Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine, cyclophosphamide, and dexamethasone treatment.
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.
Fletcher
Anne L
AL
Immune Regeneration Laboratory, Monash University, Clayton, Australia.
Lowen
Tamara E
TE
Sakkal
Samy
S
Reiseger
Jessica J
JJ
Hammett
Maree V
MV
Seach
Natalie
N
Scott
Hamish S
HS
Boyd
Richard L
RL
Chidgey
Ann P
AP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015551:Autoimmunity / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000276:immunology* / Q000502:physiology; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration; D017154:Stromal Cells; D013950:Thymus Gland / Q000166:cytology*; D014157:Transcription Factors; D000096927:AIRE Protein
D000893:Anti-Inflammatory Agents; D003520:Cyclophosphamide; D016572:Cyclosporine; D003907:Dexamethasone; D007166:Immunosuppressive Agents; D014157:Transcription Factors; D000096927:AIRE Protein