The study, published today in the Journal of Clinical Investigation, also shows that this anti-microbial immune response can be triggered by immune cell memory of previous encounters with bacteria, further complicating the body’s ability to accept a lifesaving new organ.

“Before, we thought the reason why transplanted organs in humans are less easily accepted than in sheltered laboratory animals is that humans can have immune memory responses that cross-react on the cells of the organ, and memory responses are more difficult to suppress with drugs than naïve responses,” said Maria-Luisa Alegre, MD, PhD, Professor of Medicine at UChicago and senior author of the study. “Now, we see that it’s not only memory cells that recognize the organ itself that are the problem, but also memory responses that recognize bacteria in the organ.”

Two separate immune responses

The success of organ transplants depends on the type of organ. Lungs and small intestines are notoriously difficult to transplant and have shorter survival times. Statistics show that within five years of surgery, 41% of lung and 54% of intestinal transplant recipients rejected their grafts, compared to organs like kidneys (just 27% rejection) and hearts (23%). One hypothesis was that lungs and intestines, but not kidneys and hearts, are exposed to microbes from the air and digestive system and that the organ recipients were mounting immune responses not only to the organs but also to the microbes in those organs.

In a previous study, Alegre and her team had shown that when mice received a skin graft colonized with Staphylococcus epidermidis (S. epi), a common bacteria found on the human skin, S. epi caused low grade inflammation in the graft. The team then wondered if the host mounted a separate immune response against the bacteria in the graft in addition to the more well-understood “alloresponse,” or reaction to the foreign cells in the tissue, and if both could damage the graft.

“The commensal bacteria in the graft are different from the commensal bacteria of the recipient because each individual harbors a unique set of microbes, so the host may also see these bacteria as foreign too,” Alegre said. “We thought that maybe these two separate immune responses (host-versus-transplant and host-versus-bacteria) could work additively or synergistically to mount a more robust immune response against the graft and explain why the half-life of the organs that have microbes is shorter.”

Dealing with a lifetime of immune memory

In the new study, the researchers used mice from UChicago’s gnotobiotic facility which were carefully raised in a sterile environment and not colonized by any microbe. The team transplanted skin from donor mice that were genetically identical to the recipients to avoid an alloresponse. The receiving mice mounted an immune T cell response against the graft when it was first colonized with S. epi, but not when it was left sterile. This immune response damaged the skin graft, but not very much.

Alegre and her team then tested if prior immune exposure to commensal bacteria would cause greater damage to a graft colonized by similar bacteria, so they infected some recipient mice with S. epi before transplanting them, letting them develop memory responses to the bacteria. When these mice later received a skin graft colonized with similar bacteria, the immune response was much stronger and significantly damaged the new tissue. This is significant because transplant patients already have a lifetime of exposure to many bacteria and other microbes through everyday cuts, scrapes, infections, and diet.

Most importantly, when they transplanted mice with skin grafts that were genetically different and colonized with bacteria — simulating the scenario like most human organ transplants — they saw that immunosuppressive drugs that prolonged transplant survival in naïve mice did not work in mice with anti-bacterial memory.

“That explains why when you transplant a lung or intestine, patients do less well and have to receive higher levels of immunosuppression than when you transplant sterile organs,” Alegre said. “You have to deal not only with the response against the graft, but also the response against the bacteria that come with the graft.”

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Materials provided by University of Chicago. Original written by Matt Wood. Note: Content may be edited for style and length.

The finding, researchers say, should offer reassurance to the more than 200,000 Americans who have SLE, a condition in which the body’s immune system mistakenly attacks its own healthy tissues, especially joints and skin. Immune-suppressing drugs, such as steroids, needed to control symptoms of the disease, place them at increased risk of infections, including SARS-CoV-2.

Led by researchers at NYU Grossman School of Medicine, the new study tracked the health of 163 fully vaccinated men and women being treated for SLE at its affiliated hospitals in New York City. The researchers’ goal was to see who became infected with the virus over at least six months, given that more than half were taking at least one immune-suppressing medication for their SLE. All had received some combination of the vaccines manufactured by Pfizer, Moderna, or Johnson & Johnson prior to June 2021, but only 125 had received a third or booster dose of vaccine.

Publishing in the journal The Lancet Rheumatology online July 12, the study showed that at the end of the monitoring period (April 24, 2022), 44 vaccinated SLE patients had had breakthrough infections, with two needing hospitalization (but both surviving their infection).

