The Immune Health future, today

This hardwired part of the immune system is quick to respond to injuries, viruses, bacteria, and more.

Neutrophils and macrophages are like the patrol officers responding first to an immediate threat. Both types of cells destroy viruses and bacteria soon after they are detected. Macrophages also release molecules called cytokines that cause inflammation and make it easier for more immune cells to reach the area.

Dendritic cells act like crime scene investigators. They break invader cells apart and bring their uniquely detectable component molecules and pieces, or antigens, back to the adaptive immune system to learn more about the enemy.

The adaptive immune system is a trained against specific threats, and also learns and retains a memory of antigens it has encountered before.

T cells are the body’s specialized immune soldiers. They are a type of white blood cell that will destroy the body’s own cells when necessary if it detects that cell is infected or damaged. They can also direct the activities of many other parts of the immune system.

B cells multiply in high numbers when fighting off an infection or invader, and produce antibodies, which are specialized protein molecules that are custom-made by the body to latch onto and neutralize or destroy viruses, toxins, and any foreign molecules that are perceived as a threat.

Each patient’s immune response was charted on an immune map with the responses of other hospitalized COVID-19 patients, which is when the team noticed some surprising, and important, patterns. Unlike in most other viruses, the COVID-19 patients’ immune systems were not responding to the virus in a uniformly predictable way. Instead, the patients’ immune activity patterns seem to cluster in a few distinct groups. They published these findings in Science in July 2020.

One group of patients was characterized by their overactive immune systems—with severe inflammation, high levels of activated T cells, and a large number of plasmablasts (a type of B cell actively producing antibodies). Another group had what doctors deemed an appropriate viral response to COVID-19: Their immune systems activated to fight the virus, but not to the extent that the immune system was causing harm. The third group had a low, almost negligible, immune response.

The first group—those with overactive immune responses—were likely to see the best results from steroid treatment, while the group with little to no immune response might not see such benefits from steroids, which would further suppress their immune systems. It was a finding consistent with subsequent clinical trials that helped the overwhelmed front-line physicians make informed treatment decisions for their patients amid a global pandemic.

In one memorable instance, Meyer called the COVID-19 Processing Unit with an urgent request on a Friday afternoon: Could the team map the immune state of a patient whose case was confounding physicians? By Sunday morning, the COVID-19 Processing Unit told Meyer that her patient mapped to the hyperactive immune response group.

“It gave us a lot of insight about that patient’s immune status,” Meyer said. “It was convening the right minds… to give us a sense for which features of this patient’s immune system seemed out of balance. It shows the potential for this type of work.”

For a single patient, the COVID-19 Processing Unit team’s analysis—along with a review of the patient’s clinical data—took 12 to 24 hours. “We had a team of about 6 to 10 people working in shifts 24 hours a day,” Wherry said. “To make immune health functional from a clinical perspective, this had to be real-time.”

In just three months, the COVID-19 Processing Unit analyzed the immune responses of some 750 patients. “It was team science done in a new way,” said Allie Greenplate, PhD, director of Strategic Alliances and Operations for I3H and an adjunct assistant professor of Systems Pharmacology and Translational Therapeutics, who was then part of the COVID-19 Processing Unit as a post-doctoral researcher in Wherry’s lab. “Looking in detail at the immune system and discovering something about a person’s biology [has been done before]. What was unique was the ability to return the results to a physician in real time. To do it at the scale we did, I think, is still something that hasn’t been done elsewhere.”

Among the first steps to realizing this ambitious vision was to streamline the process used during the pandemic into a more scalable and sustainable system. The I3H team simplified assays, standardized workflows, added support, organized teams, and embedded quality control into the process. Another change: Without the urgency of COVID-19, researchers could relax their timelines. “We could return results on the scale of days to weeks,” Wherry said, “and still be real-time for the patients to use that information for treatment choices.”

