(3im) Engineering Immune Responses Using Chemical Tools.

Complex immunological problems such as autoimmune diseases and evasive infections often require elegant, multidisciplinary solutions to diagnosis, study and treat. My multidisciplinary background and experience in engineering, chemistry, biology and immunology affords me a unique opportunity to apply chemical tools towards these immunological problems.

PhD Research, University of Notre Dame, Advisor: Dr. Basar Bilgicer

My training, both in chemistry and immunology, has been exceptionally productive. As a graduate student, I developed chemical tools to treat and diagnose type 1 hypersensitivity reactions (allergies) to both food and drugs. By modifying liposomes with allergy epitopes, I created a diagnostic system for both peanut and penicillin allergies. This technique was also modified to become the first reliable diagnostic test for chemotherapeutic drug allergies. Using the knowledge gleaned from the allergy diagnostic project, I developed a targeted inhibitor for the allergen specific antibodies responsible for allergies for both penicillin and peanut allergies. While the work was primarily translational, my peanut inhibitor work revealed that only a small number of peanut allergy epitopes are crucial for strong allergic reactions.

Postdoctoral Research, University of Chicago, Pritzker School of Molecular Engineering, Advisor: Dr. Aaron Esser-Kahn

My most recent work is focused on innate immune cells in two distinct areas. The most prominent is using toll-like-receptor (TLR) agonist conjugated microparticles (MPs) to identify and characterize a unique highly TLR agonist responsive DC subtype. A subset of DCs, which we call First Responder cells or FRs (<5% of all DCs) phagocytoses an unusually high number of MPs and has increased immune activation. I isolated these cells, identified their phenotype as a subset of cDC2 cells, identified several unique surface markers for FRs and demonstrated that they facilitate adaptive immune responses via paracrine signaling. Currently, I am developing FR targeted vaccine formulations for difficult to vaccinate diseases, such as HIV and TB. The other distinct area of innate immune research is using the TLR conjugated microparticles to perform quantitative measurements of TLR activation thresholds. By measuring the number of TLR agonists conjugated to the MP surface and the number of MPs phagocytosed by an innate immune cell, I can calculate a number of TLR agonists required to trigger cellular activation, as measured by TNFα secretion. Taken as a whole, my research experience has spanned a number of immunological topics, deploying chemical and biochemical tools to measure and modulate immune interaction.

Research Awards: NIH Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship (Parent F32) 2019, CBE GSO Symposium Outstanding Session Speaker, (Chemical and Biomolecular Engineering Department), 2016, Outstanding Presentation Award, (Chemistry Biology Biochemistry Interface Program) 2016, Three Minute Thesis Competition Finalist, (University of Notre Dame Graduate School) 2016.

Publications:

Deak, P.E., Kimani, F, Cassaidy B, Esser-Kahn A.E. “Determining Whether Agonist Density or Agonist Number Is More Important for Immune Activation via Micoparticle Based Assay” Front. Immunol., 09 April 2020.

Deak, P. E.; Studnitzer, B.; Steinhardt, R.; Esser-Kahn, A. Identification, Characterization, and Targeting of a Rare and Temporal Dendritic Cell State That Facilitates Adaptive Immune Responses. bioRxiv 2020, 2020.10.08.331744. https://doi.org/10.1101/2020.10.08.331744.

Deak, P.E, Baksun Kim, Amina Abdul Qayum, Jaeho Shin, Girish Vitalpur, Kirsten M. Kloepfer, Matthew J. Turner, Neal Smith, Wayne G. Shreffler, Tanyel Kiziltepe, Mark H. Kaplan and Basar Bilgicer. Designer Covalent Heterobivalent Inhibitors Prevent Peanut Induced Mast Proc Natl Acad Sci U S A. 2019 Apr 30; 116(18): 8966–8974. Published online 2019 Apr 8. doi: 10.1073/pnas.1820417116

Deak, P. E., Baksun Kim, Byunghee Koh, Amina Abdul Qayum, Tanyel Kiziltepe, Mark H. Kaplan and Basar Bilgicer. “Covalent Heterobivalent Inhibitor Design for Inhibition of IgE-Dependent Penicillin Allergy in a Murine Model..”, J Immunol. 2019 Jul 1;203(1):21-30. doi: 10.4049/jimmunol.1900225. Epub 2019 May 17.

Deak, P. E, Baksun Kim, Ather Adnan, Marina Labella, Leticia De las Vecillas, Mariana Castells and Basar Bilgicer. Nanoallergen Platform for the Detection of Platin Drugs Allergies. Journal of Allergy and Clinical Immunology. To appear in Journal of Allergy and Clinical Immunology (Revisions pending)

Deak, P. E., Vrabel, M. R., Kiziltepe, T., Bilgicer, B. (2017). Nanoallergens: A Multivalent Platform for Studying and Evaluating Potency of Peanut Allergy Epitopes in Cellular Degranulation. Scientific Reports, 7(1), 3981.

