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https://hdl.handle.net/2440/60494
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Type: | Journal article |
Title: | Ablation and Regeneration of Tolerance-Inducing Medullary Thymic Epithelial Cells after Cyclosporine, Cyclophosphamide, and Dexamethasone Treatment |
Author: | Fletcher, A. Lowen, T. Sakkal, S. Reiseger, J. Hammett, M. Seach, N. Scott, H. Boyd, R. Chidgey, A. |
Citation: | Journal of Immunology, 2009; 183(2):823-831 |
Publisher: | Amer Assoc Immunologists |
Issue Date: | 2009 |
ISSN: | 0022-1767 1550-6606 |
Statement of Responsibility: | Anne L. Fletcher, Tamara E. Lowen, Samy Sakkal, Jessica J. Reiseger, Maree V. Hammett, Natalie Seach, Hamish S. Scott, Richard L. Boyd and Ann P. Chidgey |
Abstract: | Immunosuppressive drugs and cytotoxic chemotherapy agents are designed to kill or suppress autoreactive, alloaggressive, or hyperinflammatory T cells, or disseminated malignancies. However, they also cause severe immunological side effects ranging from interrupted thymopoiesis and general immunodeficiency to, paradoxically, autoimmunity. Consistent with the cross-talk between thymocytes and stromal cells, we now show that these common therapeutic agents have major effects on murine thymic epithelial cells (TEC), crucially required to rebuild immunity posttreatment. We show that the immunosuppressant cyclosporine A, which has been linked to a thymus-dependent autoimmune syndrome in some patients, causes extensive loss of autoimmune regulator (Aire+) tolerance-inducing MHC class IIhigh medullary TEC (mTEChigh). Post-cyclosporine A, Aire expression was restored within 7 days. Full recovery of the mTEChigh subset occurred within 10 days and was linked to a decrease in a relatively resistant MHC class IIlow mTEC subset (mTEClow), consistent with a previously described precursor-product relationship. Cyclophosphamide and dexamethasone caused more extensive ablation of thymocytes and stromal cells but again severely depleted tolerance-inducing mTEChigh. Together, these data show that Aire+ mTECs are highly sensitive to damage and that mTEC regeneration follows a conserved pattern regardless of the treatment regimen used. |
Keywords: | Thymus Gland Stromal Cells Epithelial Cells Animals Mice, Inbred C57BL Mice Cyclophosphamide Cyclosporine Dexamethasone Transcription Factors Anti-Inflammatory Agents Immunosuppressive Agents Regeneration Autoimmunity Immune Tolerance AIRE Protein |
Description: | Published online before print June 29, 2009 |
Rights: | Copyright © 2009 by The American Association of Immunologists, Inc. |
DOI: | 10.4049/jimmunol.0900225 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/171601 http://purl.org/au-research/grants/nhmrc/461204 |
Published version: | http://dx.doi.org/10.4049/jimmunol.0900225 |
Appears in Collections: | Aurora harvest 5 Medicine publications |
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