Effective-mononuclear cell (E-MNC) therapy alleviates salivary gland damage by suppressing lymphocyte infiltration in Sjögren-like disease

Abstract

Introduction: Sjögren syndrome (SS) is an autoimmune disease characterized by salivary gland (SG) destruction leading to loss of secretory function. A hallmark of the disease is the presence of focal lymphocyte infiltration in SGs, which is predominantly composed of T cells. Currently, there are no effective therapies for SS. Recently, we demonstrated that a newly developed therapy using effective-mononuclear cells (E-MNCs) improved the function of radiation-injured SGs due to anti-inflammatory and regenerative effects. In this study, we investigated whether E-MNCs could ameliorate disease development in non-obese diabetic (NOD) mice as a model for primary SS.Methods: E-MNCs were obtained from peripheral blood mononuclear cells (PBMNCs) cultured for 7 days in serum-free medium supplemented with five specific recombinant proteins (5G culture). The anti-inflammatory characteristics of E-MNCs were then analyzed using a co-culture system with CD3/CD28-stimulated PBMNCs. To evaluate the therapeutic efficacy of E-MNCs against SS onset, E-MNCs were transplanted into SGs of NOD mice. Subsequently, saliva secretion, histological, and gene expression analyses of harvested SG were performed to investigate if E-MNCs therapy delays disease development.Results: First, we characterized that both human and mouse E-MNCs exhibited induction of CD11b/CD206-positive cells (M2 macrophages) and that human E-MNCs could inhibit inflammatory gene expressions in CD3/CD28- stimulated PBMNCs. Further analyses revealed that Msr1-and galectin3-positive macrophages (immunomodulatory M2c phenotype) were specifically induced in E-MNCs of both NOD and MHC class I-matched mice. Transplanted E-MNCs induced M2 macrophages and reduced the expression of T cell-derived chemokine-related and inflammatory genes in SG tissue of NOD mice at SS-onset. Then, E-MNCs suppressed the infiltration of CD4-positive T cells and facilitated the maintenance of saliva secretion for up to 12 weeks after E-MNC administration.Discussion: Thus, the immunomodulatory actions of E-MNCs could be part of a therapeutic strategy targeting the early stage of primary SS.

Recent progress in regenerative therapy for damaged salivary glands: From bench to bedside

“…However, these results clearly demonstrated that allogeneic UC‐MSC infusion is a promising and effective treatment for SS. After confirming the safety of E‐MNCs in patients with radiogenic xerostomia and therapeutic effects on NOD mice with SS‐like disease (Hasegawa et al, 2023), we will be taking part in a sponsor‐initiated clinical trial of E‐MNC treatment for SS patients. This clinical trial being conducted by CellAxia Inc. (Tokyo, Japan) is a randomized, multi‐center, phase II, double‐blind, placebo‐controlled trial.…”

“…However, these results clearly demonstrated that allogeneic UC-MSC infusion is a promising and effective treatment for SS. After confirming the safety of E-MNCs in patients with radiogenic xerostomia and therapeutic effects on NOD mice with SS-like disease(Hasegawa et al, 2023), we will be taking part in a sponsor-initiated clinical trial of E-MNC treatment for SS patients.This clinical trial being conducted by CellAxia Inc. (Tokyo, Japan) is a randomized, multi-center, phase II, double-blind, placebo-controlled trial. This phase II clinical trial will hopefully provide a strong foundation for the clinical use of E-MNC therapy, which could develop into an alternative treatment for xerostomia caused by SS.6 | FUTURE PROS PEC TS OF CELL-BA S ED THER APIE S FOR TRE ATING SG HYP OFUN C TIONAs mentioned above, cell-based therapy using MSCs is considered safe and exhibits therapeutic effects against SG dysfunction in| et alpatients undergoing radiation therapy for head and neck cancer and patients with SS.…”

“…E-MNCs are also considered to exhibit low tumorigenicity, as found in pluripotent stem cells, because E-MNCs are composed of autologous blood cells such as lymphocytes, monocytes/macrophages, and their progenitors. As mentioned above, based on the successful results of our preclinical study demonstrating that cell therapy using E-MNCs has therapeutic effects in NOD mice with SS-like disease(Hasegawa et al, 2023), a clinical trial in patients with SS (phase II) is now ongoing. These additional clinical and preclinical cell-based therapy studies will hopefully elucidate the detailed therapeutic mechanism and aid in the development of appropriate methodologies.7 | CON CLUS IONAlthough preclinical and clinical studies have shown promising effects of cell-based therapies in treating SG hypofunction, additional clinical studies as well as reverse translational studies are needed to solve the remaining clinical problems using basic research approaches.…”