The Mariana Castells Laboratory

Overview

The Castells Laboratory investigates the cellular and molecular mechanisms underlying IgE mast cell activation and desensitization in human and mouse mast cell phenotypes, and the role of phosphatases such as SHIP-1 in inhibitory mast cell mechanisms. The major goal focuses on advancing fundamental understanding of mast cell biology and mast cell IgE activation and desensitization and translating these discoveries into clinical innovation. The laboratory has identified mast cell inhibitory pathways directly relevant to IgE desensitization and leveraged these insights to develop safer, more effective protocols and strategies for patients with food and drug allergy. Its translational research includes Basophil Activation Test (BAT) for the diagnosis and risk stratification of patients with chemotherapy and monoclonal antibody hypersensitivity. The laboratory has pioneered the treatment of mast cell activation disorders and mastocytosis, bridging fundamental immunologic discovery with transformative patient care worldwide.

Research Projects

Mast Cell Inhibitory Pathway Mechanism

A central focus of our laboratory is understanding mast cell inhibitory mechanisms and the molecular basis of IgE drug desensitization. The Castells laboratory cloned the first ITIM-containing mast cell inhibitory receptor, mouse gp49B1/human LILRB4, and developed an in vitro antigen-IgE-mast cell desensitization system that diverts signal transduction and blocks mediator release from mast cells. The work has been the platform for the development of human desensitization protocols, protecting patients from anaphylaxis upon re-exposure to first-line medications to which they have become allergic. The Castells laboratory has identified SHIP-1, a key intracellular phosphatase, as a critical regulator of mast cell activation during early desensitization. Monophosphorylation of beta and gamma chain ITAMs of the FceRI by providing suboptimal antigen doses attracts single SH2 binding site molecules such as SHIP-1 generating inhibitory ITAMs, thereby redirecting signaling pathways and preventing IgE-mediated mast cell activation. The Castells laboratory is interested in investigating additional intracellular signaling molecules in vitro and in vivo models, including other phosphatases and kinases, to understand how the balance between mast cell activation and inhibition is maintained during desensitization. Uncovering the molecular and mechanistic basis of IgE desensitization will allow identification of novel pharmacologic strategies to enhance its safety and efficacy in food and drug allergy.

Carboplatin IgE Allergy and Desensitization

Carboplatin is known to induce a high rate of hypersensitivity reactions, and after multiple exposures up to 1/3 of patients can present anaphylaxis. Most of the reactions to carboplatin and other platins such as cisplatin and oxaliplatin are IgE-mediated and mast cell driven and can be modulated with desensitization, yet their underlying mechanisms remain poorly understood. To address this, the Castells lab uses in vitro mouse and human tissue mast cell subsets, including mucosal-type mast cells (MCt) and connective tissue-type mast cells (MCtc), together with active and passive in vivo mouse models. Cell culture, FACS, single cell RNA analysis and multiplex cytokine analysis are used to define cellular and molecular signatures and mechanisms of platins allergy and desensitization. Pharmacologic interventions, such as BTK inhibition and SHIP-1 agonists are being studied to identify new strategies for safer and more efficient IgE desensitization.

Basophil Activation Testing BAT for Chemotherapy and Monoclonal Antibodies

The Castells laboratory is advancing the use of the basophil activation test (BAT), a specific test that detects ex vivo IgE-mediated reactions in human basophils. BAT is being pioneered for the diagnosis of chemotherapy drugs and targeted monoclonal antibodies among other drugs. The gold standard to detect drug allergy is skin testing which poses a risk to patients by exposing them to a drug that has induced a life-threatening reaction, is time consuming and can only be done several days to weeks after the initial reaction, delaying care. The Castells laboratory is focusing on validating BAT for drug-induced hypersensitivity as a diagnostic tool to help identify allergic patients, to provide risk stratification, and to guide safe management throughout treatment. This approach aims at improving timely drug allergy diagnosis, increasing patient safety and providing personalized care for patients with cancer and chronic inflammatory diseases in need of first line therapies.

Food Allergy

Food allergy is the leading allergic disease of modern society with over 10% of children presenting peanut or other foods allergy in the first years of life. Reactions to foods may occur at first exposure, are unexpected, can be unpredictable, and life-threatening. Oral allergy immunotherapy OIT is a groundbreaking immunotherapy approach protecting patients from severe reactions, and in some cases allowing them to ingest previously allergic foods, but the mechanisms and molecular players are still unknown, compromising its safety. Understanding and dissecting mast cell reactions to food allergens is necessary to improve OIT. The Castells laboratory has developed the first in vitro IgE desensitization model for human MCt and MCtc mast cell subsets using patient serum allergic to peanuts and other food allergens providing novel insights into IgE-mediated food allergy and desensitization. Work is currently ongoing to identify its molecular pathways and to modulate these pathways with inhibitors of signal transduction such as BTK inhibitors and others.