Gurupreet S. Sethi, Ph.D.

What if we could cure asthma by erasing the immune system’s memory of allergens?

Allergic asthma is a complicated disease of the lung airways. It causes inflammation, swelling and mucus production, which makes breathing very difficult and painful. Basically, it is the result of a misguided attempt by our immune system to combat the entry of allergens into the body. Similar to an infectious disease, our immune system keeps the memory of all the previous allergen encounters within a cell type called T lymphocytes. We hypothesize that a very small population of these allergic memory T cells are long-lived and can persist in our lungs even after the removal of allergens. Interestingly, these cells can keep renewing themselves similar to stem cells. We suggest that these long-lasting immortal memory T cells of the lungs are responsible for the severity of disease upon subsequent allergen exposure and in many individuals maintain the disease from early childhood into late adulthood. We believe the main obstacle to an effective curative therapy is the need to eliminate this previous memory of our immune system. Thus, in this project we will try to discover the identity of these long-lasting memory cells and to uncover the factors and signaling pathways that make them immortal and then further use this information to eradicate these allergic memory cells from the lungs.

The SPARK funding will allow us to answer this question by conducting a series of experiments to generate a proof of concept of our hypothesis. For this, we will use a well established murine model of severe persistent asthma where long-lasting memory cells in the lungs are induced upon allergen exposure. We will sort the lung cells and examine which genes are highly expressed in the long-lasting memory T cells. For this we are using a technique called single-cell RNA sequencing. Overall, we will attempt to identify these long-lasting immortal memory stem T cells in the lungs through their genetic profiles and also discover what proteins they express that could be potential targets to develop an effective therapeutic approach for asthmatics.

SPARKing Impact: The study aims to identify and ultimately eradicate long-lived memory T cells in the lungs of severely asthmatic individuals, which could point the way to an effective curative treatment of asthma and maybe other allergic diseases.