Among those with breakthrough infections, 28 of 125, or 22%, had received a booster, while 16 of 38, or 42%, had not. Notably, according to investigators, the majority of breakthrough infections (42 of 44) occurred after Dec. 2, 2021, when the city detected its first case of the highly contagious omicron variant.

Another key study finding was among 57 of the study participants who agreed to have their blood antibody levels checked, once after full vaccination and again after receiving their booster.

Researchers found that even those on immunosuppression who had not responded to the initial round of vaccination had an immediate rise in antibody levels after the administration of a booster shot. Previous research had shown that these antibody levels were lower among many initially vaccinated patients with rheumatic diseases, including SLE, who were taking immune-suppressing drugs, sparking fears of waning immunity to COVID-19 over time.

However, study results showed those with higher levels of antibodies, needed to block the SARS-Cov-2 “spike” protein and prevent the virus from infecting human cells, were no more protected from breakthrough infection than those with lower spike-protein antibody levels.

Still, researchers say their previous work showed elevated antibody levels in fully vaccinated lupus patients strengthened key measures of long-term immunity, which may help explain the lack of severe disease in those with breakthrough infections.

“Our study results offer people living with systemic lupus erythematosus clinical confirmation that vaccines are highly effective at guarding against severe COVID-19, despite their increased risk of catching the disease,” says study co-lead investigator and rheumatologist Amit Saxena, MD, MS.

“COVID-19 vaccine boosters, or third shots, offered an added, doubled layer of protection from breakthrough infection,” says Saxena, an assistant professor in the Department of Medicine at NYU Langone Health. “Even in cases of SARS-CoV-2 infection, cases were overwhelmingly mild among SLE patients who were fully vaccinated.”

“Our research also shows that most people with systemic lupus erythematosus who are fully vaccinated and boosted mounted good responses despite being on immune suppression,” says study co-senior investigator and rheumatologist Peter Izmirly, MD. Izmirly is an associate professor in the Department of Medicine at NYU Langone Health.

However, researchers caution that further monitoring of patients is needed to determine if there is any antibody “cutoff” level below which SLE patients become more vulnerable to SARS-CoV-2 infection.

During the initial wave of the pandemic in spring 2020, NYU Langone hospitalization rates for its SLE patients were more than double those of its patients without the condition, the researchers note, although death rates were the same.

Funding support for the study was provided by grants from the National Institutes of Health (P50AR07059) and Bloomberg Philanthropies COVID-19 Response.

Besides Saxena and Izmirly, other NYU Langone researchers involved in this study are co-lead investigator Alexis Engel, BS; study co-investigators: Brittany Banbury, MD; Ghadeer Hasan, MD; Nicola Fraser, BS; Devyn Zaminski, BS; Mala Masson, BA; Rebecca Haberman, MD; Jose Scher, MD; Gary Ho, MD; Jammie Law, MD; Paula Rackoff, MD; Chung-E Tseng, MD; H. Michael Belmont, MD; Robert Clancy, PhD; and co-senior investigator Jill Buyon, MD.

Saxena has receive consulting fees from AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Eli Lilly, and Kezar Life Sciences, manufacturers of drugs used to treat SLE. Izmirly has served on an advisory board sponsored by GlaxoSmithKline and acted as a consultant to Momenta/Janssen. Haberman and Scher have acted as consultants to Janssen, while Scher has also consulted for and/or received research funding from Novartis, Pfizer, Sanofi, UCB, and Abbvie. Clancy and Buyon have acted as consultants to Momenta/Janssen, while Buyon has also consulted for and/or served on data safety monitoring boards for Ventus, Equillium, and GlaxoSmithKline. These arrangements are being managed in accordance with the policies and practices of NYU Langone.

Luckily for astronomers, this bygone era can be observed. Distant light takes time to reach us, and our telescopes can pick up light emitted by galaxies and stars billions of years ago (our universe is 13.8 billion years old). But the details of this chapter in our universe’s history are murky since most of the stars being formed are faint and hidden by dust.

A new Caltech project, called COMAP (CO Mapping Array Project), will offer us a new glimpse into this epoch of galaxy assembly, helping to answer questions about what really caused the universe’s rapid increase in the production of stars.

“Most instruments might see the tip of an iceberg when looking at galaxies from this period,” says Kieran Cleary, the project’s principal investigator and the associate director of Caltech’s Owens Valley Radio Observatory (OVRO). “But COMAP will see what lies underneath, hidden from view.”

