Regulatory T-cell based therapies for acute lung injury: a systematic review and meta-analysis

Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung injury. Regulatory T-cells (Tregs) and their extracellular vesicles (Treg-EVs) possess immunomodulatory properties that may be therapeutic in ARDS. However, evidence is scattered across individual studies, hindering the assessment of their safety and efficacy. To address this gap, we applied a systematic review (SR) methodology, a common approach in clinical research that has increasingly been recognized for its value in preclinical evidence synthesis. Specifically, we synthesized studies of Tregs/Treg-EVs in animal models of acute lung injury (ALI) or patients with ARDS. Importantly, we provide explanatory text throughout for readers less familiar with SRs. The primary preclinical and clinical outcomes were histological lung injury and mortality, respectively. Study selection and data extraction were performed in duplicate. Twenty-two preclinical and two clinical studies met the inclusion criteria, all using whole-cell Tregs. Meta-analysis of animal studies demonstrated that, compared to controls, Treg treatment significantly reduced histological lung injury (≤7 days: standardized mean difference (SMD) = -2.06 [95% confidence interval (CI): -2.96, -1.15]; >7 days: SMD = -2.18 [95% CI: -3.28, -1.08]). Tregs also reduced bronchoalveolar lavage fluid pro-inflammatory cytokines, total protein, total cells, and neutrophil counts. Clinically, early-phase study designs precluded meta-analysis; however, safety and tolerability of Tregs for ARDS were supported. Identified mechanisms underlying Treg effects included immunomodulation, cytokine regulation, and epigenetic pathways. Our review demonstrates the utility of formal preclinical evidence synthesis and supports the therapeutic potential of Tregs. Further investigations are justified to refine Tregs as a cellular therapy for ARDS.