result of BOS, 1 died and 22 were started on open-label azithromycin. Of this group, 12 were responders to azithromycin and 10 were nonresponders.

The researchers found that patients with airway neutrophilia in BAL at 3 months showed a trend toward the development of BOS (P = .05; correlation coefficient [r], 0.20). Azithromycin responders tended to have an earlier diagnosis of BOS than nonresponders (236.6 vs 322 days, respectively; P = .03), but the responders had a positive correlation with improvement in FEV1 after starting on azithromycin (P = .04; r = 0.6).

In the second study, Dr. Meloni and colleagues looked at the effects of 12 to 30 months of azithromycin therapy on 62 lung-transplant recipients, 43.5% with grade 0p BOS, 34% with grade 1 BOS, 8.1% with grade 2 BOS, and 14.5% with grade 3 BOS. As in the Belgian study, the patients received azithromycin 250 mg 3 times each week.

Patients with at least 12 months of follow-up (53 of the 62 patients) were stratified by change in FEV1 as being either responders (increase of greater than 10% in FEV1), having stable disease (change up or down within 10% of baseline), or nonresponders (decline of greater than 10% in FEV1).

There were a total of 12 responders, 10 of whom had grade 0p BOS, and 2 of whom had grade 1 to 3 BOS. Among patients with stable disease, 10 had grade 0p BOS and 21 had grade 1 to 3 BOS. Of the nonresponders, 2 had grade 0p BOS, and 8 had grade 1 to 3 BOS. The differences among the groups in the distribution of grades, on the basis of the chi-squared test, were statistically significant (P = .0045).

Among 23 patients with nearly 3 years of follow-up, the 7 nonresponders continued to show a decline in graft function, as measured by FEV1. Of patients with stable BOS, only 1 had a decline in function at 30 months, with a significant decline in FEV1 over baseline. Of the 8 responders, 7 showed improvement in FEV1 after starting on azithromycin, but 2 had a decrease in graft function at the last follow-up.

When they looked at peripheral blood cell parameters as possible indicators of efficacy, they found no significant differences, except for a significant decrease in the percentage of neutrophils at 12 months in the responders compared with the non responders, Dr. Meloni said. They also found that azithromycin significantly reduced proinflammatory chemokines, irrespective of treatment response.

The researchers concluded that chronic azithromycin therapy could result in long-term stabilization or improvement in graft function, but that this effect is highly dependent on disease grade, with 43% of patients with grade 0p disease having a response, compared with only 6.6% of those with grade 1 to 3 BOS.

A lung-transplant specialist who was not involved in the studies but who attended the session where they were presented said that the reason azithromycin is effective in some patients but not others needs to be elucidated.

"Are you dealing with 2 different diseases, 2 stages of a single disease, or . . . 2 different diseases coexisting in the same patient, like rheumatoid arthritis and osteoarthritis?" Marshall I Hertz, MD, professor of medicine at the University of Minnesota, in Minneapolis, wondered in an interview with Medscape Transplantation.

"A lot of us are working on biomarker development to get reproducible markers of one or the other phenotype so that you can measure biochemically something that we're not measuring very clinically. What we're doing right now is like treating hypertension by measuring strokes, when patients reach something very far down the road, when you'd really like something like a blood-pressure cuff."

Dr. Vos, Dr. Meloni, and Dr. Hertz have disclosed no relevant financial relationships.

International Society for Heart and Lung Transplantation (ISHLT) 29th Annual Meeting and Scientific Sessions: Abstracts 153 and 155. Presented April 23, 2009.

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Immune system 'atlas' will speed detection of kidney transplant

Exciting discoveries continue to be made in the field of transplant research and this study may help to extend the life of kidney recipients in the future.

esciencenews.com

Published: Monday, February 23, 2009 - 17:37 in Health & Medicine

Scientists at the Stanford University School of Medicine and Lucile Packard Children's Hospital have devised a new way to decode the immune signals that cause slow, chronic rejection of all transplanted kidneys.

They've created an immune-system "atlas" that will improve doctors' ability to monitor transplanted organs and shed light on the mechanisms of gradual, cumulative kidney malfunction after transplant. "The reason chronic injury occurs in transplanted organs is really a mystery," said senior study author Minnie Sarwal, MD, PhD, professor of pediatrics at the School of Medicine and a nephrologist at Packard Children's Hospital. "Even patients who receive an organ from an identical twin develop chronic rejection."

The findings will be published online Feb. 23 in the Proceedings of the National Academy of Sciences.

Before an organ transplant, doctors check for compatibility between the donor's and recipient's immune systems, Sarwal said. They examine the genes encoding small proteins, called human leukocyte antigens, that label the exterior of every cell. These proteins are the immune system's main mechanism for distinguishing "self" from "non-self" tissues. Only identical twins have perfectly matched human leukocyte antigens; for other organ recipients, doctors use a donor with the closest match they can find. After transplant, an organ recipient receives strong drugs that reduce the body's ability to crank out antibodies — immune "search-and-destroy" markers — against the donated kidney.

But the fact that chronic organ rejection occurs even between twins suggests the immune system is doing more than keeping tabs on human leukocyte antigens.

The Stanford team set out to find what that was. The researchers devised a first-of-its-kind method to catalog every one of the antibodies attacking donated kidneys after transplant. They tracked evidence of all types of immune system attack by comprehensively comparing antibody levels in 18 kidney recipients before and after transplant. To do this, they melded two biological sleuthing systems, first comparing all proteins in the subjects' blood to an array of more than 5,000 human proteins, then running the results from that analysis through a genetic database that showed which blood proteins were antibodies designed to attack the donated kidney.

"This is pretty revolutionary," Sarwal said. "It opens the door to a lot of exciting work to personalize how we monitor these patients." The new findings will allow inexpensive, noninvasive blood tests that show whether a donated kidney is infected, undergoing acute rejection or accruing chronic injuries that could cause long-term malfunction, she said.

"An individual's antibody profile is a new aspect of human physiology that can now be surveyed in an unbiased way, the same way genes can," said co-senior author Atul Butte, MD, PhD, assistant professor of medical informatics and of pediatrics. "That's very exciting." Butte is also a member of the Stanford Cancer Center. Unlike genes, the body's antibodies change over time, a factor that could improve the effectiveness of personalized medicine, Butte said.

The team's raw data on antibody profiles is now publicly available to other scientists through the Gene Expression Omnibus database maintained by the National Center for Biotechnology Information, a division of the National Library of Medicine.

In addition to improving patient monitoring, the team's comprehensive list of anti-kidney antibodies will spur research on the mechanisms of chronic kidney rejection. For example, the study establishes for the first time what part of the kidney causes the largest immune response after transplant.

"To our great surprise, the most immunogenic region of the kidney is the renal pelvis," Sarwal said. The renal pelvis is the cavity deep inside the organ that collects urine and funnels it toward the bladder. The next-largest immune responses were observed at the cortex and glomerulus, regions of the kidney with large blood supplies and extensive exposure to the recipient's immune system. The next step in understanding chronic organ rejection will be to identify which specific anti-kidney antibodies are the most reliable harbingers of renal malfunction, Sarwal said.

"If we can correlate these antibodies with clinical events in the organ, we'll have the tools to extend the life of kidney transplants," Sarwal concluded.

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Your generosity can save up to eight lives with heart, kidneys, liver, lungs, pancreas and small intestine transplants. One tissue donor can help up to 100 other people by donating skin, corneas, bone, tendon, ligaments and heart valves