A Compelling New Lupus Discovery with Jaehyuk Choi, MD, PhD

 “We were able to use this approach to identify what we think is one of the root causes of lupus. And so we've identified that their T-cells are not right, they're not normal and in fact they're disease-causing, and we think that by understanding the root mechanisms by which these T-cells become disease-causing in lupus, we can identify ways to actually cure the disease.” 

- Jaehyuk Choi, MD, PhD

• Jack W. Graffin Professor 
• Associate Professor of Dermatology in the Division of Medical Dermatology 
• Associate Professor of Biochemistry and Molecular Genetics 
• Member of Northwestern University Clinical and Translational Sciences Institute 
• Member of Robert H. Lurie Comprehensive Cancer Center 

Choi and his collaborators are researching the possibility of innovative T-cell therapies with the hope of reprogramming disease-causing cells that cause lupus and other autoimmune diseases. 

• Choi’s team recently utilized findings from patients with T-cell lymphomas to discover ways to steal the superpowers in the lymphomas to supercharge T-cell therapies for cancer.  
• Using this same approach, investigators have been investigating lupus, an incurable autoimmune disease affecting over 300,000 Americans, with the hope of identifying the root cause of the disease.  
• Choi and his collaborator, Dr. Deepak Rao of Brigham and Women’s Hospital, played basketball together in medical school, and always dreamed of identifying a cure for autoimmune diseases.  
• From studying lupus patients, investigators found imbalanced chemicals in the blood that cause a rise of T-cells which promote the production of antibodies, a critical aspect of lupus.  
• By restoring an imbalance of a molecule called Aryl hydrocarbon receptor (AhR) ligands in patients' blood, Choi believes it is possible to reprogram disease-causing T-cells into non-pathogenic cells, potentially curing lupus. 
• Using a 'seesaw' analogy, Choi explains the inverse relationship between B helper T-cells and wound healing cells. Reducing the pathogenic B helper T-cells in lupus patients can naturally increase wound healing cells, potentially leading to tissue repair. 
• In similar cases of autoimmune disease, efforts are typically made to broadly suppress the immune system. But Choi says there is a way to target the cells that are causing lupus and “flipping their identity” from bad to good cells.  
• Choi hopes that one day soon this breakthrough discovery could not only cure lupus but even reverse the damage that’s already occurred in patients.  
• Choi believes they can utilize the same “roadmap” from their lupus investigations and apply it to other autoimmune or inflammatory conditions, such as rheumatoid arthritis. Similarly, the goal would be to reprogram cells that are causing disease, helping them to actually repair the conditions that they're causing.  

Additional Reading  

• Listen to a previous episode of the show with Choi: Strengthening T-Cell Therapy for Solid Tumor Cancers with Jaehyuk Choi, MD, PhD 
• Find out more about Choi’s collaborator, Deepak Rao, MD, PhD 
• Link to published paper  

 Recorded on May 29, 2024.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

CME Credit Opportunity Coming Soon

Choi has affiliations with and financial interests in Moonlight Bio. Northwestern University has financial interests (equity, royalties) in Moonlight Bio.

[00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. In a recent episode of this show, we spoke with Northwestern Medicine physician, Dr. Jae Choi, about how a gene mutation found in T-cells of patients with lymphoma could hold the key to potent cancer fighting immunotherapy for solid tumor cancers. Today we welcome Dr. Choi back to the show to talk about another breakthrough in T-cell research and the fight against lupus, a chronic auto-immune condition affecting 300,000 Americans that can cause inflammation in many body parts, including joints, skin, kidneys, blood cells, brain, heart and lungs. These findings not only elucidate the underlying mechanisms of lupus, but also suggest potential therapeutic strategies. Here with details is Dr. Choi. Welcome back to the show. 

[00:01:11] Jaehyuk Choi, MD, PhD: Thank you for having me, Erin. 

[00:01:12] Erin Spain, MS: Let's refresh our listeners' memories a little bit. You are a cancer researcher, specifically, you have an interest in skin cancer and skin immunology, but today we are talking about lupus. This is not a condition that you typically study. Tell us a bit about your background and what led you to lupus. 

