4.7 Article

mTOR inhibition attenuates cTfh cell dysregulation and chronic T-cell activation in multilineage immune cytopenias

Journal

BLOOD
Volume 141, Issue 3, Pages 238-243

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2022015966

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mTOR inhibitors like sirolimus are increasingly used to manage multilineage immune cytopenia (m-IC) in children. However, it is unclear how sirolimus affects the broader immune dysregulation associated with m-IC.
mTOR inhibitors such as sirolimus are increasingly used in the management of multilineage immune cytopenia (m-IC) in children. Although sirolimus is effective in improving IC, it is unclear how sirolimus affects the broader immune dysregulation associated with m-IC. We profiled T- and B-cell subsets longitudinally and measured cytokines and chemokines before and after sirolimus treatment. Eleven of the 12 patients with m-IC who tolerated sirolimus were followed for a median duration of 17 months. All patients had an improvement in IC, and sirolimus therapy did not result in significant decreases in T-, B- and NK-cell numbers. However, the expansion and activation of circulating T follicular helper and the Th1 bias noted before the initiation of sirolimus were significantly decreased. Features of chronic T-cell activation and exhaustion within effector memory compartments of CD4(+) and CD8(+) T cells decreased with sirolimus therapy. Corresponding to these changes, plasma levels of CXCL9 and CXCL10 also decreased. Interestingly, no significant improvement in the proportion of class-switched memory B cells or frequencies of CD4(+) naive T cells were noted. Longer follow-up and additional studies are needed to validate these findings and evaluate the effect of sirolimus on B-cell maturation.

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