Allogenic UCB was used in this study for the first time to successfully treat pediatric ARDS. Meanwhile, this study analyzed the mechanism of ARDS at the cellular and molecular levels, and recommended the treatment. Allogeneic UCB treatment could stabilize the immune system and control self-excitation by repairing the TLR4/MyD88/NF-κB signaling pathway.
The patient had nephrotic syndrome with hormone resistance. Moreover, he was treated with prednisone, tacrolimus, and RTX for immunosuppressive therapy. RTX  prevents B-cell proliferation and differentiation and depletes B cells . Tacrolimus inhibits T-lymphocyte activation . At the onset of the disease, the patient was depleted of B cells, with low CD4 + T cells. Moreover, he had a PCP infection. Pneumocystis cell wall β-glucan binds to the Toll-like receptor (TLR) on alveolar macrophages, dendritic cells, and lung epithelial cells and activates the CD4 + T cell host. Then it produces inflammatory factors through the NF-κB pathway, enhancing the host adaptive response and clearing PCP . In this study, the patient’s intrinsic cellular immunity was suppressed, CD4 + T cell recruitment and production of IFN-γ  decreased, and DC could not stimulate CD4 + T-cell proliferation and polarization effectively . Because of the lack of B cells to regulate T cells, PCP infection was hard to remove because of heavy fungal load. T cells were recovered after stopping tacrolimus which further increased the inflammation of the lung injury. Even with ECMO-supported treatment, the survival rate of patients with non-HIV and PCP was only 8.3%, with a one-third success rate of ECMO offline .
Abnormalities in the TLR4/NF-κB signaling pathway were confirmed by genomic and proteomic analyses. TLR4/NF-κB is the main signaling pathway for lung infection , ARDS, and various inflammatory responses [13, 14]. Activation of TLR and IL-R could induce dimerization of the aptamer protein MyD88 . MyD88 is a downstream signaling adapter protein, which is essential for cytokine production in TLR ligand reactions . Then, other IRAK1 and IRAK4 interactions to form oligomer complexes and induce TRAF6 dimerization, which leads to IκB-αphosphorylation and degradation , de-inhibiting the NF-κB/Rel complex. Pro-inflammatory factors included TNF-α, IL-6, IFN-γ, IL-1, IL-5, and so forth. [18, 19]. The anti-TLR4 monoclonal antibody has been reported to reduce ventilator-induced lung injury in rats by inhibiting MyD88 and NF-κB signaling . The patient could not recover lung function after SMZ combined with caspofungin, respiratory support, and ECMO treatment after 4 weeks. Alveolar lavage still showed a heavy lung inflammatory reaction. The patient could not recover because of his natural immune deficiency and TLR4/MyD88/NF-κB signaling pathway inactivation. The key to the treatment included immune regulation and signaling pathway repair.
With the global epidemic COVID-19 in 2020, the advantages  and potential  of stem cells to prevent severe COVID-19 pneumonia-induced ARDS were confirmed. Studies proved that MSCs can secrete factors, such as BD-2  through the TLR4/NF-κB pathway, and the production IL-6 and IL-8  factors reduced to alleviate ARDS. UCB is rich in hematopoietic stem cells, MSCs, various types of immune active cells, and their precursor cells (CTL, NK, DC, and Treg) . UCB can be expanded and induced to differentiate into functional mature effector cells, which can quickly complete immune initiation, and regulation and maintain immune response . It plays a very important role in the clinical prevention and treatment of viral infection, elimination of minimal residual disease, suppression of immune rejection, and treatment of autoimmune diseases. UCB could be an effective treatment for the patient discussed in this study theoretically. After UCB infusion, the TLR4/NF-κB signaling pathway was restored, the cytokine levels in vivo returned to normal rapidly, and the number of cellular immune cells gradually returned to normal. When the patient was infected again (8 days after UCB infusion), his cellular immune cells appeared to function and the level of inflammatory factors increased. The safety and efficacy of UCB infusion were verified again.
UCB stem cells are biologically closer to embryonic stem cells, with higher plasticity, faster growth, and greater immune tolerance. Moreover, they can be obtained without invasive treatment in untreated patients. Allogeneic UCB mononuclear cell therapy in ischemic myocardial infarction, stroke, and cerebral palsy in animal experiments and preliminary clinical studies has been shown to improve cardiac and cerebral functions . Autologous UCB infusion in premature infants can reduce the use of ventilator time and oxygenation  and treat autism . UCB treatment is safe in premature infants and children, and no serious adverse reactions have been reported.
This study focused on one case of allogeneic UCB therapy for ARDS; large-scale clinical studies are required to validate the results. In addition, the pathogenesis of ARDS and the signaling pathways involved are complex and clinically heterogeneous. The immune regulation of UCB and the mechanism of lung function repair need further basic research. UCB therapy may be a safe and effective way for ARDS treatment.