Unwanted immune responses by mast cells contribute to the symptoms of allergies and asthma. In the proposed research we seek to harness members of the Siglec family of inhibitory receptors to suppress allergen mediated IgE dependent activation and degranulation of human mast cells, and desensitize them to subsequent antigen challenge. To this end we will employ Siglec tolerizing allergenic liposomes (STALs) that display both an allergen and synthetic high affinity glycan ligand of a Siglec expressed on mast cells. When STALs encounter a mast cell pre-sensitized with an allergen specific IgE bound to the high affinity IgE receptor ?RI), the glycan ligand will recruit the inhibitory Siglec to the immunological synapse. While liposomes with antigen alone will powerfully activate the cells, the glycan ligand on STALs is hypothesized to recruit the inhibitory Siglec and dampen or suppress activation and degranulation. In this project we will focus on two Siglecs on human mast cells, namely CD33 and Siglec-8. We will assess the impact of STALs for desensitizing human mast cells in models of passive cutaneous and passive systemic anaphylaxis using transgenic mice with mast cells expressing a human Siglec (Siglec-8 and CD33) and a human Fc?RI receptor, and humanized mice engrafted with human CD34+ stem cells that populate the mouse with human mast cells. A portion of our effort will also be devoted to improving the specificity of the synthetic ligand for Siglec-8 and develop a novel ligand for the Siglec-6 receptor, a mast cell target for Project 1. (Fc 0

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI136443-03
Application #
9852968
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Khoury, Paneez; Bochner, Bruce S (2018) Consultation for Elevated Blood Eosinophils: Clinical Presentations, High Value Diagnostic Tests, and Treatment Options. J Allergy Clin Immunol Pract 6:1446-1453
Bochner, Bruce S (2018) The eosinophil: For better or worse, in sickness and in health. Ann Allergy Asthma Immunol 121:150-155
Gonzalez-Gil, Anabel; Porell, Ryan N; Fernandes, Steve M et al. (2018) Sialylated keratan sulfate proteoglycans are Siglec-8 ligands in human airways. Glycobiology 28:786-801
Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83
Bolden, Jessica E; Lucas, Erin C; Zhou, Geyu et al. (2018) Identification of a Siglec-F+ granulocyte-macrophage progenitor. J Leukoc Biol 104:123-133
Johansson, Mats W; Kelly, Elizabeth A; Nguyen, Christopher L et al. (2018) Characterization of Siglec-8 Expression on Lavage Cells after Segmental Lung Allergen Challenge. Int Arch Allergy Immunol 177:16-28
Wei, Yadong; Chhiba, Krishan D; Zhang, Fengrui et al. (2018) Mast Cell-Specific Expression of Human Siglec-8 in Conditional Knock-in Mice. Int J Mol Sci 20:
Legrand, Fanny; Cao, Yun; Wechsler, Joshua et al. (2018) Siglec-8 in eosinophilic disorders: receptor expression and targeting using chimeric antibodies. J Allergy Clin Immunol :
Yu, Huifeng; Gonzalez-Gil, Anabel; Wei, Yadong et al. (2017) Siglec-8 and Siglec-9 binding specificities and endogenous airway ligand distributions and properties. Glycobiology 27:657-668