Brian S. Kim, MD, MTR , received the inaugural Stephen I Katz, MD, PhD, International Lectureship Award and presented "Neuroimmune Regulation of Itch" at the Society for Investigative Dermatology (SID) annual meeting in Portland, Oregon in May 2022. How does the skin sense itch? Is itch a truly distinct sensation? Dr. Kim discussed the emergence of itch neurobiology in recent years, the evolving paradigm of atopic itch, how dupilumab may be broadly efficacious across multiple chronic itch conditions and other aspects of his research.
thank you john it's a great honor to be here. It's very emotional to hear all these stories from uh steve's trainees and friends and colleagues um and it's a real honor to have john Stanley. Uh I went, I went to u penn for residency because of john Stanley to have him introduce me as just uh is a real honor. And of course thank you to the organizing committee for giving me the opportunity. Um it's not lost upon me as I'm sure it's very apparent that steve had many, many accomplished trainees, so it's incredibly humbling for me to be up here um and to pay tribute to steve Katz and I also want to highlight uh kind of an anecdote of how steve operates and the influence he has. As you can already see that Sherry Meltzer, his assistant of 25 years actually emailed me a couple of months ago and she said brian, I'm so happy that you're giving to steve Katz lecture and she said, I'm just so excited. Um and here I was a medical student in his lab, he said he doesn't take medical students and he took me um and that Sherry is emailing me after all these years, speaks to the fact that he, the interest he took in people resulted in his family. He was growing a family and that we all take interest in each other and I think it really speaks to steve's legacy um in a very profound way um here are my disclosures. So we heard a lot about Stevie was born in New York in 1941. He was in a very loving and wonderful husband to Linda. It was an amazing father to Mark ken and Karen and two for two brief of a moment, he was actually grandfather to Ben. And you heard about bobcats bob was his brother, a dermatologist who had actually convinced him to go into dermatology, bob was his ultimate mentor. It's really hard for me to imagine steve Katz needing a mentor. He's, I thought he came out of the womb with his eternal wisdom, you know, so it but yet bob was his, his mentor and and um had a tremendous amount of influence and as he already heard he was a mentor and friend to so many people. Um it's funny we actually collaborate with tom waldman who was a giant in the side of the infield. Uh really, really famous for I'll 15 and he actually, steve grew up in Bethesda and actually delivered newspapers to tom waldman and I thought that was a really funny story and here we were collaborating and we actually published a paper together. Um and steve grew up in Bethesda. Uh he actually something that didn't come up is that he very uh was open with the fact that he was not a good student and I think he did this to tell students, you don't have to always be a good student, you can, you know, uh and I saw him speak to a group of high school kids once. Uh but he did go to university of Maryland and excelled, went to Tulane from medical school where he got an honorary degree, uh L. A county hospital, he went all around bobcats and convinced him to go to University of Miami for residency in dermatology. And as he heard, um he was in the military at walter reed and got his PhD from the University of London. He was then recruited to the NIH and that we all know that he was director of names and really had a profound influence on dermatology. This is his beautiful, wonderful family. I was actually emailing with them the last couple of days leading up to this. Uh you can see that steve is wearing the same shirt. Uh he was very, very proud of the fact that he he was a NIH citizen. As you already heard. He was a pioneer in skin immunology. John Stanley mentioned that and uh he really honed in on the kind of skin is an immune system. I'll speak to that. And uh here's a quote from actually I think an interview that john Stanley did with him in Jama dermatology where he says giving of yourself and taking join the success of your students and that is his mantra and I think we can use the term students very, very liberally here. So if I'm gonna weave in quotes from steve, he had an amazing quotes and he loved to say on to ginny recapitulates fila ginny and I'm not sure if I still understand not an evolutionary biologist, but this is recapitulation theory where an organism in its stages of develop development actually recapitulates the embryonic stages of development of its ancestor. But I think it speaks to the fact that steve had this intense interest in watching his Children in the broadest sense grow and develop and he was always I would do something, he'd say ontology recapitulates biologic knee and uh he just loved that. And this is just a list of all of his direct trainees, I'm buried there in the middle, that