[00:01:32] Jaehyuk Choi, MD, PhD: That's right. So, it turns out that one of the most important aspects of both cancer and the skin are actually the immune system. And one of the major drivers of the immune system is a cell called the T-cell. And it turns out that this T-cell has very similar attributes in many different types of diseases, including both cancer and autoimmune disease. And so it actually turned out to be a natural offshoot of the work that we had been doing. We study human patients and we try to find out what are the molecular aberrations or changes that occur in human patients. And so our thought is that once we identify them, we can then utilize them for multiple purposes. So we recently utilized findings from patients with T-cell lymphomas to really discover ways to steal the superpowers in the lymphomas to supercharge T-cell therapies for cancer. We use the same approach from patients with lupus and autoimmune disease. It turns out they have all the same cells and all the same technologies will work. And we were able to use this approach to identify the root cause of what we think is one of the root causes of lupus. And so we've identified that their T-cells are not right, they're not normal and in fact they're disease-causing, and we think that by understanding the root mechanisms by which these T-cells become disease-causing in lupus, we can identify, you know, ways to actually cure the disease. 

[00:02:52] Erin Spain, MS: Was there a particular reason you chose to investigate lupus to use the same approach as you used with your T-cell lymphoma research? 

[00:03:01] Jaehyuk Choi, MD, PhD: We wanted to study lupus because it's a debilitating, incurable condition that affects over 300,000 Americans. We don't have really good ways to treat the root cause of lupus, and that's why we don't have any cures for lupus. All the treatments are in fact treatments, which are just ways to make the side effects of lupus better. And these drugs actually broadly affect the immune system. And therefore we know that they not only suppress lupus T-cells, but they also suppress your T-cells to other possible diseases like COVID-19, pneumonia or infections. And so the net result is that these treatments can actually be extremely dangerous for patients if taken for too long and in the wrong situations. It affects not only the blood, but also the skin, the joints, the brain, the lungs, and as well as the heart. We've made a lot of progress in the last few years, but because it's incurable, patients still die from lupus at an unacceptable rate. 

[00:03:59] Erin Spain, MS: And tell me about the team that you've assembled to look into this, who are the experts in autoimmune diseases and lupus who are on the research team? 

[00:04:08] Jaehyuk Choi, MD, PhD: My collaborator in this case is Deepak Rao, who's an assistant professor at Brigham Women's Hospital, which is one of the hospitals associated with Harvard Medical School. He is an active participant in their autoimmune network called Accelerating Medicines Partnership, and also one of the leaders of the Human Immunology Center at Brigham. It turns out he and I used to play basketball together when we were in medical school, and we had this dream of partnering together to actually cure autoimmune diseases, diseases that he sees in his patients in his clinic. He's a rheumatologist where we can use the technologies we've developed to study T-cells and be able to deploy them in this very important clinical need. Our student, Calvin Law, is actually the first PhD student in my lab. Jay Daniels was the MD, PhD student who really pioneered the other work, and it's just been remarkable to see him grow from a junior scientist to really a mature researcher who's also equally committed to being able to cure autoimmune disease. 

[00:05:01] Erin Spain, MS: And the paper that we're discussing today, published in Nature. You mentioned you found the disease-causing cells in lupus. Tell me a little bit more about that. What did you find? 

