Immune Regulatory Mechanism of Alpha1-Antitrypsin in Type 1 Diabetes and Its Clinical Application Progress
DOI:
https://doi.org/10.61173/2k6taz65Keywords:
Alpha-1 antitrypsin (AAT), Type 1 diabetes (T1D), Immunomodulation, Clinical trialAbstract
Type 1 Diabetes (T1D) is an autoimmune disease-causing selective destruction of pancreatic β-cells, requiring lifelong insulin. Current treatments cannot prevent β-cells loss or restore immune tolerance, highlighting the need for diseasemodifying therapies. Alpha-1 antitrypsin (AAT) has attracted attention due to its multiple mechanisms of action in T1D. It can regulate NKDC interactions, boost Treg function, and inhibit Th1 and CD8+ T cells. It also suppresses the NFκB/IL-1β pathway and upregulates IL1Ra. These actions reduce β-cell apoptosis and increase β-cell mass. Clinical studies show safety of AAT in new-onset T1D and islet autotransplantation, but efficacy outcomes have not been consistently met, partly due to insufficient dosing (90 mg/kg/week) and compensatory endogenous AAT elevation. Different reactions related to gender have been observed in female patients. Future larger-dose, placebo-controlled trials with gender are needed. Engineered mesenchymal stem cells overexpressing AAT and gene delivery strategies provide an effective way to achieve sustained and localized AAT expression, and are expected to overcome the current challenges in clinical translation.
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