The AJT Report: News and issues that affect organ and tissue transplantation
Who do you think you are? Microbes in humans outnumber human cells 10 to one, and “The AJT Report” looks at their potential impact on transplant outcomes. Also in this month's issue, the 2012 Lasker-DeBakey prize is awarded to two surgeon-scientists who developed safe liver transplantation, Sir Roy Calne and Thomas Starzl.
The microbiome is the collective descriptor used to encompass all microorganisms that co-exist within an individual. Several large studies focused on the microbiome are recently completed or under way—the five-year National Institutes of Health (NIH)-funded Human Microbiome Project and the European Commission's Metagenomics of the Human Intestinal Tract project (MetaHIT) are two large ones. It's known that humans are composites of microbial and human cells, with the former outnumbering the latter 10 to one. MetaHIT data have shown that a higher degree of microbe biodiversity is positively correlated with good health, while low diversity is associated with poor health.
With an increased understanding of microbial populations and dysbiosis (the imbalance of microbes) in the human body, transplant scientists may one day be able to better anticipate a patient's response to immunosuppression and their allograft. But we’re still in the very early stages of research and treatment.
Fecal Microbiome Transplantation
The idea of microbiomics is equal parts old and completely new. During the last 50 years, physicians in Australia, Europe and North America have performed fecal microbiota transplants, whereby strained feces from a healthy donor are injected into a patient's GI tract, with a goal of replacing imbalanced microbiota with healthy specimens.
In recent years, in response to an epidemic of Clostridium difficile (C. diff) infection, fecal microbiome transplantation (FMT) has been more widely used, with a success rate higher than 90%.1 At Montefore Medical Center in New York City, for example, gastroenterologist Lawrence Brandt, MD, considered one of the leaders in fecal transplants, has performed 125 FMTs, including one on a solid-organ transplant patient who had developed C. diff’s characteristic chronic diarrhea. Last October, at the American College of Gastroenterology's annual meeting, investigators presented studies on FMT for C. diff and infammatory bowel disease. In St. Louis, Washington University's Jeffrey I. Gordon, MD, is looking at an imbalance of microbiota as a contributing factor in obesity.
Jay Varkey, MD, director of Emory University's Antimicrobial Management Program in Atlanta, says his team uses FMT for C. diff patients but hopes to offer it for other diseases. “Understanding the relationship between those bacteria and different disease states is absolutely fascinating,” he says. “In a couple of places — the University of Minnesota and the Center for Digestive Diseases, Sydney, Australia, for example—they are identifying universal donors who have been tested extensively for communicable diseases and who are thought to be healthy.”
These are examples of how we’re starting to understand the implications of and the symbiosis between populations of microbes and the human body, says Thomas Fishbein, MD, executive director of the Georgetown Transplant Institute in Washington, D.C.
- • Many researchers are now studying microbiota, including how they relate to transplantation.
- • Transplantation and its required immunosuppression have potential to profoundly alter the microbiome.
- • Microbiota, through their influence on immune activation and the prevalence of pathogens, have the potential to significantly impact transplantation outcomes.
The Potential of microbiota in Transplantation
“Like any new feld, when you look at the history, we know a lot about microbiota already,” says Daniel Salomon, MD, program medical director for the Scripps Center for Organ Transplantation at The Scripps Research Institute in La Jolla, Calif. For example, he says, “We know that the mucosal and external surfaces of the body contain these incredibly complex living microbiome populations. But the new question is—why are they there?”
In this new, broader view, “it's important that we don't go down a rabbit hole where transplantation is some amazing and unique battleground of the microbiome,” he says. “If it's a unifying new component of our thinking about health and disease, as I believe, it's going to be just as important to transplantation as to diabetes, obesity, infammatory bowel disease, etc.”
With recent advances in technology, more groups are studying microbiota, including how they relate to transplantation. Importantly, transplantation represents a profound alteration to the microbiome. “That alteration could be very dynamic, given our current drug regimens, because what's going on in the first three months post-transplant is very different from what's going on in the next nine months, or three to fve years later,” says Dr. Salomon.
Among those who’ve studied microbiota in transplantation is Dr. Fishbein's team, who found in 2009 that posttransplant microbial communities in the gut were dominated by lactobacilli and enterobacteria, which is an inversion of the normal community dominated by Bacteroides organisms and Clostridia.2
A small bowel transplant study that followed the Fishbein study was published in the American Journal of Transplantation this year.3 The authors found that during episodes of rejection, certain microbiota were signifcantly decreased while others were signifcantly increased. Conceivably, this might be a potential diagnostic tool, but “future studies should investigate if the dysbiosis that we observed is a cause or a consequence of the rejection process,” the authors noted.
