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A newly published paper in The Lancet shows that an experimental vaccine against Marburg virus (MARV) was safe and induced an immune response in a small, first-in-human clinical trial. The vaccine, developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, could someday be an important tool to respond to Marburg virus outbreaks.
This first-in-human, Phase 1 study tested an experimental MARV vaccine candidate, known as cAd3-Marburg, which was developed at NIAID’s Vaccine Research Center (VRC). This vaccine uses a modified chimpanzee adenovirus called cAd3, which can no longer replicate or infect cells, and displays a glycoprotein found on the surface of MARV to induce immune responses against the virus. The cAd3 vaccine platform demonstrated a good safety profile in prior clinical trials when used in investigational Ebola virus and Sudan virus vaccines developed by the VRC.
MARV, a filovirus in the same family as Ebola virus, causes a rapidly progressive febrile illness that leads to shock and death in a large proportion of infected individuals. Many scientists think that MARV disease outbreaks in humans begin by when the virus makes the jump from its primary animal host, which is likely to be certain chronically infected bats in sub-Saharan Africa. The symptoms of MARV disease are akin to those seen with Ebola virus disease and can include fever, headache, chills, rash, abdominal pain, vomiting, and diarrhea. As the disease progresses, patients may suffer from multiple organ dysfunction, delirium, and significant bleeding from the gastrointestinal tract or other sites that may result in death. No approved vaccines or specific therapies are available for MARV disease, aside from supportive care. While some experimental vaccines have previously been tested, none have proven to be both highly effective and to provide durable protection. In areas of Africa where a vaccine for Marburg is most needed, a single-dose vaccine that could protect recipients over a long period of time would be a crucial part of quelling outbreaks.
In this study, 40 healthy adult volunteers were enrolled at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, Maryland. They received a single dose of either a low dose of the vaccine (1×1010 particle units) or a higher dose (1×1011 particle units). For safety, the volunteers were enrolled in a dose-escalation plan. Three participants received the lower dose. Then, when they did not exhibit severe adverse reactions after the first seven days, the trial proceeded to enroll the remaining 17 volunteers. The same procedure was also used for the higher dose group. Volunteers were monitored for adverse reactions to the investigational vaccine and evaluated at regular intervals for 48 weeks to track their immune responses.
The trial’s safety results were encouraging: There were no serious adverse events, and the experimental vaccine was well-tolerated. One participant in the higher dose group developed a fever following vaccination, but it resolved by the following day. In addition, the investigational vaccine appeared to induce strong, long-lasting immunity to the MARV glycoprotein: 95% of participants in the trial exhibited a robust antibody response after vaccination, and 70% maintained that response for more than 48 weeks.
Plans are in place to conduct further trials of the cAd3-Marburg vaccine in Ghana, Kenya, Uganda, and the United States. If additional data supports the promising results seen in the Phase 1 trial, the cAd3-Marburg virus vaccine could someday be used in emergency responses to MARV outbreaks.

A team of researchers, led by Trisha L. Andrew, professor of chemistry and chemical engineering at the University of Massachusetts Amherst, recently announced that they have synthesized a new material that solves one of the most difficult problems in the quest to create wearable, unobtrusive sensitive sensors: the problem of pressure.
“Imagine comfortable clothing that would monitor your body’s movements and vital signs continuously, over long periods of time,” says Andrew. “Such clothing would give clinicians fine-grained details for remote detection of disease or physiological issues.” One way to get this information is with tiny electromechanical sensors that turn your body’s movements — such as the faint pulse you can feel when you place a hand on your chest — into electrical signals. But what happens when you receive a hug or take a nap lying on your stomach? “That increased pressure overwhelms the sensor, interrupting the flow of data, and so the sensor becomes useless for monitoring natural phenomena,” Andrew continues.
To solve this problem, the team developed a sensor that keeps working even when hugged, sat upon, leaned on or otherwise squished by everyday interactions. The secret, which was detailed in the journalAdvanced Materials Technologies, lies in vapor-printing clothing fabrics with piezoionic materials such as PEDOT-Cl (p-doped poly(3,4-ethylenedioxythiophene-chloride). With this method, even the smallest body movement, such as a heartbeat, leads to the redistribution of ions throughout the sensor. In other words, the fabric turns the mechanical motion of the body into an electrical signal, which can then be monitored.
Zohreh Homayounfar, lead author of the study and a graduate student at UMass Amherst, says that “this is the first fabric-based sensor allowing for real-time monitoring of sensitive target populations, from workers laboring in stressful industrial settings, to kids and rehabilitation patients.”
Of particular advantage is that this all-fabric sensor can be worn in comfortable, loose-fitting clothing rather than embedded in tight-fitting fabrics or stuck directly onto the skin. This makes it far easier for the sensors to gather long-term data, such as heartbeats, respiration, joint movement, vocalization, step counts and grip strength — a crucial health indicator that can help clinicians track everything from bone density to depression.
Andrew and her group will next use an array of the pressure sensors under additional scenarios to determine what other types of physiological signals can be extracted, and to what accuracy.