[00:05:11] Jaehyuk Choi, MD, PhD: Sure. So, let me first start off with an analogy. So I think a lot of times we know lupus affects the skin, the brain, the lungs, and the heart. And oftentimes we actually study what caused the symptoms of the disease. And so I make the analogy for like landscaping. If you're looking at a weed, we often deal with what we see on the surface, and that's what we've been studying. But what we think we found is a fundamental root cause of lupus, which is kind of the root of the weed, and we think that by actually taking out the root, we can actually potentially cure lupus. That's why we're really excited about this. And so from patients, we found that there are chemicals that are imbalanced in their blood that causes the rise of these T-cells that actually promote the production of antibodies, which are a critical aspect of lupus. It turns out if you have lupus, you have much higher levels of these T-cells than people who are healthy. And that these T-cells seem to be chronically activated driving the production of these antibodies against yourself that lead to disease and correlate with disease activity. So our approach here has been different than what people have done before, which has been to try to treat the effects of lupus in the kidney or the skin. We wanna reprogram the cells that are actually causing the lupus. Turn them from bad guys into good guys. And so, what we found was that there was a molecule that was deficient in the blood of patients with lupus. It's called Aryl Hydrocarbon Receptor (AhR) Ligands. Normally these molecules are produced by bacteria in the gut, but also can be things that you're exposed to in the body from the outside in the environment, chemicals in water, et cetera. For many reasons, we found that patients with lupus have an imbalance of cytokines like interferon that suppress this Aryl Hydrocarbon Receptor pathway. We then found that this Aryl hydrocarbon receptor, when suppressed, actually promote the production of cells that are pathogenic lupus, these B helper T-cells, these TPH cells, and because we think we found the root cause of why patients with lupus have an abnormal abundance of this disease causing T-cells, we hypothesized that we could correct it by restoring the chemical imbalance in patients. And so we've done these studies with blood cells from patients with lupus, provided back the Aryl Hydrocarbon receptor ligands and show that we can suppress their ability to make pathogenic antibodies. And so we think that this is a possibility of not only reducing the disease-causing T-cells, but actually reprogramming them to be a potentially good cell. 

[00:07:41] Erin Spain, MS: Tell me more about these cells. In the paper you said that these cells are in a seesaw-like balance between disease causing and wound healing. Can you tell me more about that? 

[00:07:51] Jaehyuk Choi, MD, PhD: So these cells are called T peripheral helper cells, or B helper T-cells. They're highly elevated in patients with autoimmune disease, including lupus. And they're much higher in lupus patients than in healthy people. In healthy people, in contrast, you have much higher levels of these cells CD96 positive TH22 cells that are thought to be critical for wound healing in tissues. We knew we wanted to target the B helper T-cells. But what was unexpected were that these cells actually live in a seesaw with these wound healing cells. And so we think in normal people and in patients with lupus, you have these B helper T-cells and these wound healing cells actually living in a seesaw. When you have a lot of wound healing cells, that helps you to be healthy. And it seems to be associated with a lack of autoimmune disease. And then when you have autoimmune disease, you have a really high number of these B helper T-cells, and a low number of these wound healing cells. And so in general, it may be useful to reprogram T-cells across many different things, but we thought we could take advantage of this naturally occurring seesaw and be able to really push down the B helper T-cells, which would naturally push up their likelihood of becoming these wound healing cells. And so by doing this, we think we can leverage what nature already does in people to help prevent this autoimmune disease. And the added benefit is because they're wound healing at the sites of lupus associated injury, like the kidneys, the lungs, et cetera. We think that they could actually have a disproportionate outsize wound healing effect in the areas of lupus damage. 

[00:09:22] Erin Spain, MS: These are truly breakthrough discoveries. Explain to me just how unprecedented these findings are and what it could mean for advancement in the field. 

[00:09:30] Jaehyuk Choi, MD, PhD: I think what's really attractive is when we find a molecular mechanism that seems to explain the whole thing. And so what we have found is in the blood there seems to be a deficiency in these molecules called aryl hydrocarbon receptor ligands, and that this is sufficient to lead to upregulation of these B helper T-cells. And so we have, from soup to nuts, studied the molecules in the cells from patients with lupus, and shown how molecularly these chemicals can actually lead to the changes in the T-cell state, leading to chronic activation of B cells leading to the chronic activation of antibodies. What's been really a tremendous discovery is that we can bring back this molecule, rebalance this molecule cytokine in people and that if we do that, especially in lupus cells, we're able to actually turn off their ability to promote lupus antibody production. And so we think that the opportunity here is to not broadly suppress the immune system for patients with autoimmune disease, but to reprogram the cells that are actually causing the disease. And in this case, what's really incredible is the ability not only to prevent them from actually promoting the production of these antibodies, but actually to reprogram them to be a wound healing phenotype, where we're hoping that they can actually lead to repairing the damage that's been caused by lupus in these patients. 

