Emory Medicine, Winter 1999

 
True Tolerance Ahead lies the possibility of finally reaching the holy grail of transplantation science: the creation of 'tolerance' in the transplant recipient so that the transplanted organ is accepted and drug-induced immunosuppression becomes unnecessary.




Larsen and Pearson believe their clinical work enhances their research. "When answering questions of basic immunology, it helps to have in the back of one's mind that these answers must benefit the patient within a reasonable period," Pearson says.


by Susan M. Carini

In South Carolina, in 1995, a drunk driver did more than cause serious injury to a 30-year-old man: that driver also created a repeat customer for Christian Larsen, 84M, and Thomas C. Pearson, 82M, a celebrated team of Emory transplantation researchers/surgeons.

When the man first came to them with kidney failure, Larsen and Pearson performed his kidney/pancreas transplant. Eighteen months after his operation, the accident occurred, damaging his kidney irreparably. His sister provided the storybook ending a year later by donating one of her own kidneys.

No one, of course, can guard against an accident. However, Larsen and Pearson are doing all that they can, through groundbreaking research, to help their more common repeat customers: those patients whose bodies have wreaked havoc with their transplants, ending in rejection.

Larsen explains, "The average amount of time that a transplant maintains its functionality is eight years. That sounds like a pretty fair duration until you get a 30-year-old patient with a failed transplant." In the case of a 17-year-old patient, suggests Pearson, "you wonder how many transplants it will take to get this person to an average life expectancy." Doing a second transplant on the same patient constitutes about 10% of the surgeries that the two do every year.

To avoid repeating the hard work that they do as surgeons, Larsen and Pearson have used their training at Oxford University - where they both received a doctorate in transplantation immunology in 1990 - to set up an ambitious laboratory at Emory, one designed to work toward the elimination of both acute and chronic rejection. If the system that they are developing is perfected in primates, it can and will be moved into humans, thus providing solutions to shortages of human organs as well as the devastating side effects of chronic immunosuppression.

Beyond the transplant patients, whose lives of struggle they know so well, Larsen and Pearson eventually may provide relief for the many people who battle autoimmune disorders. Jonathan Bromberg, professor of surgery, microbiology, and immunology at the University of Michigan, sees broad applications for Larsen's and Pearson's research. "The work that they do is good and real," he says. "Indeed, it might constitute the next decisive stage in transplant research. Moreover, their work may eventually be of use in treating autoimmune diseases, which involve a larger population than that of transplant patients."

The Waiting List Grows


Marguerite Fugazzi Mason died in January 1991, leaving the bulk of her estate to the Carlos and Marguerite Mason Trust, valued at approximately $60 million. The Mason Trust is believed to be unique in the United States, with its primary purpose being to improve the process of organ transplantation for Georgians through the making of grants - up to $3 million a year - to nonprofit Georgia organizations associated with the transplantation process. When Mrs. Mason wrote her will in 1979, transplantation was still in its infancy. Yet she seemed to understand that it would grow, affecting many thousands of patients.

The statistics in transplantation alone, however, emphasize the critical necessity of the mission of Larsen and Pearson. The number of people on organ donation waiting lists has increased by almost 40,000 since 1978. One reason for this increase is that the number of persons willing to donate has failed to rise at the same rate as those in need of donation. Currently, organs for transplant are in short supply: almost 4,000 Americans die each year while waiting for a donor.

Emory University Hospital and Egleston Children's Hospital offer Georgia's only liver, lung, and heart-lung transplant programs and the largest heart, pancreas, and kidney transplant programs in the state. Of the surgeries in which Larsen and Pearson are most commonly involved - kidney and kidney/pancreas - there have been 682 and 57, respectively, at Emory Hospital since 1994. A growing number of patients receive their transplants at Emory.

Relatively few transplantations were performed in this country until success in this field became notable in the early to mid 1980s, with development of new immunosuppression drugs. Emory's history with transplantation is similar, according to Larsen. "It stayed a small program because that was the trend," he says. "The results didn't really warrant it to be bigger."

This modest program endured until 1986, when the university recruited John Whelchel, currently the Livingston Professor of Surgery at Emory. Whelchel emphasized cadaveric donation and, says Larsen, "developed a program that made organ donation work in Georgia. Almost instantly, the Emory University Hospital program went from about 40 transplants yearly to its present pace of about 250 a year."

Whelchel has played a key role in the maturation of the work of Pearson and Larsen. Despite Whelchel's own training - they call him a "clinician's clinician" - he saw a tremendous value in progress through research. Says Whelchel, "I have devoted my career to building a strong clinical transplantation program. At the same time, I have learned that the cornerstone of clinical transplantation is a strong research program."

A Beastly Lot of Work, Creating Chimeras




Researcher Fadi Lakkis at the Atlanta Veterans Affairs Medical Center is looking at whether interleukin-4 is important in modulating transplant rejection, using genetically engineered mice who do not produce this cytokine.

The science that Larsen and Pearson are pursuing starts with a very basic premise: the methods of immunosuppression that are available to clinicians for transplant use are good but imperfect. There is still a problem with both acute and chronic rejection. Moreover, use of immunosuppressive drugs means that infections and various forms of cancer are more likely in the patients receiving them.

The goal of the lab created by Larsen and Pearson is to find strategies to induce tolerance. They want the body to accept the transplanted organ as self but also to respond normally to any untoward occurrences, whether that be the presence of a virus or a cell going bad.

