Glucocorticoid-induced Pneumocystis pneumonia mice developed immune reconstitution inflammatory syndrome after glucocorticoid withdrawal.

Mortality from Pneumocystis pneumonia (PCP) continues to increase among non-human immunodeficiency virus (HIV) patients. Previous studies have reported that a considerable proportion of patients experience deterioration of their disease when glucocorticoids or other immunosuppressants are withdrawn. However, the underlying mechanisms responsible for this phenomenon remain poorly understood. Our findings, based on a comparative analysis of immune function in glucocorticoid-induced PCP mice at the time of glucocorticoid continuation and glucocorticoid withdrawal, suggested that the damage to lung tissues in PCP mice was significantly exacerbated and lung function deteriorated following glucocorticoid withdrawal. Mechanistically, our investigations revealed that PCP mice underwent immune reconstitution and developed immune reconstitution inflammatory syndrome (IRIS) after glucocorticoid withdrawal, which resulted in enhanced immune responses to pre-existing Pneumocystis. Prophylactic G-CSF neutralization in vivo prior to glucocorticoid withdrawal attenuated withdrawal-induced IRIS but also impaired Pneumocystis clearance. This study elucidated that the exacerbation of infection in PCP mice after glucocorticoid withdrawal is analogous to the clinical phenomenon and demonstrated that it is caused by the immune reconstitution that occurs after glucocorticoid withdrawal and resulting IRIS while also showing that G-CSF plays an important role in this process. This provides clinical comprehension of the progression of disease in non-HIV PCP patients.