was one of his last trainees in his laboratory. So what we're steve scientific pursuits, you heard a bit about it? He was very, I'm going to focus on on certain aspects of his science. He was very interested in understanding how antigen presenting cells or Langerhans cells in the skin get activated, process antigen migrate to the lymph node and really activate the adaptive immune system or T cells. But he was also very interested in understanding how the epithelium itself actually directly engages Damien system. And I realized that when I was in his laboratory because this was actually a project that I was working on. I was in the lab in 2004. So I was actually digging up papers from the eighties at that time and he was interested in understanding how karate insights themselves actually express. MHC Class two and may actually directly present antigens to T cells. And this is what we worked on. Um we actually had developed a mouse in which uh the antigen could actually be a model and could actually be expressed directly within character insights. And then you can transfer in antigen specific t cells into the skin. And what you can do is actually elicit a graft versus host disease like process in the skin and it's just kind of characteristic features with dermal infiltrate vascular change. And um and what we were studying was how Langerhans cells should regulate this process. And the idea was the dogma is that these antigen presenting cells should actually present Energen. And in collaboration with Bjorn Claussen. What we were able to do is get a mouse in which we could actually delete Langerhans cells. So if you look at just a normal mouse what you'll find are these beautiful cells and fosse looking down at the skin which are longer hand cells in a normal mouse skin. And then if you're transferring these T cells you get this G. V. H. D. Like disease in the setting and in Langerhans cells sufficient mice. But what we could actually do is delete these Langerhans cells and to our surprise the disease was uh processed unabated. And this isn't that surprising now to some degree but at the time it was rather surprising and uh and this was actually my 1st 1st author paper. And we had identified how character insights can actually function to potentially in certain context, present and again. And so the idea was that these t cells could actually get activated by directly engaging epithelial cells. But after leaving steve's lab, he had a huge influence on on me and and and my uh science and how to think about the skin. And I became increasingly obsessed with how different aspects of the skin can act as the immune system. And the question in my mind was, what else could be going on here? How can the epithelium actually activate the immune system? And the real kind of driving question of our program based on this was how does the skin become inflamed? And then how does this information lead to itch. Something that's so obvious even to a five year old, if you have a rash it's itchy. But these simple questions had not been asked in a systematic fashion, in our minds. Um and I'm gonna talk so I'm gonna talk about it a little bit. So how does the skin sense itch? And this is not something that really came to light until very recently, it was considered a mild form of pain, A trivial sensation, patients are crazy. This is not something that really needs to be studied, that that was the prevailing paradigm. And and even for me, I'm not a nurse trained neuroscientist, what I knew about the peripheral nervous system was derived much more from my experience as a physician. The autonomic nervous system which in a different faction regulates processes like breathing heart rate and even in the skin, the autonomic nervous system is important. It regulates processes like sweating and Visa motor tone, but it's still not something that we really think about a lot as a dermatologist, but we do have to think about the somatic sensory nervous system. The somatic sensory nervous system is an incredibly complex system that was designed essentially for the skin to sense the outside world. You have different nerve fibers that can even sense your hair shaft moving. You can sense different forms of mechanical stimulation and pain. And what I'm going to talk about mostly are these UNM I eliminated C fibers um which can sense things like temperature as well as heat, cold pain and a small stuff that can actually mediate itch. The whole right side actually has really. A spotlight has been put on it in the fall because of the nobel prizes for Samantha sensation. David Julius for the sensation of temperature and uh our compatibility in for the sensation of touch. And I think this is putting a bit more of a spotlight on it as well. So I mentioned that itches overlooked, but why suddenly are we taking it much more seriously? Well, in my opinion, it really starts from the science. So people were trying to figure out is it really a truly distinct sensation. And the real science came in the last 10 years or so where it's inducing