New Cornell research is providing a fresh view into the ways a common chemotherapy agent, etoposide, stalls and poisons the essential enzymes that allow cancer cells to flourish.
The findings, from the lab of Michelle Wang, the James Gilbert White Distinguished Professor of the Physical Sciences and Howard Hughes Medical Institute Investigator in the College of Arts and Sciences, will advance the study of a range of cancer inhibitors. The techniques developed by the group will also enable the creation of sensitive screening tools for identifying drug mechanisms that can improve patient treatment.
The group’s paper, “Etoposide Promotes DNA Loop Trapping and Barrier Formation by Topoisomerase II,” was published Jan. 30 in Nature Chemical Biology. The co-lead authors are research specialist Tung Le and postdoctoral researcher Meiling Wu.
For 40 years, etoposide has been a trusted chemotherapeutic for treating a variety of cancers. Etoposide succeeds by targeting Type IIA eukaryotic topoisomerases, enzymes — also known as topo IIs — that enable the replication of cancer cells.
At the center of that replication process are the long, entangled, helical coiled-strands of DNA. In order for cancer to spread, these strands need to be untangled, rotated and copied by motor proteins. Topo IIs are well-suited for the job. They perform an elaborate kind of rope trick that relaxes the supercoiled DNA by cutting it, very quickly passing another DNA strand through its middle, and then reconnecting the cut DNA back together. All of that is done without damaging the DNA’s delicate genetic structure — an incredible, and incredibly fast, feat of biology that happens in the body roughly 300 billion times a day.
Etoposide’s great virtue is that it can stabilize a DNA double-stranded break before anything is reconnected, and thereby prevents the cancer cell from replicating. However, the intricacies of how etoposide interacts with DNA’s structure have remained murky.

“We normally ask: What is the best way to study molecular machineries that take place on DNA?” Wang said. “To understand how those enzymes work, we want to mimic what might be happening in the cell. Motor proteins pull on the DNA or apply a force on the DNA. So we said, OK, we can apply a force and see what happens.”
Wang’s lab used three different single-molecule manipulation techniques to observe etoposide’s effect on three topo IIs, which were provided by collaborators led by professor James Berger of Johns Hopkins University: yeast topoisomerase II, human topoisomerase II alpha and human topoisomerase II beta.
“DNA topology, conceptually and in terms of torsional mechanical properties, is really hard for people to grasp,” Wang said. “There were very few ways to study it. But we happen to have just the right tools. And the reason we have the right tools is because for the last 20 years, we’ve been working on developing them. These tools and this problem just happened to converge at the right time.”
First, the researchers used optical tweezers to stretch DNA into various configurations, demonstrating how etoposide compacts, releases and breaks it, and creates DNA loops. This loop-trapping behavior surprised everyone as it revealed a new impact of etoposide that was not previously known. It implies that etoposide could promote topo II to significantly alter DNA structure and topology in vivo.
Then the team used optical tweezers to unzip double-stranded DNA into two single strands for high-resolution mapping of protein interactions with the DNA, and so mimicked the motor removal of a bound protein. The findings suggest that etoposide could convert topo II into a strong roadblock of DNA-processing machineries.

