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Ablation and Regeneration of Tolerance-Inducing Medullary Thymic Epithelial Cells after Cyclosporine, Cyclophosphamide, and Dexamethasone Treatment¹

Anne L. Fletcher^*, Tamara E. Lowen^*, Samy Sakkal^*, Jessica J. Reiseger^*, Maree V. Hammett^*, Natalie Seach^*, Hamish S. Scott, Richard L. Boyd^2,* and Ann P. Chidgey^2,3,*

*Immune Regeneration Laboratory, Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Australia; Division of Molecular Pathology, Institute of Medical and Veterinary Science and Hanson Institute, and School of Medicine, University of Adelaide, Adelaide, Australia

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 II^high medullary TEC (mTEC^high). Post-cyclosporine A, Aire expression was restored within 7 days. Full recovery of the mTEC^high subset occurred within 10 days and was linked to a decrease in a relatively resistant MHC class II^low mTEC subset (mTEC^low), 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 mTEC^high. 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.

³ Address correspondence and reprint requests to Dr. Ann Chidgey, Monash Immunology and Stem Cell Laboratories, Monash University, Wellington Road, Clayton VIC 3800, Australia. E-mail address: ann.chidgey{at}med.monash.edu.au

¹ This work was supported by the Australian Stem Cell Centre, Norwood Immunology, and the National Health and Medical Research Council of Australia. H.S.S. was supported by National Health and Medical Research Council Fellowships 171601 and 461204, National Health and Medical Research Council Program Grants 257501 and 264573, and Eurothymaide, the 6th Framework Programme of the European Union.

² R.L.B. and A.P.C. contributed equally to this study.

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