Targeting the CD38-NAD⁺ axis alleviates antibody-driven cytopenia in autoimmune disorders without inducing broad immunosuppression

Abstract Autoimmune diseases, including immune thrombocytopenia (ITP), are typically managed through long-term non-specific immunosuppression with limited efficacy and safety. Our previous research has shown that anti-CD38 monoclonal antibody (mAb) therapy rapidly restores platelet counts in patients with refractory ITP, although the underlying mechanism remains unknown. Here, we report that anti-CD38 mAbs induce rapid elevation in platelet counts within 3 days of administration, even upon re-treatment in relapsed cases. Using passive ITP models with CD38 knockout mice and immune cell-specific depletion, we identified CD38-driven NAD⁺ depletion as a key immunometabolic checkpoint that promote pro-inflammatory macrophage polarization and platelet destruction. Supporting these findings, immunofluorescence, single-cell transcriptomic, and proteomic analyses of spleens and peripheral blood samples from ITP patients confirmed that anti-CD38 mAb therapy reversed aberrant macrophage polarization. Consistently, modulation of NAD⁺ metabolism through genetic deletion or pharmacological inhibition of CD38, or supplementation with nicotinamide mononucleotide (NMN), reprograms macrophage polarization and prevents thrombocytopenia in mice. Complementing these preclinical findings, a first-in-human trial demonstrated that low-dose NMN rapidly restores platelet counts within 3 days, with only 2 in 25 patients experiencing grade 1 infections which may attributable to preserved plasma cell numbers and immunoglobin levels. Together, these findings establish the CD38-NAD⁺ axis as a key immunometabolic driver of autoantibody-mediated cytopenia and introduce a novel therapeutic paradigm for antibody-mediated autoimmune disorders centered on targeted macrophage metabolic modulation rather than pan-B cell or plasma cell depletion, representing a promising and transformative resolution to the long-standing trade-off between therapeutic efficacy and broad immunosuppression (ClinicalTrials.gov: NCT06776510).