Their third technique is a version of magnetic tweezers in which they twisted DNA with a bound topo II and watched the topo II relax the DNA at a steady rate. When they added etoposide, they found the chemical staggered this pattern, introducing pauses that correlate with the trapping of supercoiled loops.
By capturing the different ways etoposide enhances these actions and interferes with topo II function, the researchers now have a quantitative system for characterizing how other topoisomerase drugs behave.
“I think this gives us a set of tools that would allow us to study many different kinds of topoisomerases and other kinds of drugs in a very comprehensive way,” Wang said. “Everything we do mimics what happens in vivo. We just do it in a mechanically controlled fashion. This is why it’s so powerful.”
Co-authors include doctoral student Neti Bhatt and research specialist James Inman; and James Berger and Joyce Lee of Johns Hopkins University School of Medicine.
The research was supported by the National Institutes of Health and the Howard Hughes Medical Institute.

A collaborative team from the Terasaki Institute for Biomedical Innovation (TIBI) has developed a contact lens prototype that is specifically designed to prevent contact lens-induced dry eye (CLIDE). The lens alleviates this condition by facilitating tear flow in response to normal eye blinking. This approach can relieve the discomfort, visual impairment, and risk of inflammation experienced by millions of contact lens users suffering from CLIDE.
Of the 140 million contact wearers worldwide, 30%-50% suffer from CLIDE. The problem arises from the insufficient flow of tears from the contact lens’s outer surface to the surface behind the lens. This leads to excessive tear evaporation and all the problems associated with CLIDE.
Current treatments for this condition include rewetting drops, gels, or lubricants, more frequent lens replacement, or changes in the lens material. There are also eyelid treatments, such as eyelid massage and warm compresses. In more severe cases, physical stimulation of the tear glands may be utilized, as well as the use of punctum plugs, devices inserted into tear ducts to block drainage. Efficacy varies among these treatments, however, there may also be potentially harmful accumulations of drugs in the body, and the non-user-friendly methods contribute to patient noncompliance.
There have also been previous attempts to use contact lenses in treating dry eye syndrome, such as graphene-coated lenses designed to minimize moisture loss and self-moisturizing lenses stimulated with metallic electrodes. But these methods are costly and impractical and may compromise patient safety and comfort.
The TIBI team’s approach uses a contact lens design that incorporates microchannels to facilitate tear flow movement and flow so that dry eye can be avoided. This flow can be achieved by pressure applied by normal eye blinking so that no external devices are needed.
In fabricating their contact lens prototype, the team utilized a time-saving method — their lens mold was made from a silicone polymer mixture; this allowed for easy removal of the lens cast on it by gently bending the mold. Previous methods necessitated a twelve-hour soak in hot water to remove the lens. The approach resulted in high-quality, smooth microchannels, as well as lenses that could be thirty times thinner than previous lenses. A custom device was used to fabricate reservoirs at the ends of each microchannel for the inflow and outflow of liquids.

Innovative techniques were also utilized when encapsulating the microchannels in a sandwich-like assembly under a capping lens layer. Initially, the preparation of the two lens surfaces for stronger bonding dehydrated the lenses, causing them to curl. This problem was solved by affixing the two lenses to holders using water-soluble glue. This served not only to enable a more uniform bonding of the lenses but protected them from damage as well.
After rigorously testing their encapsulated microchannel lenses for stability and leakage, the lenses were subjected to a series of experiments using a device that the team designed to simulate a blinking eyelid. This device was integrated with the lens prototype to create artificial eyelid pressure on the lens to stimulate tear flow.
After various experiments, a configuration that proved effective was microchannels with square cross-sections arrayed in a novel circular pattern on the lens surface; this was compatible with the function and curvature of the lens and allowed for optimum liquid flow.
The team demonstrated a proof-of-concept validation of their lens’ ability to guide tear flow originating from the lens surface to the underside of the lens to combat dry eye syndrome. The team quantified these flows and established that the flows were driven by low-pressure levels like those from normal eye blinking. Further experiments could be devised to test these lenses on animal models and in patients.
“The inventive methods that our team has employed bring a potential solution for millions of people,” said Ali Khademhosseini, TIBI’s Director and CEO. “It is the hope that we may extend our efforts to bring this solution to fruition.”
Authors are: Yangzhi Zhu,Elham Davoodi, Rohollah Nasiri,Shiming Zhang, Sourav Saha, Matthew Linn, Lu Jiang, Zhuohong Wu, Reihaneh Haghniaz, Jinjoo Kim, Marvin Mecwan, Heemin Kang, HanJun Kim, Vadim Jucaud, Mohsen Akbari, Anna Herland, Mehmet R. Dokmeci, Ehsan Toyserkani, Ali Khademhosseini.
This work was supported by Cooper Vision, Inc.