molecules or predictions were identified to activate unique circuits by way of receptors such as mass related to protein coupled receptors. Uh in the peripheral sensory neurons discovered by Xin Jiang Dong at Hopkins uh close collaborator um Mark who discovered that brain natural peptide is a neuro peptide that's released from these peripheral neurons dumps into the spinal cord and activates it. And then discovered that Gaston releasing peptide receptor marks its specific neurons within the spinal cord. And then the first author from that original landmark paper Yang Sun discovered recently that there are within the brain that receive these signals. This is not to snow you in with a bunch of neuroscience but I think it's really this kind of uh seminal discovery, these discoveries that really led us to believe that it is actually tractable, it's a real thing and that this is not just a pain circuit, this is truly an itch circuit and I will drive that theme hopefully throughout. So steve one time said to me, he said there's no problem that cannot be solved and I kind of looked at him kind of you know that there's something and he said no listen to me brian and he looked me and he said there's no problem that cannot be solved and that was not a literal thing, but it was a spiritual thing that I carried with me forever. And it really told me what a force of nature this guy really is that this is how he views the world. And so we I decided okay we'll solve try to solve the problem of eczema which at that time was considered somewhat unsolvable. So that was a disease we decided to go after. What was known about it at that time was a bit of a T cell centric world, a bit of an antigen specific world that there are stimuli or allergens and environment that translate translate across the barrier activate these T cells somewhat mysteriously. And you get production of these teach two sided kinds that then uh activate the production of I. G. E. Hallmark feature of a topic disorders and decided kinds directly damage the barrier. And again going back to steve's thing. What does the epidermis do? What does the brick and mortar of the skin really have to do with this? And the and I was thinking about this I think. And the first clues came by with these epithelial cell derived cytokines or alarm inside kind of alarm immune system. They actually come out. I'll 33 T. S. L. P. Are expressed from the stress barrier. And it was already starting to emerge during my postdoc that these kinds actually potently activate this pathway And when we look downstream of these side of kinds we came to appreciate that there were cells such as rare Besa fills in circulation that come in and are major sources of aisle four and at that time entirely undiscovered cells group two innate lymphoid cells, R. I L C two is in the skin are present and embryo embryo logically actually seeded into the skin and are major sources of aisle five and 13. And this started to shift the paradigm to encompass these innate cell populations that actually through these cytokines in a way since the world. So this is where we were already starting to think of things in neuro scientific terms. And in fact when I started my laboratory uh one of the key things we started to appreciate it was that these canonical type two sided kinds that we had completely thought of just being within the immune system. Actually were communicating with the sensory nervous system. And this was very important to us because this really hinted that perhaps these side of kinds actually directly involved. Not indirectly but rather very directly involved and maybe even acting as neurotransmitters in the setting of itch. And this is just kind of uh an oldie but goodie now. But this is my first graduate student, Landon Action M. D. PhD student. The way he approached this was he simply took sensory neurons or dorsal root ganglia from both mice and through collaboration category human donors. And just look for expression of these canonical type two cytokine receptors and he's able to detect all four receptor alpha all 13 receptor alpha one. And at that time we already knew that I'll 31 was emerging to be a true city kind permitted. And so we as a control we were looking for the L 31 receptor. And what one of the things that we noticed right away was was that that was was highly conserved between both Miles and humans. And that is in fact a feature of type two immunity and which we think it's a very conserved uh kind of response. The question is that the sensory neurons do express these receptors. But does that mean anything? Does it really do anything? Is this an epic phenomenon? So to test this we do calcium imaging where we simply put DRG neurons into the dish, label them with die so that we can detect calcium influx into the cell and then look to see functionally through these neurons actually respond. And in fact they do we can actually also confirm the identity of these neurons. We find that these for example, this neuron responds to capsaicin, capsaicin activates V. One which is