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* 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 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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.
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
4 Abbreviations used in this paper: TEC, thymic epithelial cell; Aire, autoimmune regulator; CsA, cyclosporine A; RD, recovery day; cTEC, cortical TEC; mTEC, medullary TEC; mTEChigh, medullary TEC expressing high levels of MHC class II; mTEClow, mTEC expressing low levels of MHC class II; TA, transit amplifying; TRA, tissue-restricted Ag; UEA1, Ulex europeaus agglutinin 1; Treg, regulatory T cell; SP, single positive; DP, double positive.
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