Peripheral nerve agonists suppress inflammation

Small-molecule agonists to suppress unwanted immune responses without inducing global immune suppression.

Mast cells are specific types of white blood cells that form part of the immune and neuroimmune systems and are best known for their roles in allergies, anaphylaxis, immune tolerance, pathogen defense, and as such are key to the inflammatory process. Thus, finding a way to suppress mast cell activation in tissues without inducing global immune suppression could be critical in treating dangerous inflammatory conditions.

Technology Description

Based on a discovery that neurons that promote painful sensations and also drive inflammation in the skin, researchers at the University of Pittsburgh determined that a specific subset of neurons that innervate the epidermis as well as the intestine are required to suppress the activation of inflammation-causing mast cells. This unique group of neurons express a protein which, when treated with its corresponding small-molecule agonist, suppresses cutaneous mast cell function. This discovery indicates that small-molecule agonists of this neuron type could be used to suppress mast cell activation without inducing global immune suppression, fulfilling an as-yet unmet therapeutic need.

Advantages

* Suppresses mast cell activation without inducing global immune suppression
* Small-molecule agonists can be given topically, orally, or parentally
* Some identified agonists already used in over-the-counter applications

Applications

* Agonizing neurons to beneficially affect immune function, thus suppressing mast cell function
* Suppression of cutaneous inflammation, specifically: all forms of acute or chronic urticaria, mastocytosis, pseudo-allergy, all forms of dermatitis, wound healing, rosacea, acne, and psoriasis
* Suppression of neurogenic inflammation, pain, and itch
* Uses in other tissues include treatments for asthma, angioedema, and diarrhea
* Treatment for all other diseases in which mast cells play a pathogenic role

White blood cells dictate host immune response, and suppressing cutaneous mast cell function via small molecule agonists could be key to treating a number of inflammatory conditions.

Stage of Development

In vivo data

IP Status

Provisional patent application filed

Daniel H. Kaplan, MD, PhD

Professor, Departments of Dermatology and Immunology, University of Pittsburgh

The skin is a barrier organ that is exposed to a wide variety of potential pathogens including bacteria, fungi and viruses. Within the skin there are numerous components of both the innate and adaptive immune system. The research focus of my NIH-funded lab is to understand how these skin resident immune cells (e.g. dendritic cells, T cells) interact with specific pathogens and other non-immune cells in the skin to contribute to the development of both innate and adaptive immune responses that provide host protection. He has been awarded the AHC Young Investigator Award, the McKnight Land Grant Professorship, and the Dr. Al Zelickson Endowed Professorship during his time as an associate professor at the University of Minnesota. He has also been honored with the Young Leader Award from the American Dermatological Association.

Education

Residency, Dermatology, Yale University
Postdoctoral Fellowship, Yale University
PhD, Immunology, Washington University in St. Louis
MD, Washington University in St. Louis
BS, Molecular Biophysics and Biochemistry, Yale

Recent Publications

* Cutaneous TRPV1+ Neurons Trigger Protective Innate Type 17 Anticipatory Immunity. Cohen JA, Edwards TN, Liu AW, Hirai T, Jones MR, Wu J, Li Y, Zhang S, Ho J, Davis BM, Albers KM, Kaplan DH. Cell. 2019 Aug 8;178(4):919-932.e14. doi: 10.1016/j.cell.2019.06.022. Epub 2019 Jul 25. PMID: 31353219
* Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. Menter A, Strober BE, Kaplan DH, Kivelevitch D, Prater EF, Stoff B, Armstrong AW, Connor C, Cordoro KM, Davis DMR, Elewski BE, Gelfand JM, Gordon KB, Gottlieb AB, Kavanaugh A, Kiselica M, Korman NJ, Kroshinsky D, Lebwohl M, Leonardi CL, Lichten J, Lim HW, Mehta NN, Paller AS, Parra SL, Pathy AL, Rupani RN, Siegel M, Wong EB, Wu JJ, Hariharan V, Elmets CA. J Am Acad Dermatol. 2019 Apr;80(4):1029-1072. doi: 10.1016/j.jaad.2018.11.057. Epub 2019 Feb 13. Review.
* Cutaneous immune responses mediated by dendritic cells and mast cells. Sumpter TL, Balmert SC, Kaplan DH. JCI Insight. 2019 Jan 10;4(1). pii: 123947. doi: 10.1172/jci.insight.123947. Review. PMID:30626752
* Keratinocyte-Mediated Activation of the Cytokine TGF-β Maintains Skin Recirculating Memory CD8+ T Cells. Hirai T, Zenke Y, Yang Y, Bartholin L, Beura LK, Masopust D, Kaplan DH. Immunity. 2019 May 21;50(5):1249-1261.e5. doi: 10.1016/j.immuni.2019.03.002. Epub 2019 Apr 2. PMID: 30952606
* Ontogeny and function of murine epidermal Langerhans cells. Kaplan DH. Nat Immunol. 2017 Sep 19;18(10):1068-1075. doi: 10.1038/ni.3815. Review. PMID: 28926543
* Antigen-Presenting Cells in the Skin. Kashem SW, Haniffa M, Kaplan DH. Annu Rev Immunol. 2017 Apr 26;35:469-499. doi: 10.1146/annurev-immunol-051116-052215. Epub 2017 Feb 6. Review. PMID: 28226228
* Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β. Mohammed J, Beura LK, Bobr A, Astry B, Chicoine B, Kashem SW, Welty NE, Igyártó BZ, Wijeyesinghe S, Thompson EA, Matte C, Bartholin L, Kaplan A, Sheppard D, Bridges AG, Shlomchik WD, Masopust D, Kaplan DH. Nat Immunol. 2016 Apr;17(4):414-21. doi: 10.1038/ni.3396. Epub 2016 Feb 22.
* Nociceptive Sensory Fibers Drive Interleukin-23 Production from CD301b+ Dermal Dendritic Cells and Drive Protective Cutaneous Immunity. Kashem SW, Riedl MS, Yao C, Honda CN, Vulchanova L, Kaplan DH. Immunity. 2015 Sep 15;43(3):515-26. doi: 10.1016/j.immuni.2015.08.016. Erratum in: Immunity. 2015 Oct 20;43(4):830. PMID: 26377898
* Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Kashem SW, Igyarto BZ, Gerami-Nejad M, Kumamoto Y, Mohammed JA, Jarrett E, Drummond RA, Zurawski SM, Zurawski G, Berman J, Iwasaki A, Brown GD, Kaplan DH. Immunity. 2015 Feb 17;42(2):356-366. doi: 10.1016/j.immuni.2015.01.008. Epub 2015 Feb 10. PMID: 25680275