Researchers have developed a neural network model that uses terahertz time-domain spectroscopy (THz-TDS) data for non-invasive burn assessment. They combined the new approach with a handheld imaging device that they developed specifically for fast THz-TDS imaging of burn injuries.
“It is important for healthcare professionals to accurately assess the depth of a burn to provide the most appropriate treatment,” said research team leader M. Hassan Arbab from Stony Brook University. “However, current methods of burn depth evaluation, which rely on visual and tactile examination, have been shown to be unreliable, with accuracy rates hovering around 60-75%. Our new approach could potentially improve the accuracy of burn severity assessments and aid in treatment planning.”
THz-TDS uses short pulses of terahertz radiation to probe a sample. It is being examined for assessing burn injuries because physical changes caused by a burn will produce alterations in the skin’s terahertz reflectivity.
In the Optica Publishing Group journal Biomedical Optics Express, the researchers report the results showing that their artificial neural network classification algorithm can accurately predict the ultimate healing outcome of in vivo burns in an animal study with 93% accuracy. Compared to previous machine learning approaches used by the researchers, the new method reduces the amount of training data necessary by at least two orders of magnitude. This could make it more practical to process big data sets obtained over large clinical trials.
“In 2018, approximately 416,000 patients were treated for burn injuries in emergency departments in the United States alone,” said Arbab. “Our research has the potential to significantly improve burn healing outcomes by guiding surgical treatment plans, which could have a major impact on reducing the length of hospital stays and number of surgical procedures for skin grafting while also improving rehabilitation after injury.”
Better burn assessment
Various technologies have been developed to improve burn assessment, but they haven’t been widely adopted in the clinic due to drawbacks such as long acquisition times, high costs and limited penetration depth and field of view. Although THz-TDS looks promising for burn assessment, early demonstrations were limited to point spectroscopy measurements, which don’t account for burn heterogeneity and spatial variations. THz spectroscopy setups also tend to be bulky and expensive and require cumbersome optical alignments, making them impractical for clinical use in real-world settings.

“To address these challenges, we developed the portable handheld spectral reflection (PHASR) scanner, a user-friendly device for fast hyperspectral imaging of in vivo burn injuries using THz-TDS,” said Arbab. “This handheld device uses a dual-fiber-femtosecond laser with a center wavelength of 1560 nm and terahertz photoconductive antennas in a telecentric imaging configuration for the rapid imaging of a 37 x 27 mm2 field of view in just a few seconds.”
Previously, the researchers used numerical methods to extract features from the THz-TDS images and machine learning techniques to estimate the severity grade of in vivo burn injuries using measurements from the PHASR scanner. However, this approach did not consider the physical dynamics and macroscopic changes of the dielectric permittivity of burned skin tissue. Dielectric permittivity describes how a material responds to an electric field.
To investigate the mechanisms that change the complex dielectric function of skin burns in terahertz frequencies, the researchers turned to the double Debye theory, which has been successfully used to explain the interaction of THz radiation with various types of biological tissue.
Predicting severity and healing
“We developed a neural network model utilizing the five parameters obtained from fitting the double Debye model to the dielectric permittivity of burn injuries,” said Arbab. “This physics-based approach allows for the extraction of biomedical diagnostic markers from broadband THz pulses, reducing the dimensionality of THz data for training the artificial intelligence models and improving the efficiency of machine learning algorithms.”
The researchers tested their method by using the PHASR scanner to obtain spectroscopic images of skin burns and measure the permittivity of the burns. After determining the Debye parameters, the researchers used this data to create a neural network model based on labeled biopsies. The model estimated the severity of the burns with an average accuracy rate of 84.5% and predicted the outcome of the wound healing process with an accuracy rate of 93%.
The researchers note that clinical testing of both the technique and the handheld imaging device are needed before this technique could be integrated into the existing workflow of clinical burn assessment.
The research reported in this study was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM112693.

