OC 13.5 - DPP4 inhibitor restores immune tolerance and thrombopoiesis in Immune thrombocytopenia

Background: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder. Despite existing many treatments, resistance in some patients necessitates new therapeutic targets. CD26/DPP4, crucial for T cell activation and proliferation, has been implicated in various autoimmune diseases. However, the specific function and underlying mechanisms of CD26 in ITP remain unclear.

Aims: To investigate the effects of DPP4 inhibitors on immune tolerance and thrombopoiesis in ITP, providing novel targets for the treatment of ITP.

Methods: In vitro cell culture combined with in vivo animal experiments are employed to study the correction of T cell imbalance by DPP4 inhibitors. In vitro culture is coupled with sequencing to investigate the enhancement of megakaryocyte function by DPP4 inhibitors.

Results: We observed a significant elevation of CD26 expression in CD4+ T cells of ITP patients compared to healthy controls. These patients exhibited lower soluble CD26 levels and diminished enzymatic activity in plasma, highlighting a potential complex regulatory mechanism, as the CD26 mRNA expression in CD4+ T cells was comparable between ITP patients and healthy subjects.
Vildagliptin, a DPP4 inhibitor, reduces Th1 and Th17 cell populations in CD4+ T cell cultures from ITP patients. This effect is attributed to the disruption of the NF-κB signaling pathway. In an active ITP murine model, vildagliptin improved thrombocytopenia by modulating Th1/Th17 cell differentiation.
HE-stained bone marrow from the ITP model indicated enhanced megakaryocyte maturation post-DPP4 inhibitor treatment. In vitro studies revealed that vildagliptin stimulates platelet production and induces megakaryocyte polyploidy in anti-serum treated cultures. Mitochondrial stress metabolism analysis under DPP4 inhibition showed an increase in oxidative phosphorylation. Metabolomic and proteomic sequencing linked this effect to augmented fatty acid oxidation and reduced NCoR1 protein levels, facilitating ploidy maturation and heightened platelet production.

Conclusion(s): Vildagliptin offers a dual benefit of rectifying CD4+ T cell imbalance and enhancing megakaryocyte function, underscoring its potential in ITP management.