Yonsei Med J.  2018 Sep;59(7):807-815. 10.3349/ymj.2018.59.7.807.

Generation, Characteristics and Clinical Trials of Ex Vivo Generated Tolerogenic Dendritic Cells

• Kim SH
• Jung HH
• Lee CK

• KMID: 2428906
• DOI: http://doi.org/10.3349/ymj.2018.59.7.807

Abstract

Dendritic cells (DCs) play a key role not only in the initiation of primary immune responses, but also in the development and maintenance of immune tolerance. Numerous protocols have been developed to generate tolerogenic DCs (tolDCs) ex vivo, and the therapeutic efficacy of ex vivo-generated tolDCs has been demonstrated in autoimmune disease animal models. Based on successes in small animal models, several clinical trials have been completed or are on-going in patients with autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and Crohn's disease. Here we describe the methods used to generate tolDCs ex vivo, and the common features shared by tolDCs. In addition, we overview five completed clinical trials with reported outcomes and summarize the tolDC-based clinical trials that are currently registered with the U.S. National Institutes of Health. Although the number of tolDC-based clinical trials is much smaller than the hundreds of clinical trials using immunogenic DCs, tolDC-based treatment of autoimmune diseases is becoming a reality, and could serve as an innovative cellular therapy in the future.

Keyword

Dendritic cell; immune tolerance; autoimmune disease; clinical trial; cellular therapy

MeSH Terms

Arthritis, Rheumatoid
Autoimmune Diseases
Crohn Disease
Dendritic Cells*
Humans
Immune Tolerance
Models, Animal
Multiple Sclerosis
National Institutes of Health (U.S.)

Figure

• 

  Fig. 1 Generation, characteristics, and mechanisms of action of tolDCs. Human tolDCs are mostly produced from peripheral blood monocytes by culturing with GM-CSF, IL-4, and an agent(s) known to confer tolerogenic properties. In murine systems, immature DCs are first generated by culturing bone marrow cells with GM-CSF and IL-4, and then induced to tolDCs by additional culturing with an agent(s) known to confer tolerogenic properties. TolDCs induce several subtypes of regulatory lymphocytes such as CD4+CD25+Foxp3+ Tregs, and CD25+Foxp3+/− Tr-1 cells from precursor T cells (pTh). DC, dendritic cell; tolDCs, tolerogenic DCs; GM-CSF, granulocyte macrophage-colony stimulating factor; IL, interleukin; MHC, major histocompatibility complex; PD-L1, programmed death-ligand 1; ICOSL, inducible costimulator ligand; TNF, tumor necrosis factor; IFN, interferon; TLR, toll-like receptor; IDO, indoleamine 2,3-dioxygenase; FasL, Fas ligand; TGF, transforming growth factor.

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