TMED Student Showcase: Tezepelumab in Allergic Rhinitis and asthma Study (TEZARS) and the Role of the Periocular Mucosa in Immune Responses

TMED Blog

| 23 March 2024

Written by Rachel Di Iorio, MSc 25' (Candidate)

On March 7th, the Department of Medicine had the pleasure of hearing from Abbie Davis and Jana Livingston, two Translational Medicine (TMED) graduate students whose remarkable research was showcased at Medical Grand Rounds. Abbie is a second-year MSc student, currently transitioning into a PhD under the supervision of Dr. Anne Ellis. Jana is a PhD student completing her studies under the supervision of Dr. Jacob Rullo.

Abbie presented her work regarding the Tezepelumab in Allergic Rhinitis and asthma Study (TEZARS). Allergic asthma (AA), impacting 300 million people worldwide, is a chronic airway disease resulting in bronchoconstriction and mucus hypersecretion.1-4 Allergic rhinitis (AR), an immunoglobulin E (IgE) mediated inflammation of the nasal mucosa, impacts 80% of allergic asthmatics.1-3 Patients who are comorbid for AR and AA experience greater asthma severity and greater healthcare usage, emphasizing the additive effects of comorbidity among these conditions.5,6

It is well studied that thymic stromal lymphopoietin (TSLP) is involved in the initiation and persistence of inflammatory pathways in asthma, however, the role of TSLP in AR is largely neglected in the literature.7-9 Tezepelumab, a monoclonal anti-TSLP antibody,10 was recently approved in Canada to treat asthma patients, but has not been studied in patients comorbid for AR. The CATNIP study looked at Tezepelumab in cat-sensitized AR patients, concluding that Tezepelumab alone did not significantly reduce AR symptoms versus placebo.11 However, the study is limited in that it only investigates cat allergen, does not study comorbid AR and AA patients, and its repeatability is unknown.

TEZARS, working to bridge this gap in knowledge, will test the use of Tezepelumab in comorbid patients aged 18-65. A validated and optimized model of the nasal allergen challenge (NAC) will deliver individual concentrations of allergen into the nose. Then, patients will receive a total of 12 doses of Tezepelumab over a span of 12 months, with follow-up NAC performed at 6-month points. To determine the effectiveness of Tezepelumab in comorbid patients, validated tests will be performed to measure changes in symptoms and quality of life. Additionally, TEZARS will evaluate the mechanism of action of Tezepelumab in comorbid patients by collecting nasal secretions and cells to quantify eosinophil cell count, IgE in the blood, and TSLP concentration.

Jana presented her research regarding the role of the eye in contributing to antiviral immunity. The motivation behind this research is the poor understanding of the relationship between viral entry and immune response, and the lack of investigation into mucosal vaccines. The periocular mucosa is constantly surveying the external environment; however, it rarely succumbs to infection, making it an ideal model to study viral infection.12,13 As tears drain from the eye, they travel systemically while carrying pathogens from the external environment.14 Thus, ocular exposure can generate a systemic immune response, observed in tetanus toxoid, salmonella, and H1N1 influenza.15-17 Jana’s goal is to determine whether the eye, when exposed to pathogens, can prime the immune system for subsequent exposure both locally and systemically.

Measures of weight and temperature in mouse models deduced that topical ocular exposure of murine coronavirus (MHV-1) does not produce observable symptoms of infection. 7-days post-infection, Jana observed signs of both local and systemic innate and adaptive immune responses with tissue-specific differences, evidenced by the upregulation of myeloid cells, B-cells, and T-cells. Additionally, results show that the innate immune response peaks 4-5 days post-infection, whereas the delayed adaptive immune response peaks 7-8 days post-infection.

Together, these results show that MHV-1 induces a local and systemic immune response with upregulation of innate and adaptive immune players. Jana’s findings emphasize that exposure at the eye can induce a safe and robust immune response, proving useful in eliciting future studies on immunization. She highlighted that the next steps in her PhD work will be to investigate immunological memory and downstream protective effects post-ocular exposure to murine coronavirus.

Following their presentations, Abbie and Jana met with TMED students to discuss aspects of their projects, including how their work benefits patients, the triumphs and challenges in their research, and their academic and career journeys within the TMED program. Both students underlined the translational capabilities of their work, including the potential to change first-line treatments, increase accessibility of vaccines, and improve patient outcomes. It was both reassuring and motivating for current TMED students to hear Abbie and Jana discuss their resiliency when facing setbacks in research, along with the importance of mentorship and having a strong support system.