That’s how it worked for Bar-Or’s work in COVID-19 immunity, where he led a key study published in Nature Medicine in 2021 showing that MS patients taking drugs that suppressed their immune systems’ production of antibodies still gained robust protective T cell responses to the COVID vaccines. His next I3H partnership will focus on getting the patients the right MS treatments for their own body’s immune type. There are a number of FDA-approved therapies available for MS, but doctors have little guidance about which work best for individual patients. Mapping out how different patients respond to the various treatments could help doctors better target their therapies—just as they did with extra COVID-19 protection.

Autoimmune diseases like MS are among I3H’s first targets because they are fundamentally diseases of the immune system itself. Autoimmune diseases, including rheumatoid arthritis, lupus, and Graves' disease, affect almost three times the number of people with cancer but receive seven times less funding, Greenplate said. At Penn, however, generous gifts totaling $60 million from Judy and Stewart Colton in 2021 and 2022 established and accelerated the Colton Center for Autoimmunity, which will partner with I3H. Penn researchers are already making advances in multiple approaches that arm the immune system to fight autoimmune disorders, such as a modified version of CAR T therapy for the autoimmune skin condition pemphigus vulgaris and for myasthenia gravis, a neuromuscular condition.

Another researcher is working to understand long COVID—perhaps the world’s newest autoimmune disease. With blood samples offering few clues about why some people develop long COVID, researchers in the laboratory of Michela Locci, PhD, an assistant professor of Microbiology at the Perelman School of Medicine, are adapting a tool from basic science to a question with clinical implications. Locci’s lab uses a fine needle aspirate (FNA) method to collect samples from the cervical lymph nodes of COVID-19 survivors and study their ongoing immune responses in the lymphoid tissue. A closer look at these immune cells might help clarify what’s causing some survivors to develop long COVID.

Locci said she believes the study is the first attempt to use FNAs to study immune responses to long COVID infection in humans. “I could not think of a better place to conduct immune health–related studies than Penn,” she said. “This increased focus on immune health will act as a propeller to facilitate human immunology studies with potential to guide clinical decisions.”

But first there are regulatory considerations to address before bringing research data to patients in a clinical setting. Research laboratories, where immune health breakthroughs are made, don’t have the clinical laboratory certification needed to return their data into patient’s medical records, Greenplate said. One option currently being studied by Angela Bradbury, MD, a Perelman School of Medicine associate professor of Hematology /Oncology and Medical Ethics and Health Policy, is asking patients if they are willing to receive research data.

So, while Greenplate envisions someday giving patients access to their immune health testing data inside their electronic medical records, “We’ll probably start on a smaller scale with research data,” she said. “Then, depending on the response, consider whether it’s worth the cost of making it an insurance reimbursable test.”

Making sense of that research data to arrive at useful insights for patients is itself another large area still scaling up. The informatics team at I3H is building an infrastructure of data management, sharing, and analysis that will make their discoveries not only possible, but also actionable. Dokyoon Kim, PhD, an assistant professor of Informatics in Biostatistics and Epidemiology, does work that integrates electronic health record information with various biomedical data sources such as biobanks, medical imaging, and different types of genomics and other “multi-omics” data, to predict disease outcomes. Now, as I3H associate director of informatics, Kim is leveraging artificial intelligence to further enhance his clinical risk prediction models. “If we have well-trained multimodal AI models,” Kim said, “we could bridge the gap between clinicians and data scientists, opening doors to broad applications including personalized medicine.”

Building those immune health data and prediction models into a standardized and scalable database is a multidisciplinary collaboration—encompassing data scientists and software engineers, immunologists, and phlebotomists—led by Joost Wagenaar, PhD, also an assistant professor of Informatics. The goal is a comprehensive data ecosystem combining multimodal clinical and research data that is easily accessible. Imagine the power of a database, Wagenaar said, that enables a physician to pull a quick analysis of patients on a specific medication or a scientist to build a cohort of information for drug discovery.

“What if all of the data is at your fingertips, and all you have to do is ask the right question?” Wagenaar said. “Would we be able to accelerate research? Would we be able to get to cures for patients faster? I think the answer is yes. Immune health is an extremely good use case where we can demonstrate that.”