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Identification of lineage-specific marker for therapeutic targeting of mast cells

Plum, Thomas

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Abstract

The number of people in the modern world being affected by allergic diseases and asthma has reached epidemic proportions. With over 1 out of three people requiring some sort of treatment for allergic disease, the burden placed onto industrialized nations healthcare systems is increasing. Mild forms of allergic diseases, such as allergic rhinitis, can be treated with anti-histamines or immunological desensitization. However, more severe forms of disease, such as asthma and atopic dermatitis, require a reduction of systemic inflammation by administration of broad acting systemic immunosuppressants, to effectively alleviate symptoms. However, systemic immunosuppression often results in susceptibility to infection. Mast cells, which are evidently involved in numerous allergic pathologies, have not been adequately targeted by conventional therapeutics. Specific removal of mast cells, by means of antibody-dependent depletion, would interrupt the allergic cascade and might yield significant benefit for patients. In order to develop such a mAb- mediated mast cell ablation approach we sought to established proof of principle in a well-controlled system with our newly developed transgenic mouse model. The Cpa3hCD4 mouse model expresses a truncated human CD4 receptor from a knockin into the mast cell specific Cpa3 locus. With this model system, employing an artificial mast cell marker cell surface protein, we could show that several tissue-resident mast cell compartments can be safely and efficiently depleted after intravenous α- hCD4 administration. To identify a physiologically relevant target on the surface of mast cells, we underwent extensive mass spectrometry-assisted proteomic profiling of primary mouse and human mast cells. Analysis of the data revealed a cross- species conserved mast cell protein signature, among which we found several drugable receptors. Quantitative analysis, paired with flow cytometry-based verification of the cell surface expressed mast cell proteins allowed us to identify several highly expressed mast cell specific cell surface markers. Targeting of one of these receptors with an α-CD63-Immunotoxin resulted in the efficient depletion of mast cells in vitro. In vivo however, efficacy of mast cell depletion was limited by excessive on-target toxicities. Along these lines, we are currently evaluating the herein identified physiological mast cell targets for cellular depletion by different antibody-mediated mechanisms.

Item Type: Dissertation
Supervisor: Rodewald, Prof. Dr. Hans-Reimer
Date of thesis defense: 21 September 2017
Date Deposited: 15 Jan 2019 13:16
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Service facilities > German Cancer Research Center (DKFZ)
Subjects: 500 Natural sciences and mathematics
Uncontrolled Keywords: Mast cells, allergy, immunotherapy
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