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Targeting Th17 Cells with Small Molecules and Small Interference RNA.

Lin H, Song P, Zhao Y, Xue LJ, Liu Y, Chu CQ - Mediators Inflamm. (2015)

Bottom Line: Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA) and Crohn's disease.Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine.In this review, we highlight the development and therapeutic potential of small molecules inhibiting Th17 cells by targeting RORγt and aptamer mediated CD4(+) T cell specific delivery of small interference RNA against RORγt gene expression to inhibit pathogenic effector functions of Th17 lineage.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

ABSTRACT
T helper 17 (Th17) cells play a central role in inflammatory and autoimmune diseases via the production of proinflammatory cytokines interleukin- (IL-) 17, IL-17F, and IL-22. Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA) and Crohn's disease. Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine. Retinoic acid-related orphan receptor gamma t (RORγt) which acts as the master transcription factor of Th17 differentiation has been an attractive pharmacologic target for the treatment of Th17-mediated autoimmune disease. Recent progress in technology of chemical screen and engineering nucleic acid enable two new classes of therapeutics targeting RORγt. Chemical screen technology identified several small molecule specific inhibitors of RORγt from a small molecule library. Systematic evolution of ligands by exponential enrichment (SELEX) technology enabled target specific aptamers to be isolated from a random sequence oligonucleotide library. In this review, we highlight the development and therapeutic potential of small molecules inhibiting Th17 cells by targeting RORγt and aptamer mediated CD4(+) T cell specific delivery of small interference RNA against RORγt gene expression to inhibit pathogenic effector functions of Th17 lineage.

No MeSH data available.


Related in: MedlinePlus

Predicted secondary structure of CD4-aptamer-RORγt shRNA chimera (modified from Song et al., BBRC, 2014, Figure  1(b) [104] with permission).
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fig1: Predicted secondary structure of CD4-aptamer-RORγt shRNA chimera (modified from Song et al., BBRC, 2014, Figure  1(b) [104] with permission).

Mentions: CD4 aptamers that bind surface CD4 can be applied as T helper cell-specific delivering vehicles. CD4-AsiCs bearing siRNAs or shRNA targeting RORγt might suppress Th17 differentiation and treat Th17-mediated autoimmune diseases. We selected CD4 RNA aptamers (86 nucleotides in length) that delivered RORγt-shRNA (Figure 1) into CD4+ T cells and investigated its efficacy in suppressing Th17 cell differentiation and IL-17 production in human CD4+ T cells in vitro [104]. Chemical modifications of nucleotides 2′-F-dCTP and 2′-F-dUTP were done to enhance the nuclease resistance of the aptamer chimeras [104]. In vitro using fluorescent microscope and flow cytometric analysis, Cy3-labeled CD4 aptamer-RORγt shRNA chimeras (CD4-AshR-RORγt) (133 nucleotides in length) were shown to enter into human CD4+ T cells but not Cy3-labeled mock CD4-AshR- RORγt. In vitro expression of RORγt is significantly and specifically diminished by CD4-AshR-RORγt in a concentration-dependent manner in human CD4+ T cells compared with control CD4 aptamers [104]. Consistent with decreased RORγt, CD4-AshR-RORγt displayed a concentration-dependent inhibition of IL-17A release from CD4+ T cells and intracellular IL-17A staining in CD4+ T cells, while mock CD4-AshR-RORγt and CD4-AshR-scrambled control have no impacts [104]. This study indicates that intracellular delivery of CD4-AshR-RORγt could target RORγt and manipulate Th17 cell differentiation and IL-17 production in CD4+ T cells. Additionally, CD4-AshR-RORγt does not significantly impact the expression of Th1 and Th2 lineage transcription factors T-bet and GATA-3 in PMBCs. Consistent with these, synthesis of IFN-γ and IL-4 in PBMCs is not changed by CD4-AshR-RORγt.


Targeting Th17 Cells with Small Molecules and Small Interference RNA.

Lin H, Song P, Zhao Y, Xue LJ, Liu Y, Chu CQ - Mediators Inflamm. (2015)

Predicted secondary structure of CD4-aptamer-RORγt shRNA chimera (modified from Song et al., BBRC, 2014, Figure  1(b) [104] with permission).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4697089&req=5

fig1: Predicted secondary structure of CD4-aptamer-RORγt shRNA chimera (modified from Song et al., BBRC, 2014, Figure  1(b) [104] with permission).
Mentions: CD4 aptamers that bind surface CD4 can be applied as T helper cell-specific delivering vehicles. CD4-AsiCs bearing siRNAs or shRNA targeting RORγt might suppress Th17 differentiation and treat Th17-mediated autoimmune diseases. We selected CD4 RNA aptamers (86 nucleotides in length) that delivered RORγt-shRNA (Figure 1) into CD4+ T cells and investigated its efficacy in suppressing Th17 cell differentiation and IL-17 production in human CD4+ T cells in vitro [104]. Chemical modifications of nucleotides 2′-F-dCTP and 2′-F-dUTP were done to enhance the nuclease resistance of the aptamer chimeras [104]. In vitro using fluorescent microscope and flow cytometric analysis, Cy3-labeled CD4 aptamer-RORγt shRNA chimeras (CD4-AshR-RORγt) (133 nucleotides in length) were shown to enter into human CD4+ T cells but not Cy3-labeled mock CD4-AshR- RORγt. In vitro expression of RORγt is significantly and specifically diminished by CD4-AshR-RORγt in a concentration-dependent manner in human CD4+ T cells compared with control CD4 aptamers [104]. Consistent with decreased RORγt, CD4-AshR-RORγt displayed a concentration-dependent inhibition of IL-17A release from CD4+ T cells and intracellular IL-17A staining in CD4+ T cells, while mock CD4-AshR-RORγt and CD4-AshR-scrambled control have no impacts [104]. This study indicates that intracellular delivery of CD4-AshR-RORγt could target RORγt and manipulate Th17 cell differentiation and IL-17 production in CD4+ T cells. Additionally, CD4-AshR-RORγt does not significantly impact the expression of Th1 and Th2 lineage transcription factors T-bet and GATA-3 in PMBCs. Consistent with these, synthesis of IFN-γ and IL-4 in PBMCs is not changed by CD4-AshR-RORγt.

Bottom Line: Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA) and Crohn's disease.Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine.In this review, we highlight the development and therapeutic potential of small molecules inhibiting Th17 cells by targeting RORγt and aptamer mediated CD4(+) T cell specific delivery of small interference RNA against RORγt gene expression to inhibit pathogenic effector functions of Th17 lineage.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

ABSTRACT
T helper 17 (Th17) cells play a central role in inflammatory and autoimmune diseases via the production of proinflammatory cytokines interleukin- (IL-) 17, IL-17F, and IL-22. Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA) and Crohn's disease. Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine. Retinoic acid-related orphan receptor gamma t (RORγt) which acts as the master transcription factor of Th17 differentiation has been an attractive pharmacologic target for the treatment of Th17-mediated autoimmune disease. Recent progress in technology of chemical screen and engineering nucleic acid enable two new classes of therapeutics targeting RORγt. Chemical screen technology identified several small molecule specific inhibitors of RORγt from a small molecule library. Systematic evolution of ligands by exponential enrichment (SELEX) technology enabled target specific aptamers to be isolated from a random sequence oligonucleotide library. In this review, we highlight the development and therapeutic potential of small molecules inhibiting Th17 cells by targeting RORγt and aptamer mediated CD4(+) T cell specific delivery of small interference RNA against RORγt gene expression to inhibit pathogenic effector functions of Th17 lineage.

No MeSH data available.


Related in: MedlinePlus