On behalf of TMED students, I would like to thank Abbie and Jana for their insightful presentations and discussions.

References

1. Acevedo-Prado A, Seoane-Pillado T, Lopez-Silvarrey-Varela A, et al. Association of rhinitis with asthma prevalence and severity. Sci Rep. Apr 16 2022;12(1):6389. doi:10.1038/s41598-022-10448-w

2. Bousquet J, Anto JM, Bachert C, et al. Allergic rhinitis. Nat Rev Dis Primers. Dec 3 2020;6(1):95. doi:10.1038/s41572-020-00227-0

3. Rosati MG, Peters AT. Relationships among allergic rhinitis, asthma, and chronic rhinosinusitis. Am J Rhinol Allergy. Jan-Feb 2016;30(1):44-7. doi:10.2500/ajra.2016.30.4252

4. Habib N, Pasha MA, Tang DD. Current Understanding of Asthma Pathogenesis and Biomarkers. Cells. Sep 5 2022;11(17)doi:10.3390/cells11172764

5. Tiotiu A, Plavec D, Novakova S, et al. Current opinions for the management of asthma associated with ear, nose and throat comorbidities. Eur Respir Rev. Dec 31 2018;27(150)doi:10.1183/16000617.0056-2018

6. Kaplan A, FitzGerald JM, Buhl R, Vogelberg C, Hamelmann E. Comparing LAMA with LABA and LTRA as add-on therapies in primary care asthma management. NPJ Prim Care Respir Med. Nov 11 2020;30(1):50. doi:10.1038/s41533-020-00205-9

7. Li Y, Wang W, Lv Z, et al. Elevated Expression of IL-33 and TSLP in the Airways of Human Asthmatics In Vivo: A Potential Biomarker of Severe Refractory Disease. J Immunol. Apr 1 2018;200(7):2253-2262. doi:10.4049/jimmunol.1701455

8. Chorvinsky E, Nino G, Salka K, Gaviria S, Gutierrez MJ, Pillai DK. TSLP bronchoalveolar lavage levels at baseline are linked to clinical disease severity and reduced lung function in children with asthma. Front Pediatr. 2022;10:971073. doi:10.3389/fped.2022.971073

9. Ying S, O'Connor B, Ratoff J, et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. Aug 15 2008;181(4):2790-8. doi:10.4049/jimmunol.181.4.2790

10. Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N Engl J Med. May 13 2021;384(19):1800-1809. doi:10.1056/NEJMoa2034975

11. Corren J, Larson D, Altman MC, et al. Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: A randomized controlled trial. J Allergy Clin Immunol. Jan 2023;151(1):192-201. doi:10.1016/j.jaci.2022.08.029

12. Kugadas A, Gadjeva M. Impact of Microbiome on Ocular Health. Ocul Surf. Jul 2016;14(3):342-9. doi:10.1016/j.jtos.2016.04.004

13. Sun CB, Wang YY, Liu GH, Liu Z. Role of the Eye in Transmitting Human Coronavirus: What We Know and What We Do Not Know. Front Public Health. 2020;8:155. doi:10.3389/fpubh.2020.00155

14. Mestecky J. The Common Mucosal Immune System and Current Strategies for Induction of Immune Responses in External Secretions. J Clin Immunol. 1987;7(4)doi:0271-9142/87/0700-0265505,00/

15. Barisani-Asenbauer T, Inic-Kanada A, Belij S, et al. The ocular conjunctiva as a mucosal immunization route: a profile of the immune response to the model antigen tetanus toxoid. PLoS One. 2013;8(4):e60682. doi:10.1371/journal.pone.0060682

16. Seo KY, Han SJ, Cha HR, et al. Eye mucosa: an efficient vaccine delivery route for inducing protective immunity. J Immunol. Sep 15 2010;185(6):3610-9. doi:10.4049/jimmunol.1000680

17. Yoon S, Kim ED, Song MS, et al. Eyedrop Vaccination Induced Systemic and Mucosal Immunity against Influenza Virus in Ferrets. PLoS One. 2016;11(6):e0157634. doi:10.1371/journal.pone.0157634

TMED Student Showcase: Tezepelumab in Allergic Rhinitis and asthma Study (TEZARS) and the Role of the Periocular Mucosa in Immune Responses

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TMED Student Showcase: Tezepelumab in Allergic Rhinitis and asthma Study (TEZARS) and the Role of the Periocular Mucosa in Immune Responses

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