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Publications of the Week

A Regulatory T Cell Notch4–GDF15 Axis Licenses Tissue Inflammation in Asthma

By September 24, 2020No Comments

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This week we profile a recent publication in Nature Immunology from Dr. Hani Harb
(pictured below) in the laboratory of Dr. Talal Chatila (above) at Boston Children’s Hospital.

Can you provide a brief overview of your lab’s current research focus?

The lab focuses on the role of failed immune tolerance in the pathogenesis of common chronic inflammatory diseases such as asthma and food allergy, and means of restoring immune tolerance in these disorders by manipulating regulatory T cells. Our studies have led to the identification of specific immune regulatory switches that allow chronic inflammation to proceed and which, once antagonized by means of precision therapies, allow for resolution of disease. A case-in-point is our study on Notch4 in asthma — the subject of this paper.

Hani Harb

Hani Harb

What is the significance of the findings in this publication?

This work for the first time provides evidence that severe asthma entails disruption of mechanisms that normally support immune tolerance in the lung, such that the failure of these mechanisms results in sustained tissue inflammation. Specifically, our findings identify a key molecular switch involving Notch4 on regulatory T cells whose activation derails immunological tolerance in the lung and licenses allergic tissue inflammation. Furthermore, it identifies novel pathways including Notch4 and the cytokine GDF15 that can be targeted by precision therapies hitherto unavailable to treat severe asthmatics. Our studies provide a comprehensive framework for understanding inflammation in asthma, a disease that affects many millions of individuals in the U.S. and worldwide. As such, this manuscript may find a broad audience among scientists, physicians and patients in the field of asthma and related respiratory disease.

What are the next steps for this research?

This work open new possibilities for developing therapeutics that target Notch4 and related pathways in asthma, especially in its severe form. We are also interested in elucidating  the role of different Notch pathways in other immunological circuits. In particular, we would like to investigate how Notch4 licenses immune tolerance breakdown in the lung in different disease conditions.

This work was funded by:

Our studies have been supported by grants from the National Institutes Health (nos. R01 AI115699 and
R01 AI065617 to Talal Chatila., U01AI110397 and R01 HL137192 to Wanda Phipatanakul.)  and a German Research
Society grant (no. HA 8465/1-1 to Hani Harb).

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