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Abstract

Hematopoietic stem cell transplant (HSCT) is a critical medical procedure used to treat various blood and bone marrow diseases. However, it is often associated with severe complications, including chronic graft-versus-host disease (cGVHD), a systemic condition that occurs when donor immune cells attack the recipient's tissues, leading to significant morbidity, with an incidence of 42% within three years and a non-relapse mortality rate of 30%. To date, most studies on cGvHD biomarkers have focused on adults, and the scientific mechanisms underlying the onset of cGvHD in the pediatric population remain poorly understood. Building on previous work that identified sCD13, an aminopeptidase, and the key intermediate metabolite in the TCA cycle, α-KG, as potential biomarkers, this thesis investigated their roles in cGvHD. Using two independent pediatric cohorts, I validated the elevation of α-KG at cGvHD onset. In vitro, recombinant sCD13 suppressed CD4⁺ and CD8⁺ T cell proliferation in a dose-dependent manner with minimal effects on cell survival, indicating an immunomodulatory role. Although no truncation of CXCL9, CXCL10, or CXCL11 was observed, sCD13 levels correlated with increased CD26, suggesting possible cooperative regulation of chemokines. Complementary experiments showed that α-KG enhanced NK cell cytotoxicity against K562 targets, slightly increased perforin expression, and exhibited trends towards improved metabolic fitness, while not significantly altering T cell proliferation. Together, these findings validate α-KG as a reproducible biomarker in children, establish sCD13 as an immune regulator of T cell responses, and reveal α-KG as a modulator of NK cell function. By uncovering mechanisms of biomarker activity, this work advances understanding of cGvHD pathogenesis and supports biomarker-driven strategies to improve diagnosis and treatment in pediatric HSCT.