which is a cast iron channel that is essentially marks what we call, know susceptible sensory neurons. And I'll come back to that a little bit later. But in the interest of time I'm not gonna show this data. But what we were able to tease out is that this kind of neuro immune access of how these cytokines interact with the sensory nervous system is a critically important process by which the city kinds either activate or sensitized neurons to a variety of other signals and make you very sensitive to uh a whole host of signals and perhaps what drives it. It's also why we think that drugs like or other sadikin blockers can actually disrupt itch in ways that we have not seen before with prior therapeutics. But the other thing that we started to notice was that neuroscientists who had somewhat of an indifference towards itch we're discovering through single cell RNA sequencing that these that there are specific neurons that were code. You could codify based on historical functional work that had laid the foundation. So you could see these blue, green or red neurons that are specific. And one of the things that we observed was that actually although specific for this cluster that the receptors for these type of two sided kinds of rather broadly expressed across these different subsets and why get into this kind of science? Well, it actually provoked a hypothesis already at that time that maybe this has much more to do with just a topic dermatitis. Maybe conditions that are inherently itchy primarily neurogenesis. So, an itch drives the formation of hypercar atomic nodules, Perego nodule areas being the condition. Maybe even in that condition. Drugs like tupelo map would actually be effective. And we pressed this point even though being a basic science lab really pressed this point and actually uh submitted an investigator initiated trial proposal to Regeneron to try to accelerate this process. And we went back and forth. And what happened was they decided they're just gonna jump straight ahead to phase three. And at that point I said we don't need any funding for this trial. Uh this is great for our patients and in fact these results came out in the fall uh met key primary and secondary endpoints. And I think we'll see this drug approved here very soon. But we've treated other patients with idiopathic peratis. These are individuals who have scratch marks where they can reach uh clear skin where they can't and off label. We found that anecdotally these patients do quite well, especially individuals with very severe itch uh from our clinic. And we feel that this also deserves a randomized trial investigation. But at the time as we were discovering how these cytokines act on the nerve, we also knew that they had to signal through downstream signaling pathways like Jack signaling, Janice kind of signaling. And in fact if you go back to the single cell RNA sequencing, you find that in fact within perceptive itch neurons you see high enrichment for Jack one in particular And in recent studies in fact this is confirmed in humans, Jack one actually lights up a very distinct cluster of human, it's specific neurons at the single cell level as well. So again highly conserved. But we were able to predict then that perhaps if we can choke upside kinds that we don't haven't even discovered or map that what they do, you know, spend a whole are one cycle trying to figure out what one sided kind does. We could just jump ahead and go go into these jack pathways. And there were drugs already available that we could uh perhaps use uh to to really figure out if this really works. And we felt that this kind of activity by using JAK inhibitors would result in rapid, potent and broad anti itch activity. And in fact this is what we've seen in phase three trials now with a personal which is now approved for moderate to severe a topic dermatitis, pattison, Jak one selective inhibitor as well. And we played a hand in this as well. We again uh instigated uh the uh pivotal Phase two trials for topical Rexall in which is now approved and you can get, it was actually the first JAK inhibitor approved for uh in dermatology. And we've used JAK inhibitors, we could get our hands on in patients with idiopathic priorities. These are patients that are suffering dearly. This is mostly what I see in the clinic. They've seen 67 dermatologists coming from all over the country and anecdotally we found that these patients can do well as well. And we feel that randomized trials are certainly warranted and um we would love to see that happen, but this is to highlight the therapeutic landscape in the development landscape is just incredibly vast and the efficacy of these pathways has really proven their worth. And we think that beyond the anti inflammatory paradigm, there is a truly bona fide neuromodulation Torey paradigm that we can actually take advantage of. And recently fang wang, a postdoctoral fellow who's now vice director of the department at the first affiliated hospital and full professor identified that also even in a topic