An innovative technique from Cornell University researchers finds seminal fluid protein transferred from male to female fruit flies during mating changes the expression of genes related to the fly’s circadian clock.
The finding, published in the Proceedings of the National Academy of Sciences, could help explain how this protein, called sex peptide, alters the female’s behavior.
Post-mating, sex peptide has been shown to elicit increased egg-laying, aggression, activity and feeding, while reducing sleep and interest in mating in previously unmated females.
“Flies like to eat at certain times of day,” said Mariana Wolfner, professor of molecular biology and genetics and one of the paper’s senior authors. “They sleep at certain times, and the circadian clock machinery controls when flies are likely to do these things.
“What we’re seeing,” she said, “is that these very same behaviors — such as sleeping and eating — are changed after mating by the sex peptide. One way it might do that is by basically shifting the whole clock of the fly.”
The surprising findings were made possible by examining transcriptomes — RNA sequencing that reveals gene expression, or which genes are turned on and off — at many different time points, providing high-resolution data that illuminates the order in which changes occur.
In the first four hours after mating, researchers found changes in expression of genes involved in the female fly’s metabolism and the circadian clock. It is unknown what triggered these initial changes, but pheromones or seminal fluid proteins other than sex peptide are possible candidates. The initial effects were short term; they didn’t last without sex peptide and seemed to prime the system.
In a second phase, four hours after mating, the researchers discovered that sex peptide caused changes to genes that regulate circadian rhythms and genes that are regulated by circadian clock pathways.
The study opens the door for future work that explores such questions as: how long the effect lasts and whether these effects occur in other organisms, given that circadian clock genes are highly conserved in many life forms.

Dogs are humans’ best friendsand it is always distressing for dog owners when their beloved pets contract terminal illnesses. Canine cancer is the leading cause of death in dogs and when they are diagnosed with late-stage or terminal illness, there are often no treatment options available. In a recent study, however, a novel form of chemoimmunotherapy has proven to be a promising treatment in altering the course of the dogs’ lives.
Scientists at the NUS Centre for Cancer Research (N2CR) Translational Research Programme (TRP) at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) used stem cell precision engineering technology to treat the cancer-stricken canines. In the study led by Associate Professor Too Heng-Phon from the N2CR TRP and Department of Biochemistry at NUS Medicine, the team modified Mesenchymal Stem Cells (MSCs), which are able to seek out cancerous tumours. These modified cells carry a potent ‘kill-switch’ (cytosine deaminase) that produces a high, localised concentration of a cancer killing drug (5-fluorouracil) in the tumour environment and subsequently induces anti-cancer immunity. The development of this therapy to treat canine patients leads the team toward a better understanding of cancer treatments, as well as its use in human patients, as helping dogs with naturally occurring cancers provides valuable clues about human cancers.
Assoc Prof Too said, “To repurpose stem cells for cancer treatment, it is usual to use viruses to introduce therapeutic genes into the cells. We have however, designed a non-viral gene delivery platform that introduces a high payload of therapeutic genes into the stem cells, to effectively destroy the out-of-control growing cancer cells. With this therapy that has been proven safe and demonstrated promising clinical benefits in animal patients, we hope to develop effective treatment options to help human patients with cancer as well, which can improve their health without compromising their quality of life.”
Application of the technology on canine cancer patients
The technology developed by the NUS Medicine team was first applied on canine patients in Singapore in 2018, in a collaboration with Dr Jean Paul Ly, Chief Executive Officer and Founder, Animal Wellness. The research team thereafter collaborated with more veterinary partners and institutions, delivered the therapy to a total of 65 dogs, as well as two cats, with conditions such as perianal adenoma, lung metastasis, and sarcoma. The patients first received the precision-engineered MSCs through direct tumour-site injections or through blood stream, followed by the ingestion of oral pills containing a drug commonly used to treat fungal infection (5-flucytosine), over a few days. After a week, the cycle was repeated for two more weeks before the first course of treatment was completed. The team then monitored the condition of the patients and repeated the course where necessary.
Among the animal patients which received the treatment over a duration ranging from three to eight weeks, 56 showed signs of positive response, including 14 which showed full recovery from the treatment. Two animal patients remain cancer free, at least 30 months post treatment, while 46 patients showed good quality of life over two to 32 months, with the treatment. Through the course of treatment on all the animal patients involved in the study, there were no significant side effects observed — possibly due to the localised presence of the therapeutic cells which remain within the tumour environment.

