THE THYMUS: SCHOOL FOR T-CELLS

Scientific Focus

Immune Tolerance at the core of most remaining unmet medical need - and the thymus controls central immune tolerance

THE THYMUS HAS A CRITICAL ROLE IN ESTABLISHING AND MAINTAINING IMMUNE TOLERANCE

  • “The school for T cells”: The thymus is the primary immune organ which provides education for the developing adaptive immune system, predominantly the T cell compartment

  • It facilitates positive selection for TCR-HLA binding, and negative selection of T cells that bind too strongly to self-antigens. This results in an adaptive immune system that recognizes pathogens but is tolerant to self [1]

  • The thymus starts to involute after two years of age, with loss accelerated after puberty. If thymus is partially maintained into adult age, recirculation of activated T cells to the thymus is believed to maintain self-tolerance, cancer surveillance, immune regulation [2]

1. Lin et al. Revisiting the Thymus: the origin of T cells. Frontiers in Immunology 2023
2. Kooshesh et al. Health Consequences of Thymus Removal in Adults. NEJM 2023

Thymic Insufficiency Leads to Immune Disease – Tolerance Bio Will Restore It

THE PROBLEM

Thymic involution/loss leads to immune disease and increased mortality

  • AGE-RELATED THYMIC INVOLUTION: The thymus is the first organ to start atrophy during adolescence, leading to reduced T cell output. Maintaining thymus function as adults may lead to longer life in better health with less immune disease [1-4]

  • ACUTE THYMIC INVOLUTION: Caused by surgery, medications (steroids, immune-suppressants, chemotherapy), infection, inflammation

  • CONGENITAL THYMIC DEFECTS: DiGeorge syndrome, ultra-orphan congenital athymia, Down and Good's syndromes [5]    

  • Thymus impairment, failure, or removal leads to increased risk for cancer, autoimmunity, infection, and allergy [6-7]

1. Steinmann et al. The Involution of the Ageing Human Thymic Epithelium is Independent of Puberty. Scandinavian Journal of Immunology 1985
2. Duah et al. Thymus degeneration and regeneration. Frontiers in Immunology 2021
3. Srinivasan et al. Age-Related Changes in Thymic Central Tolerance. Frontiers in Immunology 2021
4. Paparazzo et al. Thymic function and survival at advanced ages in nursing home residents from Southern Italy. Immunity and Ageing 2023
5. Marx et al. Thymus and Autoimmunity. Seminars in Immunopathology 2021
6. Kooshesh et al. Health Consequences of Thymus Removal in Adults. NEJM 2023
7. Biggs et al. Chromosome 22q11.2 Deletion (DiGeorge Syndrome): Immunologic Features, Diagnosis, and Management. Current Allergy Asthma Reports 2023

THE SOLUTION

Delay/prevent thymic involution, and restore thymic function if lost

  • RESTORE THYMIC FUNCTION WITH ADULT STEM CELL-DERIVED THYMIC EPITHELIAL CELL TRANSPLANTS 

    1. Artificial, bio-engineered thymus made from iPSC-derived thymic epithelial cells 

    2. Disease-specific thymic spheroids/organoids

  • DELAY/PREVENT NATURAL AND ACCELERATED THYMIC INVOLUTION WITH DRUGS/THERAPEUTICS 

    1. For acute and age-related thymic involution 

Publications

1. Generation of functional thymic organoids from human pluripotent stem cells

Ramos, S. A., Armitage, L. H., Morton, J. J., Alzofon, N., Handler, D., Kelly, G., Homann, D., Jimeno, A., & Russ, H. A. (2023). Stem cell reports, 18(4), 829–840. https://doi.org/10.1016/j.stemcr.2023.02.013

2. Generation of functional human thymic cells from induced pluripotent stem cells

Ramos, S. A., Morton, J. J., Yadav, P., Reed, B., Alizadeh, S. I., Shilleh, A. H., Perrenoud, L., Jaggers, J., Kappler, J., Jimeno, A., & Russ, H. A. (2022). The Journal of allergy and clinical immunology, 149(2), 767–781.e6. https://doi.org/10.1016/j.jaci.2021.07.021