One of the paper's authors, Daniel A. Peterson, MD, PhD, a clinical pathologist with Johns Hopkins University School of Medicine in Baltimore, says that the potential might be “to use the microbiota the same way we use a potassium level to follow kidney disease.” However, to move microbiota studies from science to clinical applications, “we need to develop an assay that can provide a diagnosis with the specifcity and sensitivity of pyrosequencing, so that physicians have meaningful results in a day or less,” he says.
Microbiota and Specifc Organs
Dr. Fishbein notes that the parts of the body most in contact with the outside world—the gastrointestinal tract, the respiratory tract and the skin—are more likely to be exposed to microbes than are organs such as the heart, kidney and liver. As it turns out, the intestine, lung and skin are also the organs most likely to be rejected, he says. “The immunogenicity of those three organs is very high. There is something that is allowing the ecology of those organs to live harmoniously in one person (the donor), but they become disruptive when you transplant them to someone else.”
Alternately, Dr. Salomon and his group have found that the infuence of microbiota is not limited to lungs, skin and gut. “Our two recent papers study chronic kidney transplant rejection, where focal B cells are often found,” he says. “The presence of B-cell clusters in chronically injured tissue raises a lot of questions as to why they are there and what they are doing. The answers have eluded us. Although it would make sense that these B cells are making anti-donor HLA antibodies, we showed they are not. These infltrates in patients with chronic rejection, at least according to our new work, are making antibodies that recognize E. coli lipopolysaccharide endotoxin.”4,5
“It was startling,” he adds. “It begged the question of whether or not this was the intersection of chronic rejection in transplantation immunology with the microbiome of the genitourinary tract. And that is directing the work that we’re doing now.”
Where is the lipopolysaccharide coming from?“I don't know yet,” says Dr. Salomon, “but my hypothesis is that it's stimulating B cells in these chronically rejecting kidneys through tolllike receptor 4, and that this chronic stimulation is one mechanism of tissue injury and immune activation.”
Meanwhile, those interviewed for this article agreed that the potential importance of microbiota and how they impact transplant outcomes is huge. “Most likely, in the future, we’ll understand what the signature of acceptance is versus the signature of the microbiome of failure,” says Dr. Fishbein. His group is currently in the fnal stages of an NIH grant application for a multicenter collaborative to study the microbiome, the genome, the metabolome and metabolic pathways that are active as a result of certain organisms, from the time of transplant to transplant outcomes.
ROY Y. CALNE AND THOMAS E. STARZL WIN LASKER AWARD FOR CLINICAL RESEARCH
THE 2012 LASKER-DEBAKEY CLINICAL Medical Research Award has been awarded by the Albert and Mary Lasker Foundation to Roy Y. Calne, FRS, emeritus professor of surgery at the University of Cambridge, and to Thomas E. Starzl, MD, PhD, professor of surgery at the University of Pittsburgh, two scientists who independently developed safe liver transplantation. The two share a $250,000 award that was presented Sept. 21 in new york City.
According to the Lasker Foundation, “Calne and Starzl persevered on a bold course against a backdrop of doubt. By following glints of hope, they have brought new life to thousands of individuals.”
Dr. Starzl performed the world's frst successful liver transplant in 1967 and Dr. Calne did the frst european liver transplant in 1968. Prior to the procedures, both worked on immunosuppression protocols. Dr. Calne deployed a drug, 6-mercaptopurine, in 1960 with canine kidney recipients, and then obtained better results with azathioprine (Imuran), a chemical relative of 6-mercaptopurine. Dr. Starzl also tried azathioprine and then added prednisone. In further improvements, Dr. Starzl used an antibody, anti-lymphocyte globulin (ALG), that restrains rejection and demonstrated that portal-vein blood contains substances that keep livers healthy.
In his early transplants, Dr. Starzl treated patients with three drugs: azathioprine, steroids and ALG. In the 1970s, Dr. Calne pioneered cyclosporine A, which Dr. Starzl then showed could be less toxic when combined with prednisone. In 1989, Dr. Starzl introduced FK506 (tacrolimus), which gained fast-track U.S. FDA approval in november 1993. Dr. Calne added rapamycin, a chemical that resembles FK506 structurally, but has a different mechanism of action and toxicity profle. He also pioneered the use of alemtuzumab (Campath) in organ transplantation.