apyrase and Lupus-Nephritis

Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptive transfer of GMSCs homes to and maintains in the kidney and has a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39

Topics: 5'-Nucleotidase; Animals; Antigens, CD; Apyrase; B-Lymphocytes; Cell Differentiation; Cell Proliferation; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Female; Gingiva; GPI-Linked Proteins; Humans; Lupus Nephritis; Lymphocyte Activation; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Plasma Cells; Primary Cell Culture; RNA-Seq; Signal Transduction; Single-Cell Analysis

Many patients with systemic lupus erythematosus (SLE) have lupus nephritis, one of the severe complications of SLE. We previously reported that CD8+CD103+ T regulatory cells induced ex vivo with transforming growth factor β (TGF-β) (iTregs) inhibited immune cells responses to ameliorate excessive autoimmune inflammation. However, the molecular mechanism(s) underlying the role of these CD8+ iTregs is still unclear. Here we identified that CD39, which is highly expressed on CD8+ iTregs, crucially contributes to the immunosuppressive role of the CD8+CD103+ iTregs. We showed that adoptive transfer of CD8+CD103+ iTregs significantly relieves the chronic graft-versus-host disease with lupus nephritis and CD39 inhibitor mostly abolished the functional activities of these CD8+ iTregs in vitro and in vivo. CD39+ cells sorted from CD8+CD103+ iTregs were more effective in treating lupus nephritis than CD39- partner cells in vivo. Furthermore, human CD8+ iTregs displayed increased CD103 and CD39 expressions, and CD39 was involved in the suppressive function of human CD8+ iTregs. Thus, our data implicated a crucial role of CD39 in CD8+CD103+ iTregs in treating lupus nephritis, and CD39 could be a new phenotypic biomarker for the identification of highly qualified CD8+ Tregs. This subpopulation may have therapeutic potential in patients with SLE nephritis and other autoimmune diseases.

Topics: Antigens, CD; Apyrase; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Proliferation; Chronic Disease; Graft vs Host Disease; Humans; Immune Tolerance; Immunomodulation; Integrin alpha Chains; Lupus Nephritis; T-Lymphocytes, Regulatory; Transforming Growth Factor beta