Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fet...Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fetal alloantigens during murine pregnancy. In mice, IDO expression is an inducible feature of specific subsets of dendritic cells (DCs), and is important for T cell regulatory properties. However, the effect of IDO and tryptophan deprivation on DC func- tions remains unknown. We report here that when tryptophan utilization was prevented by a pharmacological inhibitor of IDO, 1-methyl tryptophan (1MT), DC activation induced by pathogenic stimulus lipopolysaccharide (LPS) or inflam- matory cytokine TNF-α was inhibited both phenotypically and functionally. Such an effect was less remarkable when DC was stimulated by a physiological stimulus, CD40 ligand. Tryptophan deprivation during DC activation also regu- lated the expression of CCR5 and CXCR4, as well as DC responsiveness to chemokines. These results suggest that tryptophan usage in the microenvironment is essential for DC maturation, and may also play a role in the regulation of DC migratory behaviors.展开更多
Objective: To investigate the relationship between serum IDO levels and Treg/Th17, Th1/Th2 immune balance in patients with ulcerative colitis (UC). Methods: 78 cases of UC patients in our hospital during September 201...Objective: To investigate the relationship between serum IDO levels and Treg/Th17, Th1/Th2 immune balance in patients with ulcerative colitis (UC). Methods: 78 cases of UC patients in our hospital during September 2015 to January 2018 were divided into Light UC group (n=42) and Severe UC group (n=36) according to severity of diarrhea. 50 cases of healthy volunteers underwent physical examination at the same time were selected as Normal control group. Serum contents of IDO, Treg, Th17, Th1, Th2-related cytokines were measured between three groups, the relationship between IDO and Treg/Th17, Th1/Th2 immune balance in UC patients was evaluated. Results: There were significant differences in serum contents of IDO, Treg, Th17, Th1, Th2 related cytokines among three groups (P<0.05). As aggravation of UC, serum content of IDO increased, contents of Treg cytokines IL-10, TGF-β decreased, contents of Th17 cytokines IL-17, IL-21 increased, contents of Th1 cytokines IL-2, IFN-γ increased, contents of Th2 cytokines IL-4, IL-13 decreased (P<0.05). Correlation analysis showed that serum IDO level was negatively correlated with Treg cytokines and positively correlated with Th17 cytokines, positively correlated with Th1 cytokines and negatively correlated with Th2 cytokines (P<0.05). Conclusion: Serum content of IDO in UC patients increases abnormally and is directly related to the immune balance of Treg/Th17 and Th1/Th2. It can be used as an effective index to evaluate the immune status of UC patients.展开更多
Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is develope...Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is developed by conjugating polypeptide inhibitor of PD-1 signal pathway(AUNP-12),which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2(MMP-2)cleavable peptide(GPLGVRGD).This targeted liposome is prepared through a mature preparation process,and indoleamine-2,3-dioxygenase(IDO)inhibitor NLG919 was encapsulated into it.Moreover,mediated by the enhanced permeability and retention effect(EPR effect)and AUNP-12,NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues.At the same time,the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12,thus realizing the precise block of PD-1 signal pathway,and restoring the activity of T cells.The exposure of secondary targeting moduleⅡVRGDC-NLG919@Lip mediated tumor cells targeting,and further relieved the immunosuppressive microenvironment.Overall,this study offers a potentially appealing paradigm of a high efficiency,low toxicity,and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer,which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.展开更多
Cancer immunotherapy has been widely recognized as a powerful approach to fight cancers.To date,over 50 phase III trials in cancer immunotherapy are in progress.Among the many immunotherapy approaches,immune checkpoin...Cancer immunotherapy has been widely recognized as a powerful approach to fight cancers.To date,over 50 phase III trials in cancer immunotherapy are in progress.Among the many immunotherapy approaches,immune checkpoint therapy has attracted considerable attention.The reported clinical success of targeting the T cell immune checkpoint receptors PD-1 or CTLA4 by antibodies blockade in advanced stages of cancers has demonstrated the importance of immune modulation.But antibodies-based immunotherapy confronted with some disadvantages,such as immunogenicity,stability,membrane permeability,and production cost.Therefore,alternative approaches including small-molecule-regulated immune response are being introduced.In this review,we focused on some of the key intracellular pathways where small-molecule therapeutic is potential and attractive,which highlights the great potential of natural products in this field.展开更多
文摘Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fetal alloantigens during murine pregnancy. In mice, IDO expression is an inducible feature of specific subsets of dendritic cells (DCs), and is important for T cell regulatory properties. However, the effect of IDO and tryptophan deprivation on DC func- tions remains unknown. We report here that when tryptophan utilization was prevented by a pharmacological inhibitor of IDO, 1-methyl tryptophan (1MT), DC activation induced by pathogenic stimulus lipopolysaccharide (LPS) or inflam- matory cytokine TNF-α was inhibited both phenotypically and functionally. Such an effect was less remarkable when DC was stimulated by a physiological stimulus, CD40 ligand. Tryptophan deprivation during DC activation also regu- lated the expression of CCR5 and CXCR4, as well as DC responsiveness to chemokines. These results suggest that tryptophan usage in the microenvironment is essential for DC maturation, and may also play a role in the regulation of DC migratory behaviors.