Despite significant advancements in human cancer treatments, there is a massive lag in the development of oncology therapies for animal patients comparatively. Up until 2009, all animals were treated with generic human chemotherapy medicines on an off-label basis as there were no animal-specific anti-cancer agents approved by the U.S. Food and Drug Administration (FDA). Dr Lee Yee Lin, Founder and Head Veterinarian, Gentle Oak Veterinary Clinic in Singapore, who the research team collaborated with and is one of the authors of the study said, “Therapies and advances in allopathic medicine are usually developed primarily for humans, before they are applied to animals. As part of the trials for this study however, dogs with cancer with no other viable treatment options available are the primary receivers of the therapy — and many of them showed promising results with an improvement to their quality of life. Hopefully the therapy can become one of the standard options available to dogs in the near future, so that more patients can benefit from it.”
One of the team’s collaboration partners, Associate Professor Antonio Giuliano, Department of Veterinary Clinical Sciences, City University of Hong Kong, will also be taking the therapy into animal clinical studies in 2023.
Providing the therapy as an accessible and affordable option for human patients
The stem cell modification therapy differs from other cell and gene therapies that use viruses to introduce genes into cells. Instead of using virus, the modification involves using a chemical carrier, which is safer and faces less regulatory restrictions in the development of the treatment. Compared to other cell and gene therapies, the therapy design has a significantly shorter cycle and much lower costs of production, paving the way for a more accessible and affordable option for cancer patients in future.
Dr Ho Yoon Khei, Senior Research Fellow, N2CR TRP and Department of Biochemistry at NUS Medicine, and first author and lead scientist of the study, said, “Currently, we can develop this therapy for up to 18 human patients every week. Beyond results that have shown to benefit our companion animals, it is our hope to extend the therapy to human patients in the future and improve healthcare outcomes for those who have cancer — especially when they have no treatment options left.”
The research team is working with local and global health institutions to review the therapy’s safety and efficacy for veterinary medicine and discuss plans for clinical trials on human patients in Singapore and the Asia Pacific region. These are expected to begin in 2024.
Prof Chong Yap Seng, Lien Ying Chow Professor in Medicine, Dean of NUS Medicine, added, “Our research work at NUS Medicine aims to create real, meaningful health benefits for the populations we serve, and eventually, drive better healthcare outcomes for all. We believe this therapy developed by the N2CR will have a major impact on the health and well-being of patients with solid tumours and late-stage cancer.”
The N2CR is one of 10 Translational Research Programmes (TRPs) at NUS Medicine aimed at creating a strong and coherent scientific base to deliver impactful and meaningful research outcomes for the School and Singapore’s health system. Besides Cancer, the other areas are Cardiovascular Disease, Digital Medicine, Healthy Longevity, Human Potential, Immunology, Infectious Diseases, Precision Medicine, Synthetic Biology and Nanomedicine. These 10 key focus areas, which are multi-disciplinary, and health and disease-based will create greater synergies and collaboration between basic scientists and clinician scientists, strengthen programmatic research and deliver research outcomes to address clinically relevant issues and applications that are aligned to national priorities.