[00:10:47] Erin Spain, MS: That's really incredible. I want to talk about some of the technology that you used to perform this research. It was really a critical part, some of the tools that you used in this investigation. Can you explain that to me? 

[00:10:57] Jaehyuk Choi, MD, PhD: Yeah, so we were able to combine just fundamental aspects of T-cell biology, immunology, single cell genetics, single cell transcriptomics, as well as these incredible technologies that give us this idea of what we call the epigenetic state of the cells. And so by using epigenetics, we can see how this one T cell that was born, probably polyfunctional, able to do anything, has actually become hardwired to become lupus promoting. And by utilizing these kinds of molecular mechanisms from the Aryl hydrocarbon receptor all the way through to the disease-causing T-cell state, we think that we're able to find the exact places where we can intervene and reprogram the cells. I think this concept of reprogramming the cells that are causing disease is actually relatively novel. Most people try to either broadly suppress the immune system as we discussed, or they actually try to kill the cells that are actually in patients. But we think there's an advantage of actually targeting the cells that are causing lupus and flipping their identity because they're already in the tissues that are where the disease is being caused. And they're also being chronically activated. So instead of being chronically activated to produce molecules that promote lupus, we're hoping to reprogram them to be chronically activated, to produce molecules that promote wound healing. And I think that this kind of opportunity will be available to us to be able to sort of repair the damage in all the organs where these immune cells are. 

[00:12:22] Erin Spain, MS: So for people who already have the disease, is this something that you're saying could reverse damage that's been done? 

[00:12:29] Jaehyuk Choi, MD, PhD: I think it's possible. We really hope so. We don't know for sure, and I think that one of the issues in lupus is that the preclinical models are mostly based on these small mice. You know, we know that mice are not humans, and so, but we think that because our discoveries are made in human T-cells, our hope is that we can translate this directly into humans and predict what will happen to patients. 

[00:12:54] Erin Spain, MS: So what are the next steps at this point? You've proven that this can be done in the lab and the blood samples from people with lupus. Now we're talking about real patients who want to see if this could be successful. So are clinical trials on the horizon? 

[00:13:07] Jaehyuk Choi, MD, PhD: We're actively working on this. The key aspect is how do we deliver these chemicals safely and surgically to the cells that we're targeting? And so, our lab and Dr. Rao's lab are actively working on ways to do this. And the goal would be is to produce these molecules, turn them into drugs that can be given worldwide to patients with lupus and other autoimmune diseases. And again, the goal will be not only to treat them, but to potentially cure them of their disease by reprogramming disease causing cells. Our goal is to really make it simple. If we can, we'd like to make it into a pill and that we can then give to people and then they could do better. What we think is these cells only represent a small fraction of the cells in the blood. We just wanna leave the 90 plus percent of the cells that are helping you to defend yourself against cancer and infection intact and unchanged. We only want to target the cells that are causing lupus, and our goal is to do that. 

[00:14:02] Erin Spain, MS: So you said you're actively working on this. So what does that mean? Tell me about this endeavor and I know that there is a startup or a company involved as well. What can you share with us? 

[00:14:12] Jaehyuk Choi, MD, PhD: Anything we find in the lab is very difficult to give to patients. And so there has to be an intermediate step where the intellectual property has to be licensed by a company that will be able to make commercial grade drugs that can be given to people throughout the world. So, Dr. Rao and I have focused on finding these technologies and we're actively working on trying to translate this into discoveries that can be put into a startup that would be able to be given to people. 

[00:14:38] Erin Spain, MS: What has the reaction been like in the community, especially people who study lupus? What has the reaction been? 

[00:14:46] Jaehyuk Choi, MD, PhD: It's been really outstanding. And as an example my student Calvin Law just presented at the plenary session for the American College of Rheumatology, and it was just really refreshing to see that both clinicians and scientists could be unified in their enthusiasm for a paper that bridges basic science and patient samples. We made one of the first studies into the molecular mechanisms, into these lupus causing T-cells, which was really important. But I think the obvious idea that this is a root cause of the disease and that it could potentially be addressed by chemical matter is something that's really resonated with both the clinicians and the basic scientists. 