dermatitis, if we go back to it, uh the chronic inflammation and topic dermatitis results in activation of besa fills that activates an alternative immunological circuit that actually underlies the acute itch flares. We think in a topic dermatitis it activates a unique pathway by way of Luca try and see for non histamine ergic and what's emerging is that a lot of these pathways at the neuro immune interface actually converge upon many of the same neurons and these represent both molecular and cellular targets for therapy in the future. And what's interesting about it just I mentioned, it's very overlooked, it was probably one of the most underfunded areas uh yet the translational successes is quite striking. In other words, the return on investment for this field has just been amazing and we're starting to see how really big of a problem. This is. So sometimes the solution reveals how big of the problem actually really was. But the other interesting thing is people are finding again, the neuroscientists are finding that there are, its specific neurons, even within the vagus nerve which innovates the viscera, the heart, the lungs, and the gut, why would you itch in those areas? You don't? And and what's interesting is that these they're not really looking for these nerves and they have the same molecular machinery and and so what's going on here? And so we verified this as well, masato. Tomorrow, very talented postdoctoral fellow looked at Trip V one expression, the sensor cat ion channel. And if I blinded you to the vagal ganglia and the dorsal root ganglia, you would think you wouldn't be able to tell the difference. In fact, 80% of the vagus nerve is actually sensory something I did not realize until recently and in fact, what I've been talking about entirely is the somatic affluence. You know that the nerves in the skin that immediate itch. But we don't even know what these spinal visceral difference which also innovate the visceral do. It's a complete mystery. I mean, it's an absolute frontier. The vagus nerve is a sensory nerve very little. No, and so what we actually think is that it represents actually a paradigm of irritation. Um and in fact, if you look at this paper from neuron in the context of migraine. If you look in the trigeminal ganglia, this is the itch nerve. If you go from mouse to human, you see increased expression of neuro peptide CTRP. So why neuro peptide, what we think is, yes, cytokines can hit the nerve and cause all matter of sensory dysfunction and you might get rich but these nerves actually have the machinery to release neuro peptides and influence the scope and intensity of inflammation. And in fact individuals here Nicole ward dan Kaplan, others like von Andrian Isaac chiu have really been in this space how the neurons actually regulate inflammation. So the idea that just itch or pain of hot nerve can cause is a truly inflammatory state is an emerging paradigm. So what we think is it is probably the tip of a sensory iceberg, the molecular and cellular cellular machinery which might actually even better represent a lot of these irritable conditions. We talked about pain earlier, it may be that even pain is not the right description. So the science may actually indicate that it is a better paradigm to approach a lot of these conditions that are all unmet lacking therapies and huge, huge areas within medicine. So we started with steve what causes a rash. G. V. H. D. Went into unexpectedly into neuro immunology which we're able to then help accelerate and inform therapeutic developments, clinical trials new FDA approved drugs but then also reverse translate this and to identify new forms of itch and also perhaps revise sensory paradigms to think about things differently. Well beyond the skin as well. I want to thank the individuals who did the work. Uh many of them are the former members that I highlighted. We have a very growing lab at Mount Sinai in new york are wonderful collaborators. I really want to highlight names uh as the directors here, we've made good on our promise um and then um and then Emma Guttman who recruited me to Mount Sinai who's just absolutely building a fantastic department, Please join us. Um and uh lastly I wanna highlight uh this was back in 2005 with steve and then later he came to visit me when I was at washoe building up the lab. And it was just, and he was with my students and it was such a great time and I think these pictures do represent how he really does build family. You know, I trained with steve and he meant towards john Stanley and used to have amy Pain here who trained with john Stanley and here we are together um all taking deep interest in each other for years to come. So thank you very much. It's a true honor to be presenting in tribute to steve. Thank you very much. Wonderful top. I can, I think I can say without any doubt that steve would have been so proud of you. Uh you've done such a fantastic job in opening a new field and an innovative field and in that we will end our session. Thank you very much all for attending
