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Attenuation of Apoptotic Cell Detection Triggers Thymic Regeneration after Damage

By October 15, 2021No Comments

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This week we profile a recent publication in Cell Reports from first author Sinéad Kinsella (pictured, third from right) in the laboratory of Dr. Jarrod Dudakov (fourth from right) at Fred Hutch.

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

Our lab is broadly interested in improving immune function, and particularly, the function of T cells –  a fundamental part of the adaptive immune system. T cells sometimes need a little boost because the factory that produces them, the thymus, is both extremely sensitive to acute injury such as everyday insults like stress and infection, but also more profound damage like common cancer therapies and radiation. Additionally, the thymus also undergoes a chronic decline in function with age (starting from around puberty). This means that our ability to fight new infections or clear tumors decreases with age, and our ability to recover from insults like cancer therapies also declines, leading to profound T cell suppression for years and, potentially, forever. We try and study how the thymus is damaged and then able to recover in young healthy animals (what we call endogenous thymic regeneration), with the hope that we can harness those same pathways to boost thymic function in older patients.

What is the significance of the findings in this publication?

Over the last decade, we have revealed a number of distinct cellular and molecular pathways that underlie this process of natural thymus regeneration. More recently we have become interested if there is a central trigger for the activation of these pathways – in the hope that if we can target the central regulator of all regeneration pathways, this would lead to a superior therapy. And that is what we have done here. Revealing a complicated molecular switch that orchestrates the regenerative response. Specifically, what we have found is what we call a “dead man’s switch” – where the developing T cells in the thymus, just by being developing T cells, actually actively suppresses the triggering of regenerative responses. But if those developing T cells are removed for any reason, such as because of depletion due to chemotherapy or steroids, the regenerative mechanisms are initiated. Therefore, we have described a “dumb” system that merely requires the absence of a suppressive signal to initiate repair. We have also found that we can pharmacologically target this pathway to improve thymic function after damage. The main significance of this is not only the revelation of an intricate molecular switch but also a therapeutic target to broadly improve immune function.

What are the next steps for this research?

The next steps we are talking about are to interrogate when this can be therapeutically effective. We have shown improvement in thymic function when we give a dose of radiation, simulating what many patients get in the clinic. However, all the studies we have done thus far have been in young, otherwise healthy, animals. Therefore, our next steps are to determine if these therapeutic targets can be effective in older animals, with or without damage, and to test if this translates into better functional T cells. We are also interested in then establishing a clinical trial, likely in recipients of bone marrow transplant who receive a profoundly damaging conditioning regime to ensure effective transplant. This conditioning also wipes out the T cells and has severe effects on thymic function such as that the recovery of T cells after transplant takes years even in young individuals.

If you’d like us to mention your funding sources, please list them.

Indeed. This work was funded by NIH grants from the NHLBI, NCI, and NIA. We also received funding from the American Society for Hematology (ASH), The American Society for Transplantation and Cellular Therapy (ASTCT), and the DKMS Foundation for Giving Life.

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