Deak, P. E., Vrabel, M. R., Pizzuti, V. J., Kiziltepe, T., Bilgicer, B. (2016). Nanoallergens: A Multivalent Platform for Studying and Evaluating Potency of Allergen Epitopes in Cellular Degranulation. Experimental Biology and Medicine, 241(9), 996-1006.

Stefanick JF, Omstead DT, Ashley JD, Deak PE, Mustafaoglu N, Kiziltepe T, Bilgicer B. “Optimizing design parameters of a peptide targeted liposomal nanoparticle in an in vivo multiple myeloma disease model after initial evaluation in vitro. J Control Release. 2019 Oct;311-312:190-200. doi: 10.1016/j.jconrel.2019.08.033. Epub 2019 Aug 29.

Handlogten, M. W., Deak, P., Bilgicer, B. Z. (2014). Two-Allergen Model Reveals Complex Relationship between IgE Crosslinking and Degranulation. Cell Press Chemistry and Biology, 21(11), 1445–1451.

Handlogten, M. W., Stefanick, J. F., Deak, P., Bilgicer, B. (2014). Affinity-based precipitation via a bivalent peptidic hapten for the purification of monoclonal antibodies. Analyst, 17(139), 4247-4255.

Future Research Interests:

My future research plans will have similar themes but focus mainly upon leveraging chemical tools for autoimmune therapies. One major problem for autoimmune diseases is that they widely vary in their pathogenesis and symptoms; however, they do share an underlying cause, namely the inappropriate activation of immunity via self-antigen presentation leading to auto-reactive adaptive (T and B cell) responses. My proposal seeks to modulate the initial self-antigen presentation by activated antigen-presenting cells (APC) toward a more tolerogenic phenotype as a treatment for autoimmunity. In normal development of immunity, APCs are activated via molecular pattern recognition receptors (PPR) and present a local antigen to adaptive immune cells. In this case, any self-antigens are accompanied with various inhibitory signals leading to self-antigen specific T regulatory cells (Treg) that actively suppress autoreactive responses to the self-antigen. I plan to treat autoimmunity by mimicking this natural response and use a combination of chemical signals to alter the APC phenotype to generate Treg responses that abrogate autoimmune T and B cells in a process I call “molecular immune tuning” or MIT.

Most clinical autoimmune therapies rely upon broad immunosuppressive drugs that impair multiple immune signaling cascades in both innate and adaptive immune cells, thereby reducing symptoms associated with overactive self-immunity but also reducing overall immune effectiveness. Rather than broad immune suppression, I plan to combine activating and inhibitory signals for a particular PPR called toll-like-receptors (TLR) present on APCs to generate a more “active” (by leading to the development of antigen specific Tregs) and specific (by targeting APCs) immune suppression rather than non-specific inhibitory signals alone. Furthermore, I plan to improve the tolerogerizing potential of this therapy by specifically targeting APCs that are more inclined to facilitate T regulatory responses. In addition to the translational outcomes of this project, I anticipate that the MIT project will also yield more understanding into the mechanism of inhibitory/activation balance in innate immune cells and DCs in particular.

Furthermore, my future research plans will also branch out into different areas of immunology in the following areas: (1) FR targeted vaccines, (2) autoinflammatory disease diagnostics and therapeutics and (3) quantitative immunology. I plan to continue working on FR targeted vaccine formulation and moving them into more translational diseases such as HIV and TB. Furthermore, I also plan on targeted FRs with inhibitory molecules as a potential “vaccine” against autoimmune disease. For autoinflammatory diseases, I plan to develop novel diagnostics for IL-1β detection by innate cells, given that serum IL-1β is a well-known diagnostic criterion for autoinflammatory diseases, but is known to fluctuate widely. I will also develop novel therapeutics for an autoinflammatory condition, mast cell activation syndrome, by designing molecules to cluster the receptor CD23 for inhibition of mast cell signals. Finally, I can use my experience in both chemistry and immunology to successfully increase our fundamental knowledge of immune interactions by quantitively measuring immune interactions (innate cell-pathogen interactions, T cell-APC interactions, ect...).

Teaching Interests:

Both as a graduate student and postdoctoral researcher, I have had many opportunities to gain experience in a classroom setting. As a graduate student, I was a teaching assistant for Transport Phenomena and Intro Bioengineering classes where I held office hours, graded the student’s work, and performed a few guest lectures. I was also involved in as a mentor to an undergraduate fermentation-based energy project at Notre Dame. Later in my career, I had an opportunity 2-3 times per year to give a lecture for my advisor’s advanced bioengineering course, which I deeply enjoyed. I have also had the opportunity several times to do this for my postdoctoral advisor. These experiences have given me a great appreciation for teaching and a willingness to teach any core chemical engineering class (particularly Transport Phenomena) and bioengineering or immune-engineering based courses.