[00:15:24] Erin Spain, MS: So when a study like this is published, there is often a lot of press, there's a lot of excitement and people really want to know, well, when can we expect to see this in the clinic? You know, when can my loved one with this disease expect some relief? What would you like to say to those folks who are listening, who are very excited about your research and really can't wait to see this come to fruition? 

[00:15:45] Jaehyuk Choi, MD, PhD: So what I would say is that actually many of the therapies that are out there are actually leveraging this particular seesaw that we're talking about. And so you may not be aware, but even if you're taking some of the medications that are prescribed now, like anifrolumab, it seems to be one of the effects of cytokine blockade is rebalancing this seesaw between these B helper lupus causing T-cells and these wound healing T-cells. What I would say is that rest assured that you're receiving the best care possible in the clinic, but that there are many medications that are actually in development that may be actually leveraging unintentionally the seesaw between the bad helper T-cells and the good helper T-cells. So I think that those would be in the clinic and be available to you very soon. And then what we wanna do in our lab is to be able to really develop next generation potential cures. Our hope is that this will come to the clinic within a few years. 

[00:16:38] Erin Spain, MS: Now we're talking about lupus today, but there are many autoimmune conditions out there that are really debilitating and not a lot of great treatments. Could you see this idea, this platform, this way of flipping the cells, something that could be done to help other conditions that are autoimmune. 

[00:16:55] Jaehyuk Choi, MD, PhD: You know, we've just been so inspired by, just a beauty and intrinsic logic to how nature works and the T-cells follow this logic in incredible ways. And until we have the technology to understand it, we really didn't understand how these diseases are caused. But now that we can see this real thread between blood imbalances into how the cells are programmed, into how they produce the molecules that cause lupus. We think we can take the same kind of roadmap and use this for other autoimmune or inflammatory conditions where our goal is to really reprogram the cells that are causing disease, helping them to actually repair the conditions that they're causing. This could easily be adopted to rheumatoid arthritis, as well as a number of debilitating autoimmune diseases. You know, it turns out that inflammation can actually be the root of many diseases. It's obviously deficient in patients who have cancer. They can't mount the appropriate immune response to the cancer. It may be over-exuberant in patients with autoimmune disease. But we think actually it's altered in many diseases associated with aging, including cardiovascular, heart disease, neurodegenerative diseases, and many other syndromes associated with aging. And so we think that we can apply these very powerful tools to be able to understand the molecular defects that occur across these different diseases. And we can now engineer new solutions for many of them. So our goal is to be able to really broadly identify new solutions for people with a broad suite of inflammatory diseases, which include aging in general. 

[00:18:25] Erin Spain, MS: This idea of team science and it takes a lot of experts and expertise to bring something like this to publication. Can you just talk about that a little bit and just the roles that everyone plays to make a discovery like this happen? 

[00:18:39] Jaehyuk Choi, MD, PhD: That's a really great question. Our goal is not to further our lab. Our goal is really to cure diseases and really improve human health. And if you have that kind of ambition, I think what you should think about is how do I assemble the right team to make this happen as quickly as possible? This kind of team science has been really archetype by, you know, getting to the moon with the NASA, the Moonshot projects, obviously the Manhattan Project. If you have a number of people with non-overlapping expertise who are smart and committed to solving these problems, things can go very quickly. And Deepak and I are close friends. We always dreamed of trying to cure autoimmune disease together and we're really gratified this is happening This is a truly 50-50 collaboration with his lab and really synergize our ability to make an impact that hopefully will help patients with these diseases 

[00:19:28] Erin Spain, MS: Well, Dr. Jae Choi, thank you so much for coming on the show and talking about another incredible breakthrough from your lab along with your collaborators. We really appreciate it. 

[00:19:38] Jaehyuk Choi, MD, PhD: Thank you so much, Erin. 

[00:19:38] Erin Spain, MS: You can listen to shows from the Northwestern Medicine Podcast Network to hear more about the latest developments in medical research, health care, and medical education. Leaders from across specialties speak to topics ranging from basic science to global health to simulation education. Learn more at feinberg.northwestern.edu/podcasts.