New research challenges the prevailing hypothesis for how donor stem cell grafts cause graft-versus-host disease, or GVHD, and offers an alternative model that could guide development of novel therapies.
Published today in Immunity, the study showed in a mouse model that GVHD, which often affects the skin, gut and liver, is maintained by donor T cells that seed those tissues soon after transplant and not by the continual recruitment of T cells from the blood as previously thought.
“This study changes the paradigm of how people think about GVHD,” said co-senior author Warren Shlomchik, M.D., director of the Hematopoietic Stem Cell Transplant and Cell Therapy program at UPMC Hillman Cancer Center and professor of medicine and immunology at the University of Pittsburgh School of Medicine. “It provides important mechanistic detail about what’s going on in the tissues affected by GVHD, which could ultimately inform the development of better therapeutics and lead to better outcomes for stem cell recipients.”
Allogeneic stem cell transplantation involves infusion of stem cells from a healthy donor’s blood or bone marrow to a recipient. While often lifesaving for patients with leukemia and other blood disorders, the treatment also comes with a risk of developing GVHD, a life-threatening disease that occurs when donor alloreactive T cells attack the recipient’s healthy tissues.
According to a widely held theory, GVHD is maintained by T cells that continually migrate from secondary lymphoid organs throughout the body — including the spleen and lymph nodes — to affected tissues via the blood.
However, a different model posits that the disease is maintained locally by T cells in the tissues with little input from the blood. In the new study, Shlomchik, lead author Faruk Sacirbegovic, Ph.D., research assistant professor of surgery at Pitt, and their team investigated the two hypotheses for how GVHD is sustained in tissues.

The researchers developed a system to track alloreactive T cells in a mouse model of GVHD by labelling individual cells with unique tags to create different T cell “flavors.” By measuring the tags over time, they monitored where the T cells traveled and replicated.
The analysis showed that each tissue affected by GVHD had unique T cell populations with varying frequencies of each T cell flavor.
“This finding is strong evidence that the disease is locally maintained by T cells in each of the tissues,” explained Shlomchik, who also holds the Pittsburgh Foundation chair in cancer immunology. “If tissues were constantly getting T cells from circulating blood, then the frequencies of T cell flavors in each tissue should become more and more alike over time — but we didn’t see that.”
Led by co-senior author Thomas Höfer, Ph.D., division head of the German Cancer Research Center and professor of theoretical systems biology at the University of Heidelberg, the team used mathematical models to predict that progenitor T cells seed out into recipient tissues early after transplant, differentiating there into disease-causing cells.
Sacirbegovic next performed a series of experiments to confirm this prediction and identified these progenitors as T cells expressing a gene called Tcf7.

“We think that progenitor T cells are long-lived in target tissues and are critical for maintaining GVHD,” said Sacirbegovic. “After the initial seeding phase, the disease is mostly sustained within the tissue itself without a lot of input from new T cells in the blood.”
Stem cell recipients are typically treated with immunosuppressants to prevent and treat GVHD. As these powerful drugs act systemically to suppress the immune system, they also lower immunity to infections and have other side effects.
According to the researchers, the study’s insights could eventually lead to new, targeted therapies for GVHD.
“Now that we know the identity of progenitor cells, we might be able to prevent them forming early post-transplant or target them directly after they’ve formed,” said Shlomchik. “The findings also suggest that treating GVHD in the tissues themselves would be effective — although targeting tissues beyond the skin remains a challenge.”
With better ways to minimize the risk of GVHD after stem cell transplantation, the procedure could become more widely used to treat a broader range of diseases, including blood disorders such as sickle cell anemia and autoimmune diseases such as lupus and multiple sclerosis.
Other authors who contributed to this research were Matthias Günther, Ph.D., Alessandro Greco, M.S., and Xi Wang, Ph.D., all of the German Cancer Research Center and the University of Heidelberg; Daqiang Zhao, M.D., Ph.D., Meng Zhou, Ph.D., Sarah Rosenberger, M.S., Martin H. Oberbarnscheidt, M.D., Ph.D., all of Pitt; Werner Held, Ph.D., of the University of Lausanne; and Jennifer McNiff, M.D., and Dhanpat Jain, M.D., both of Yale University.