Stromal cells from perinatal and adult sources modulate the inflammatory immune response in vitro by decreasing Th1 cell proliferation and cytokine secretion.

Oula Khoury,Anthony Atala,Sean V Murphy

doi:10.1002/sctm.19-0123

Abstract

Many immune‐mediated conditions are associated with a dysregulated imbalance toward a Th1 response leading to disease onset, severity, and damage. Many of the therapies such as immunomodulators or anti‐TNF‐α antibodies often fall short in preventing disease progression and ameliorating disease conditions. Thus, new therapies that can target inflammatory environments would have a major impact in preventing the progression of inflammatory diseases. We investigated the role of human stromal cells derived from the amniotic fluid (AFSCs), the placenta (PLSCs), and bone marrow‐derived mesenchymal stromal cells (BM‐MSCs) in modulating the inflammatory response of in vitro‐stimulated circulating blood‐derived immune cells. Immune cells were isolated from the blood of healthy individuals and stimulated in vitro with antigens to activate inflammatory responses to stimuli. AFSC, BM‐MSCs, and PLSCs were cocultured with stimulated leukocytes, neutrophils, or lymphocytes. Inflammatory cytokine production, neutrophil migration, enzymatic degranulation, T cell proliferation, and subsets were evaluated. Coculture of all three stromal cell types decreased the gene expression of inflammatory cytokines and enzymes such as IL‐1β, IFN‐γ, TNF‐α, neutrophil elastase, and the transcription factor NF‐κB in lipopolysaccharide‐stimulated leukocytes. With isolated phytohemagglutinin‐stimulated peripheral blood mononuclear cells, cells coculture leads to a decrease in lymphocyte proliferation. This effect correlated with decreased numbers of Th1 lymphocytes and decreased secreted levels of IFN‐γ.

Highlights

Inflammation is a tightly regulated phenomenon that requires coordination of cytokine signaling.[1]
Cytokines involved in the inflammatory response are most abundantly produced by T helper cells (Th), a subtype of T lymphocytes that are distinguished by expressing the surface marker CD4, as opposed to effector T lymphocytes that express the surface marker CD8
Given that our data showed that coculture with stromal cells had modulatory effects on the gene expression related to T lymphocytes such as NF-κB, IL-1β, and TNF-α, we investigated the effect of all three stromal cell types on lymphocyte proliferation and T cell subsets following antigen stimulation

Summary

| INTRODUCTION

Inflammation is a tightly regulated phenomenon that requires coordination of cytokine signaling.[1]. Th1-mediated inflammation is implicated for many types of autoimmune diseases, including rheumatoid arthritis (RA), multiple sclerosis (MS), corneal transplant rejection, and type I diabetes.[10-13] Current treatments for these types of diseases include the use of Th1 pre-inflammatory cytokine antagonists, such as antibodies to TNF-α or IFN-γ.14. Human amnion-derived mesenchymal stromal cells (hAMSC) have been shown to skew macrophage polarization toward M2, inhibit monocyte differentiation into dendritic cells, and reduce the expression of Th1, Th2, and Th17 associated markers and their corresponding subset cytokines including TNF-α, IFN-γ, IL-1β, IL-5, IL-9, and IL-22.17 In another study, human umbilical cord-derived MSCs (UC-MSCs) inhibited the proliferation of lymphocytes stimulated with phytohemagglutinin (PHA) under coculture setting in vitro, and enhanced the abundance of T regulatory (Tregs) cells, while increasing IL-10 levels.[18]. We compared the potential immunomodulatory properties of amniotic fluidderived cells (AFSCs), placenta-derived cells (PLSCs), and BM-derived mesenchymal stem cells (BM-MSCs) on antigen-stimulated leukocytes, lymphocytes, neutrophils, and T cell subsets derived from the blood of healthy donors

| MATERIALS AND METHODS

Significance statement

| RESULTS

| DISCUSSION

| CONCLUSION

Findings

CONFLICT OF INTEREST