文摘Objective: To investigate the relationship between serum IDO levels and Treg/Th17, Th1/Th2 immune balance in patients with ulcerative colitis (UC). Methods: 78 cases of UC patients in our hospital during September 2015 to January 2018 were divided into Light UC group (n=42) and Severe UC group (n=36) according to severity of diarrhea. 50 cases of healthy volunteers underwent physical examination at the same time were selected as Normal control group. Serum contents of IDO, Treg, Th17, Th1, Th2-related cytokines were measured between three groups, the relationship between IDO and Treg/Th17, Th1/Th2 immune balance in UC patients was evaluated. Results: There were significant differences in serum contents of IDO, Treg, Th17, Th1, Th2 related cytokines among three groups (P<0.05). As aggravation of UC, serum content of IDO increased, contents of Treg cytokines IL-10, TGF-β decreased, contents of Th17 cytokines IL-17, IL-21 increased, contents of Th1 cytokines IL-2, IFN-γ increased, contents of Th2 cytokines IL-4, IL-13 decreased (P<0.05). Correlation analysis showed that serum IDO level was negatively correlated with Treg cytokines and positively correlated with Th17 cytokines, positively correlated with Th1 cytokines and negatively correlated with Th2 cytokines (P<0.05). Conclusion: Serum content of IDO in UC patients increases abnormally and is directly related to the immune balance of Treg/Th17 and Th1/Th2. It can be used as an effective index to evaluate the immune status of UC patients.
基金the National Natural Science Foundation of China(82173762,China)111 Project(B18035,China)+2 种基金the Fundamental of Research Funds for the Central Universities(China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,China)Project of Chengdu Science and Technology Bureau(2020-GH03-00003-HZ)。
文摘Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is developed by conjugating polypeptide inhibitor of PD-1 signal pathway(AUNP-12),which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2(MMP-2)cleavable peptide(GPLGVRGD).This targeted liposome is prepared through a mature preparation process,and indoleamine-2,3-dioxygenase(IDO)inhibitor NLG919 was encapsulated into it.Moreover,mediated by the enhanced permeability and retention effect(EPR effect)and AUNP-12,NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues.At the same time,the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12,thus realizing the precise block of PD-1 signal pathway,and restoring the activity of T cells.The exposure of secondary targeting moduleⅡVRGDC-NLG919@Lip mediated tumor cells targeting,and further relieved the immunosuppressive microenvironment.Overall,this study offers a potentially appealing paradigm of a high efficiency,low toxicity,and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer,which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.
基金supported financially by the funding of Exploitation and Utilization of Abundant Natural Products from Plants from Kunming Institute of Botany(KIB2017009)the National Natural Science Foundation of China(U1402227)+2 种基金the 100 Talents Program of the Chinese Academy of Sciences(Y.Li)the Program of Recruited Top Talent of Sciences and Technology of Yunnan Province(2009CI120)the Independent Program of Key Laboratory of Natural Pharmaceutical Chemistry of Yunnan Province(Y.Li).
文摘Cancer immunotherapy has been widely recognized as a powerful approach to fight cancers.To date,over 50 phase III trials in cancer immunotherapy are in progress.Among the many immunotherapy approaches,immune checkpoint therapy has attracted considerable attention.The reported clinical success of targeting the T cell immune checkpoint receptors PD-1 or CTLA4 by antibodies blockade in advanced stages of cancers has demonstrated the importance of immune modulation.But antibodies-based immunotherapy confronted with some disadvantages,such as immunogenicity,stability,membrane permeability,and production cost.Therefore,alternative approaches including small-molecule-regulated immune response are being introduced.In this review,we focused on some of the key intracellular pathways where small-molecule therapeutic is potential and attractive,which highlights the great potential of natural products in this field.
