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Review
. 2022 Feb 11;22(1):e10.
doi: 10.4110/in.2022.22.e10. eCollection 2022 Feb.

Recent Advances in Cell Therapeutics for Systemic Autoimmune Diseases

Youngjae Park  1 , Seung-Ki Kwok  1
Affiliations
Review

Recent Advances in Cell Therapeutics for Systemic Autoimmune Diseases

Youngjae Park et al. Immune Netw. .

Abstract

Systemic autoimmune diseases arise from loss of self-tolerance and immune homeostasis between effector and regulator functions. There are many therapeutic modalities for autoimmune diseases ranging from conventional disease-modifying anti-rheumatic drugs and immunosuppressants exerting nonspecific immune suppression to targeted agents including biologic agents and small molecule inhibitors aiming at specific cytokines and intracellular signal pathways. However, such current therapeutic strategies can rarely induce recovery of immune tolerance in autoimmune disease patients. To overcome limitations of conventional treatment modalities, novel approaches using specific cell populations with immune-regulatory properties have been attempted to attenuate autoimmunity. Recently progressed biotechnologies enable sufficient in vitro expansion and proper manipulation of such 'tolerogenic' cell populations to be considered for clinical application. We introduce 3 representative cell types with immunosuppressive features, including mesenchymal stromal cells, Tregs, and myeloid-derived suppressor cells. Their cellular definitions, characteristics, mechanisms of immune regulation, and recent data about preclinical and clinical studies in systemic autoimmune diseases are reviewed here. Challenges and limitations of each cell therapy are also addressed.

Keywords: Autoimmune disease; Cell therapy; Mesenchymal stromal cells; Myeloid-derived suppressor cells; Regulatory T cells.

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Conflict of interest statement

Conflict of Interest: The authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1. Schematic immunosuppressive mechanisms of MDSCs. Tissue-derived MDSCs (e.g., from bone marrows, umbilical cords, and adipose tissues) are licensed by inflammatory stimulation such as IL-1β, TNF-α, and IFN-γ to exert more potent immune-regulatory properties. MDSCs can suppress effector immune cells through secretion of TGF-β, NO, prostaglandin E2, and IDO, and direct cell-to-cell contacts. Furthermore, they also induce differentiation of Tregs.
Figure 2
Figure 2. Types of Treg therapies and their immunosuppressive mechanisms. Two types of Tregs are generated by in vitro expansion. Polyclonal Tregs can be made under IL-2 and anti-CD3/CD28 Ab stimulation. Polyclonal Tregs exert diverse TCR repertoire and suppress effector T cells by the ‘Ag-nonspecific’ pathway called ‘bystander immunosuppression’. Ag-specific Tregs are made by representative 2 methods: the CRISPR/Cas9 system and the CAR system. These Tregs secret IL-10, IL-35, and TGF-β to suppress effector T cells, and promote differentiation of ‘tolerogenic’ DC through expression of CTLA-4.
Figure 3
Figure 3. Schematic immunosuppressive mechanisms of MDSCs. 1) MDSCs produce ROS and NO, and increase expression of ARG-1, which can exert immunosuppressive activities. 2) MDSCs deplete amino acids such as cysteine and L-arginine, essential for proliferation and activation of T cells. 3) MDSCs suppress expression of adhesion molecules (e.g., L-selectin) of effector cells. 4) MDSCs express CD39 and CD73, which can generate adenosine from extracellular ATP. 5) MDSCs express inhibitory molecules such as PD-L1, which is interacting with its corresponding ligand, PD-1 on effector T cells. All these mechanisms contribute to immunosuppressive functions of MDSCs.
ARG-1, arginase-1.
See this image and copyright information in PMC

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