The current phase of the project uses a 10.4-meter “Leighton” radio dish at OVRO to study the most common kinds of star-forming galaxies spread across space and time, including those that are too difficult to view in other ways because they are too faint or hidden by dust. The radio observations trace the raw material from which stars are made: cold hydrogen gas. This gas is not easy to pinpoint directly, so instead COMAP measures bright radio signals from carbon monoxide (CO) gas, which is always present along with the hydrogen. COMAP’s radio camera is the most powerful ever built to detect these radio signals.

The first science results from the project have just been published in seven papers in The Astrophysical Journal. Based on observations taken one year into a planned five-year survey, COMAP set upper limits on how much cold gas must be present in galaxies at the epoch being studied, including the ones that are normally too faint and dusty to see. While the project has not yet made a direct detection of the CO signal, these early results demonstrate that it is on track to do so by the end of the initial five-year survey and ultimately will paint the most comprehensive picture yet of the universe’s history of star formation.

“Looking to the future of the project, we aim to use this technique to successively look further and further back in time,” Cleary says. “Starting 4 billion years after the Big Bang, we will keep pushing back in time until we reach the epoch of the first stars and galaxies, a couple of billion years earlier.”

Anthony Readhead, the co-principal investigator and the Robinson Professor of Astronomy, Emeritus, says that COMAP will see the not only the first epoch of stars and galaxies, but also their epic decline. “We will observe star formation rising and falling like an ocean tide,” he says.

COMAP works by capturing blurry radio images of clusters of galaxies over cosmic time rather than sharp images of individual galaxies. This blurriness enables the astronomers to efficiently catch all the radio light coming from a larger pool of galaxies, even the faintest and dustiest ones that have never been seen.

“In this way, we can find the average properties of typical, faint galaxies without needing to know very precisely where any individual galaxy is located,” explains Cleary. “This is like finding the temperature of a large volume of water using a thermometer rather than analyzing the motions of the individual water molecules.”

The project has received funding from the Keck Institute for Space Studies (for critical early technology development) and from the National Science Foundation (NSF), for building the “Pathfinder” early phase of the project and performing the survey. The project is a collaboration between Caltech; the Jet Propulsion Laboratory (JPL), which is managed by Caltech for NASA; New York University; Princeton University; Stanford University; Université de Genève; University of Oslo; The University of Manchester; University of Maryland; University of Miami; and the University of Toronto (including the Canadian Institute for Theoretical Astrophysics and the Dunlap Institute for Astronomy and Astrophysics).

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Materials provided by California Institute of Technology. Original written by Whitney Clavin. Note: Content may be edited for style and length.

Cory Simon, assistant professor of chemical engineering, and Xiaoli Fern, associate professor of computer science, led the project, which involved training a machine learning model to predict whether any proposed new herbicide, fungicide or insecticide would be toxic to honey bees based on the compound’s molecular structure.

The findings, featured on the cover of The Journal of Chemical Physics in a special issue, “Chemical Design by Artificial Intelligence,” are important because many fruit, nut, vegetable and seed crops rely on bee pollination.

Without bees to transfer the pollen needed for reproduction, almost 100 commercial crops in the United States would vanish. Bees’ global economic impact is annually estimated to exceed $100 billion.

“Pesticides are widely used in agriculture, which increase crop yield and provide food security, but pesticides can harm off-target species like bees,” Simon said. “And since insects, weeds, etc. eventually evolve resistance, new pesticides must continually be developed, ones that don’t harm bees.”

Graduate students Ping Yang and Adrian Henle used honey bee toxicity data from pesticide exposure experiments, involving nearly 400 different pesticide molecules, to train an algorithm to predict if a new pesticide molecule would be toxic to honey bees.

“The model represents pesticide molecules by the set of random walks on their molecular graphs,” Yang said.

A random walk is a mathematical concept that describes any meandering path, such as on the complicated chemical structure of a pesticide, where each step along the path is decided by chance, as if by coin tosses.

Imagine, Yang explains, that you’re out for an aimless stroll along a pesticide’s chemical structure, making your way from atom to atom via the bonds that hold the compound together. You travel in random directions but keep track of your route, the sequence of atoms and bonds that you visit. Then you go out on a different molecule, comparing the series of twists and turns to what you’ve done before.

“The algorithm declares two molecules similar if they share many walks with the same sequence of atoms and bonds,” Yang said. “Our model serves as a surrogate for a bee toxicity experiment and can be used to quickly screen proposed pesticide molecules for their toxicity.”

The National Science Foundation supported this research.

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Materials provided by Oregon State University. Original written by Steve Lundeberg. Note: Content may be edited for style and length.