Azathioprine therapy induces selective NK cell depletion and IFN-g deficiency predisposing to herpesvirus reactivation

Objective: We sought to comprehensively investigate therapy-associated patient risks and the underlying immune dysfunction of azathioprine use. Methods: Peripheral blood leukocytes were analyzed using single-cell mass and spectral flow cytometry to detect specific effects of azathioprine use on the systemic immune signature. Therapy-associated clinical features were analyzed in 2 independent cohorts of myasthenia gravis patients. Results: Azathioprine therapy selectively induced pronounced CD56dimCD161 natural killer cell depletion and concomitant IFN-g deficiency. Cytokine profiling revealed a specific contraction of classical TH1 cells during azathioprine treatment. We further observed an increased occurrence of reactivation of endogenous latent herpesviruses in the azathioprine-treated group versus in patients with myasthenia gravis who were not receiving immunomodulatory treatment; this increased occurrence was validated in an independent cohort. Conclusion: Our study highlights the risk of development of adverse events during azathioprine therapy and suggests that natural killer cell monitoring could be valuable in clinical practice. (J Allergy Clin Immunol 2023;151:280-6.)

Automated summary

This study comprehensively investigates the risks and immune dysfunction associated with azathioprine therapy. Using single-cell mass and spectral flow cytometry, the specific effects of azathioprine on the systemic immune signature were analyzed. Clinical features associated with therapy were analyzed in two independent cohorts of myasthenia gravis patients. The study highlights the risk of adverse events during azathioprine therapy and suggests that monitoring natural killer cells could be valuable in clinical practice.