Endogenous regeneration of the thymus is a crucial function that allows for renewal of immune competence following infection, shock, cytoreductive chemo- or radiation therapy and other causes of thymic injury. Thymic regenerative capacity diminishes with age and remains a poorly understood area. One of the major goals of this project is to elucidate the processes of endogenous thymic regeneration so that they may be exploited into clinically relevant strategies for immune rejuvenation. This is particularly relevan for recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), who experience prolonged post-transplant T cell deficiency caused by cytoreductive conditioning and graft-versus-host disease (GVHD), which results in increased morbidity and mortality from infections and malignant relapse. Interleukin-22 (IL-22) is produced by T-helper (Th)17 cells and innate lymphoid cells (ILCs) and promotes innate immunity and homeostasis of epithelial cells in the intestines, lung and skin. We have found a novel role for IL-22 in the endogenous regeneration of thymic epithelial cells (TECs) after thymic damage. We found that IL-22 was redundant for steady-state thymopoiesis but following thymic damage a) absolute levels of IL-22 in the thymus were increased, b) IL-22 production by thymic ILCs (tILCs) was increased, c) IL-23 production by thymic dendritic cells (tDCs) was increased and could enhance IL-22 production by innate lymphoid cells, and d) IL-22 administration could enhance overall thymic cellularity and proliferation and survival of TECs. Our preliminary findings also suggest that IL-22 can affect T cell development as early as bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Based on these findings, we hypothesize that (a) IL-22 plays an important role in endogenous T cell regeneration following thymic insult, (b) IL-22 promotes differentiation and commitment of HSPCs to the lymphoid lineage, and (c) IL- 22 can be utilized as a therapeutic strategy in the clinic to boost thymic function following immune depletion. Our proposal has the following aims: (1) To study the role of IL-22 in endogenous regeneration of thymopoiesis, (2) To study the role of IL-22 in pre-thymic lymphoid commitment and development, and (3) To study the potential for IL-22 administration to improve T cell reconstitution following allo-HSCT. The mechanistic and pre-clinical studies outlined in this proposal have the potential to define an important novel pathway in thymic regeneration, which could result in clinical approaches to enhance T cell immunity, not only for recipients of allo-HSCT, but also for individuals with T cell deficiencies due to aging (lymphoid atrophy), autoimmune diseases, infectious diseases, shock, radio- or chemo-therapy and radiation injury (nuclear accident or terrorism).

Public Health Relevance

Despite being exquisitely sensitive to injury, the thymus (which is fundamental for the development of T cells and the immune system in general) is remarkably resilient in young healthy animals. Understanding the processes involved with this natural regeneration can help us overcome the barriers to repair imposed by age, infection, shock or repeated treatments of chemotherapy or radiation. This proposal aims to further investigate a new framework of natural thymic repair based on a recently identified cytokine, IL-22, and seeks to exploit this process as an innovative clinical strategy for immune regeneration.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Prabhudas, Mercy R
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Shono, Yusuke; Tuckett, Andrea Z; Liou, Hsiou-Chi et al. (2016) Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB-Controlled Oxidative Stress Responses. Cancer Res 76:377-89
Mitchell, Emma; Klein, Shifra L; Argyropoulos, Kimon V et al. (2016) Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms. Nat Commun 7:11492
Shono, Yusuke; Docampo, Melissa D; Peled, Jonathan U et al. (2016) Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med 8:339ra71
Chaudhry, Mohammed S; Velardi, Enrico; Dudakov, Jarrod A et al. (2016) Thymus: the next (re)generation. Immunol Rev 271:56-71
Ferrando-Martínez, Sara; Ruiz-Mateos, Ezequiel; Dudakov, Jarrod A et al. (2015) WNT signaling suppression in the senescent human thymus. J Gerontol A Biol Sci Med Sci 70:273-81
Velardi, E; Dudakov, J A; van den Brink, M R M (2015) Sex steroid ablation: an immunoregenerative strategy for immunocompromised patients. Bone Marrow Transplant 50 Suppl 2:S77-81
Lindemans, Caroline A; Calafiore, Marco; Mertelsmann, Anna M et al. (2015) Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528:560-4
Jenq, Robert R; Taur, Ying; Devlin, Sean M et al. (2015) Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease. Biol Blood Marrow Transplant 21:1373-83
Dudakov, Jarrod A; Hanash, Alan M; van den Brink, Marcel R M (2015) Interleukin-22: immunobiology and pathology. Annu Rev Immunol 33:747-85
Tuckett, Andrea Z; Thornton, Raymond H; Shono, Yusuke et al. (2014) Image-guided intrathymic injection of multipotent stem cells supports lifelong T-cell immunity and facilitates targeted immunotherapy. Blood 123:2797-805

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