Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Predicting the storm: Can computer models improve stem cell transplantation?

05.12.2014

Massey scientists seek to improve stem cell transplant outcomes through computer modeling of next generation sequencing data

Is the human immune system similar to the weather, a seemingly random yet dynamical system that can be modeled based on past conditions to predict future states? Scientists at VCU Massey Cancer Center's award-winning Bone Marrow Transplant (BMT) Program believe it is, and they recently published several studies that support the possibility of using next-generation DNA sequencing and mathematical modeling to not only understand the variability observed in clinical outcomes of stem cell transplantation, but also to provide a theoretical framework to make transplantation a possibility for more patients who do not have a related donor.

Despite efforts to match patients with genetically similar donors, it is still nearly impossible to predict whether a stem cell transplant recipient will develop potentially fatal graft-versus-host disease (GVHD), a condition where the donor's immune system attacks the recipient's body.

Two studies recently published by the online journal Frontiers in Immunology explored data obtained from the whole exome sequencing of nine donor-recipient pairs (DRPs) and found that it could be possible to predict which patients are at greatest risk for developing GVHD and, therefore, in the future tailor immune suppression therapies to possibly improve clinical outcomes. The data provides evidence that the way a patient's immune system rebuilds itself following stem cell transplantation is representative of a dynamical system, a system in which the current state determines what future state will follow.

"The immune system seems chaotic, but that is because there are so many variables involved," says Amir Toor, M.D., member of the Developmental Therapeutics research program at Massey and associate professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine. "We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor's immune system will graft to a patient."

Toor's first study revealed a large and previously unmeasured potential for developing GVHD for which the conventional approach used for matching DRPs does not account. The conventional approach for donor-recipient compatibility determination uses human leucocyte antigen (HLA) testing. HLA refers to the genes that encode for proteins on the surface of cells that are responsible for regulating the immune system. HLA testing seeks to match DRPs who have similar HLA makeup.

Specifically, Toor and his colleagues used whole exome sequencing to examine variation in minor histocompatibility antigens (mHA) of transplant DRPs. These mHA are protein fragments presented on the HLA molecules, which are the receptors on cells' surface to which these fragments of degraded proteins from within a cell bind in order to promote an immune response. Using advanced computer-based analysis, the researchers examined potential interactions between the mHA and HLA and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.

These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients experience none remains a mystery. This seeming paradox is explained in a companion paper, also published in the journal Frontiers in Immunology. In this manuscript, the team suggests that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplantation, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.

Following stem cell transplantation, a patient begins the process of rebuilding their T-cell repertoire. T cells are a family of immune system cells that keep the body healthy by identifying and launching attacks against pathogens such as bacteria, viruses or cancer. T cells have small receptors that recognize antigens. As they encounter foreign antigens, they create thousands of clones that can later be called upon to guard against the specific pathogen that presented the antigen. Over the course of a person's life, they will develop millions of these clonal families, which make up their T-cell repertoire and protect them against the many threats that exist in the environment.

This critical period where the patient rebuilds their immune system was the focus of the researchers' efforts. In previous research, Toor and his colleagues discovered a fractal pattern in the DNA of recipients' T-cell repertoires. Fractals are self-similar patterns that repeat themselves at every scale. Based on their data, the researchers believe that the presentation of minor histocompatability antigens following transplantation helps shape the development of T-cell clonal families. Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is backed by data from clinical studies that show immune suppression soon after transplantation improves outcomes in unrelated DRPs.

The researchers suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient's future risk of GVHD.

"Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants. The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach," says Toor. "We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients."

Toor collaborated on these studies with Michael C. Neale, Ph.D., professor in the Department of Psychiatry at the VCU School of Medicine; Gregory A. Buck, Ph.D., a Massey research member and director of the Center for the Study of Biological Complexity at VCU Life Sciences; Masoud H. Manjili, D.V.M., Ph.D., member of the Cancer Cell Signaling research program at Massey and associate professor in the Department of Microbiology and Immunology at the VCU School of Medicine; Roy T. Sabo, Ph.D., member of the Developmental Therapeutics research program at Massey and associate professor in the Department of Biostatistics at the VCU School of Medicine; Michael L. Hess, M.D., professor of cardiology and physiology in the VCU Pauley Heart Center; Max Jameson-Lee, Ph.D., from the Department of Internal Medicine at the VCU School of Medicine; Catherine H. Roberts, Ph.D., Allison F. Scalora, Salman Salman, and Phil Griffith from the Massey Bone Marrow Transplant Program; Michael Batalo, a fellow in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine; Jeremy Meier, VCU M.D./Ph.D. student; Jared D. Kobulnicky, M.D., resident in the Department of Internal Medicine at the VCU Medical Center; Vishal N. Koparde, postdoctoral researcher in the Institute for Structural Biology and Drug Discovery at the VCU School of Medicine; and Myrna G. Serrano, Ph.D., Nihar U. Sheth, M.S., and Juliana K. Sampson, all from the Center for Biological Complexity at VCU Life Sciences; John M. McCarty, M.D., medical director of the Bone Marrow Transplant Program and member of the Developmental Therapeutics research program at Massey and professor in the VCU Division of Hematology, Oncology and Palliative Care; Harold Chung, M.D., associate professor in the VCU Division of Hematology, Oncology and Palliative Care; and William B. Clark, M.D., assistant professor in the VCU Division of Hematology, Oncology and Palliative Care.

These studies were supported by Virginia's Commonwealth Health Research Board Award #236-11-13, Massey pilot project grant JUP11-0.9 and, in part, by Massey's NIH-NCI Cancer Center Support Grant P30 CA016059.The authors also gratefully acknowledge Jamie Teer, Ph.D., at the Moffitt Cancer Center for his helpful suggestions in determining peptide sequence from exome sequence variation.

The full manuscripts of these studies are available at: http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00529/abstract  and http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00613/abstract

News directors: Broadcast access to VCU Massey Cancer Center experts is available through VideoLink ReadyCam. ReadyCam transmits video and audio via fiber optics through a system that is routed to your newsroom. To schedule a live or taped interview, contact John Wallace, (804) 628-1550.


About VCU Massey Cancer Center

VCU Massey Cancer Center is one of only 68 National Cancer Institute-designated institutions in the country that leads and shapes America's cancer research efforts. Working with all kinds of cancers, Massey conducts basic science, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It offers one of the largest selections of cancer clinical trials in Virginia and serves patients at multiple sites throughout the state. Its 1,000-plus researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately cure cancer. Visit Massey online at massey.vcu.edu or call 877-4-MASSEY for more information.

About VCU and the VCU Medical Center

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see http://www.vcu.edu

John Wallace | EurekAlert!

More articles from Life Sciences:

nachricht Bacteria as pacemaker for the intestine
22.11.2017 | Christian-Albrechts-Universität zu Kiel

nachricht Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Corporate coworking as a driver of innovation

22.11.2017 | Business and Finance

PPPL scientists deliver new high-resolution diagnostic to national laser facility

22.11.2017 | Physics and Astronomy

Quantum optics allows us to abandon expensive lasers in spectroscopy

22.11.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>