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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI101406-03
Application #
8659342
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Prabhudas, Mercy R
Project Start
2012-06-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
City
New York
State
NY
Country
United States
Zip Code
10065
Matsuzawa-Ishimoto, Yu; Shono, Yusuke; Gomez, Luis E et al. (2017) Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium. J Exp Med 214:3687-3705
Staffas, Anna; Burgos da Silva, Marina; van den Brink, Marcel R M (2017) The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease. Blood 129:927-933
Dudakov, Jarrod A; Mertelsmann, Anna M; O'Connor, Margaret H et al. (2017) Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease. Blood 130:933-942
Chaudhry, Mohammed S; Velardi, Enrico; Malard, Florent et al. (2017) Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation: Time To T Up the Thymus. J Immunol 198:40-46
Peled, Jonathan U; Devlin, Sean M; Staffas, Anna et al. (2017) Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation. J Clin Oncol 35:1650-1659
Ghosh, Arnab; Smith, Melody; James, Scott E et al. (2017) Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med 23:242-249
Fischer, Julius C; Bscheider, Michael; Eisenkolb, Gabriel et al. (2017) RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. Sci Transl Med 9:
Tuckett, Andrea Z; Thornton, Raymond H; O'Reilly, Richard J et al. (2017) Intrathymic injection of hematopoietic progenitor cells establishes functional T cell development in a mouse model of severe combined immunodeficiency. J Hematol Oncol 10:109
Ito, Reiko; Hale, Laura P; Geyer, Susan M et al. (2017) Late Effects of Exposure to Ionizing Radiation and Age on Human Thymus Morphology and Function. Radiat Res 187:589-598
Weber, Daniela; Jenq, Robert R; Peled, Jonathan U et al. (2017) Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant 23:845-852

Showing the most recent 10 out of 32 publications