Some of their previous work - and that of many other researchers - has been with T-lymphocytes, which become activated in the presence of any foreign body. T cells also receive other signals - a process that is known as costimulation. It became clear - in work that the doctors were doing throughout 1991 and 1992 - that if one could block costimulation, one could prevent rejection by, in effect, paralyzing the T cell. Scientists would, of course, choose to block only the T cells that were activated in response to an organ transplant; the other host of T cells would be left intact. The two pathways that were established as being crucial to transplantation were CD28 and CD40.

The other major cornerstone of their research is based on "chimerism." The biologic chimera, in which tissues or cells of one organism happily coexist with those of another, corresponds to the mythological chimera, formed by the commingling of a lion, goat, and snake.

Larsen and Pearson are interested specifically in hematopoietic chimerism, or the stable coexistence of self and foreign hematopoietic cells. For instance, if a mouse is lethally irradiated, then "saved" by receiving a bone marrow transplant from both an identical twin and another donor, then the mouse will recover, becoming robustly tolerant to that other donor for life because his body will view that other donor as self. This scenario is what is known as a mixed chimera. However, as Larsen points out, "This set of steps is terribly unappealing for human applications." He nonetheless finds the concept - that the underpinning of chimerism is necessary to establish stable tolerance - "incredibly exciting."

Larsen and Pearson are trying to devise ways to take advantage of this finding without the necessity of conditioning human recipients in the same way. One way around this dilemma is to use costimulation blockade to allow transfer of the donor's bone marrow at the same time as the organ transplant, in essence establishing a partial chimera. Exciting as this finding is - and it has progressed to the point of testing in primates - Larsen acknowledges that "we don't have all the answers yet. We still have a lot of work to do, given that there is costimulation blockade-resistant rejection." Conceptually, though, they believe that costimulation blockade can be used or harnessed to protect the bone marrow transplant, and that such is the nucleus of tolerance induction.

Both men acknowledge that they have been "incredibly lucky" - that even a great scientist can spend an entire career without "bringing a single thing to clinic." In their field, movement has been rapid, going from what Pearson calls "unknown molecules to clinical trials in eight years." As recently as when both men were studying at Oxford, neither CD28 nor CD40 were recognized as important molecules in transplantation.

Finding a Good Match at Emory

An ALTA tennis player and kidney/pancreas recipient, Joanne Barrett has dedicated herself to helping other patients through the transplant process.

The research of Larsen and Pearson has become so well respected that Oxford University - which has one of the more prestigious programs internationally in transplantation - recently attempted to recruit them. The program is headed by Peter Morris, who currently holds the Nuffield Chair of Surgery at Oxford, the most acclaimed surgery chair in Europe. Morris will be stepping down in three years and had promised his post to Larsen. "The opportunity to take the reigns of his program was really exciting," says Larsen. "It was the most difficult no I've ever had to say."

Good as the Oxford offer was, there are better funding opportunities in the United States. "The opportunity at Emory in particular," says Larsen, "is about the most exciting anyplace, especially in terms of clinical base and resources." Gifts totaling $3.5 million this past year from the Mason Trust were not the first from this organization, which has funded Larsen's and Pearson's work since 1995.

The current money provided by the Mason Trust will help establish a Center for Transplantation Research that will complement the clinical transplantation programs at Emory. The plan is to build on existing collaborations between Larsen and Pearson, who represent the Department of Surgery, and the renal division, represented by James Tumlin and Fadi Lakkis. The researchers will be (a) investigating biochemical actions of antirejection drugs to reduce toxicity and improve efficacy, and (b) exploring cellular mechanisms leading to rejection of a transplanted organ.

Such collaborative research has attracted public funding as well. In fact, Pearson and Larsen recently received notification of a five-year NIH program project grant totaling $7.5 million. This grant supports their transplant research as well as collaborative work relative to broader issues in immunology, including, among others, that of Georgia Research Alliance Eminent Scholar Rafi Ahmed in Emory's vaccine center.

Partners



Their names usually mentioned in the same breath, Larsen and Pearson manage to personify the spirit of chimerism. They've been performing transplant surgery together since 1991. "We don't talk all that much during surgery," says Larsen, "yet we silently are able to hand over instruments, and one of us can finish, say, an anastomosis that the other started."

Asked what the principal ingredient of their partnership is, both Larsen and Pearson had the same response: "We need each other." In a BBC interview several years ago, they surprised the interview crew by finishing one another's sentences. This same blending of selves is apparent in the operating room. "We don't talk all that much," says Larsen, "yet we silently are able to hand over instruments, and one of us can finish, say, an anastomosis that the other had started."

It is often difficult for physicians to start up a lab, since their clinical responsibilities easily can prove overwhelming. "You cannot," says Pearson, "sit down to write a grant proposal when patients need you." On the flip side, when the work in the lab stalls, each man is there to offer the other the creative spark that is necessary to get a particular experiment back on track.

They alternate their clinical and lab duties by the month, although they find that the undertow often pulls them, unscheduled, to the opposite side. After rounds, one of them goes back to the clinic and one to the lab. Donor calls, however, often upset any regularity that this system may pretend to have. The doctors always do kidney/pancreas transplants together.

"When lab and clinic go badly on a particular day," says Larsen, "it's awful. When they both go well, there is nothing quite like it."

The Mason gift already is becoming a force for change, even though it is only a few months' old. Larsen anticipates that the chair of the Center for Transplantation Research will start in the next couple of years. The physical space already has begun expanding and will continue to do so. In addition, the doctors want to bring in two or three, as they phrase it, "brilliant young scientists" to complement what they do. "Once you have assembled a group of people who are incredibly talented and who are doing things you would never have thought possible, you want to stick around. And we do," Larsen says.


Susan M. Carini is associate director of Emory University's Publications office.

 


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