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Crossing Disciplines

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Evolving now for more than half a century, the Benaroya Research Institute at the Virginia Mason Research Center in Seattle was formed in 1956 and then reconstituted itself in 2002 as a center for interdisciplinary and translational medicine. When Director Gerald Nepom came on board in 1985, his idea was prescient: to build it with a "more modern molecular and cellular focus on medicine," Nepom says. While the institute initially focused on immunology and diabetes research, Nepom says it became obvious that the area of autoimmune diseases had become very broad, spanning transplantation, asthma, allergy, inflammation, as well as classic autoimmune disorders like arthritis, diabetes, MS, and lupus. "I guess [the decision to change] was, you could say, driven by the acquisition of scientific knowledge that spurred our thinking that this is really a very broad area that needs an approach that crosses disciplines," Nepom says.

Now Benaroya is a translational immunology center that includes research into the molecular biology and genetics of immune diseases, development of novel and high-throughput ways to study this, and multiple phase I and II clinical trials of new diagnostic tools and therapies. "What's different about us compared to a lot of other immunology places is that we are all under one roof," Nepom says. "All of this is tied together through a series of translational core technologies and laboratories."

Nepom's work revolves around studying the four stages of immune response, which consist of immune cell development, expansion in the circulation, activation at the site of immune stimulation, and counter-regulation that turns the system off at the right time. "What we try to do is figure out how to develop technologies that will measure the activity level at all four stages," he says. "It has major implications for when you treat and what type of immunotherapy is used."

Better transplants

Benaroya's Brad Stone started 10 years ago as a postdoc at the institute and now heads his own lab studying minor histocompatibility antigens in bone marrow transplants. He combines genotyping and bioinformatic analysis to predict how donor T cells will respond to novel recipient antigens and whether the recipient will accept or reject the transplant, also known respectively as graft-versus-leukemia and graft-versus-host-disease.

The major and minor histocompatibility complexes are genes that make proteins that present antigens, either foreign or not, to T cells. These genes are highly polymorphic, and T cells have learned to ignore self-peptides and react to foreign antigens. Between two people, the minor histocompatibility genes have many normally occurring polymorphisms that result in a different set of peptide antigens — some of these will be recognized by T cells from donor tissue as foreign. Most of the polymorphisms are either nonsynonymous SNPs or coding deletion polymorphisms.

"In the first generation of my work, I would use off-the-shelf SNP chips and genotype donors and recipients and compare those genotypes," Stone says. "The goal is to list those alleles unique to the recipient because that defines the protein polymorphisms that the donor T cells have not been tolerized against." After considering what he would do with that information, Stone developed a high-throughput T-cell assay that will tell him which of these polymorphisms will be targeted after the transplant. "The idea that is that it is an unbiased approach, so these SNPs could've occurred in any gene — they could be expressed exclusively in tissues that are targets of graft-versus-host-disease or they could be ubiquitously expressed," he says. "There's basically no bias there as far as tissue expression profile."

His method aims to take some of the uncertainty out of transplantation, in terms of possibility and probability of rejection. Because it's really "sort of a crapshoot for the recipient, the overall goal is to map responses in multiple transplants, and see if there is a hierarchy of minor histocompatibility antigens," Stone says. "Certain types of leukemia … can actually be cured by a bone marrow transplant, and the graft-versus-leukemia response plays a significant role in those patients that are cured. But the flipside is that they risk severe graft-versus-host-disease. Both are caused by T cells from the donor, and both are responding to these polymorphisms that are unique to the recipient."

The first application of his high-throughput T-cell assay would be as a prognostic, for use as a biomarker in the sense of a clinician being able to predict graft-versus-host-disease and be able to, for example, increase immunosuppressive therapy early in the course of the transplant. The longer-term goal is as a therapeutic — the idea is to identify a subset of minor histocompatibility antigens that are only targeted in the graft-versus-leukemia response and "modify the transplant such that we promote the response to the minor [histocompatibility complex] that gives you the benefits that eradicate your cancer, but don't cause a problem in terms of graft-versus-host-disease," Stone says.

Stone thinks that having everybody in one building makes the atmosphere very collegial. What he calls an open-door policy at Benaroya has resulted in several current collaborations, including one with Jane Buckner, director of the translational research program there. He and Buckner are taking genotyping data to find alleles unique to the donor, and then are trying to develop T regulatory cells specific for the donor tissue. "The idea is to use T-reg cells to shut down rejection of that organ," Stone says. In another collaboration with Jay Shendure at the University of Washington, he's just submitted a grant to work on whole exome sequencing of donors and recipients in order to get much more comprehensive lists of all disparate protein polymorphisms. Stone predicts that instead of the 50 percent of polymorphisms that microarrays can find, sequencing will be able to find 95 percent of all nonsynonymous disparities, including frequent SNPs, rare SNPs, and completely unknown SNPs.

Future focus

Benaroya has been at the forefront of probing early-stage immune response for the past decade. Researchers there have developed probes that are now widely used to monitor immune response and to figure out whether the immune system has been activated. Their antigen-specific multi-mer probes can identify and quantify immune cell response. The multi-mer consists of a peptide antigen (which is the immune target and normally is presented to T cells by the MHC protein) bound to an MHC molecule bound in turn to a fluorescent probe. When mixed with blood, the multi-mer acts as a "fluorescent surrogate of the target that T lymphocytes ordinarily see," Nepom says. Typically, he says, the frequency of any antigen-specific T cell in an autoimmune disease is between one in 100,000 and one in 200,000 — that is, too rare to visualize with conventional technologies. In the future, Nepom says the goal is to be able to use the probes for early detection of disease, allowing a clinician to ask, "Is this somebody who's developing a pro-inflammatory phenotype that's predictive of disease, or do they have a regulatory phenotype that indicates that things are under control?"


Benaroya Research Institute

Seattle, Washington
Director: Gerald Nepom
Established: 1956, renamed in 2002
Facility: Located in a single building across the street from the Virginia Mason Research Center; academically affiliated with the University of Washington School of Medicine
Staff: 220 employees
Funding: $24 million a year research volume, local philanthropic gifts
Focus: Basic and translational research of autoimmune diseases
Core labs: Labs for Sanger sequencing, microarrays, flow cytometry, imaging, and histopathology

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