Scoparone (SCO), also known as 6,7-Dimethoxycoumarin, is a naturally occurring bioactive ingredient originally derived from Chinese herb Artemisiae Scopariae Herba (Yin-Chen-Hao). Previous studies have shown that it is effective in treating some of the liver diseases. Beyond its hepatoprotective effects, an expanding body of research has underscored the immunoregulatory properties of SCO, indicating its potential therapeutic benefits for autoimmune and other inflammatory diseases. Over the past decade, significant advances have been made in understanding the mechanistic insights into its effects on immune-mediated diseases as well as liver diseases. SCO has an impact on various immune cells, including mast cells, monocytes, macrophages, neutrophils and T cells, and affects a broad range of intracellular signaling pathways, including TLR4/Myd88/NFκB, TGFβR/Smad3 and JNK/Sab/SHP-1 etc. Therefore, this review not only summarizes the immunomodulatory and therapeutic effects of SCO on immune-based inflammatory diseases (IMIDs), such as inflammatory bowel disease, osteoarthritis, allergic rhinitis, acute lung injury, type 1 diabetes and neuroinflammatory diseases etc., but also provides a comprehensive summary of its therapeutic effects on hepatic diseases, including non-alcoholic steatohepatitis, fulminant hepatic failure and hepatic fibrosis. In this review, we also include the broad impacts of SCO on intracellular signaling pathways, such as TLR4/Myd88/NFκB, TGFβR/Smad3, Nrf2/P38, JAK2/STAT3 and JNK/Sab/SHP-1 etc. Further researches on SCO may help understand its in-depth mechanisms of action and pave the way for the development of novel drugs to prevent and treat various immune-mediated inflammatory disorders as well as hepatic diseases, thereby significantly advancing its innovations and pharmaceutical applications.
// Huazhen Liu 1 , Yeshu Wang 2 , Qiaohuang Zeng 2 , Yu-Qun Zeng 2,3 , Chun-Ling Liang 1 , Feifei Qiu 1 , Hong Nie 4 and Zhenhua Dai 1 1 Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences, and Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, P.R. China 2 Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China 3 Student Exchange Program, Mayo Clinic, Rochester, MN, USA 4 Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, Guangdong, P.R. China Correspondence to: Zhenhua Dai, email: // Keywords : transplantation, Treg, immunoregulation, T cell apoptosis, Immunology and Microbiology Section, Immune response, Immunity Received : January 21, 2017 Accepted : February 13, 2017 Published : February 20, 2017 Abstract Mounting evidence has shown that naturally occurring CD8+CD122+ T cells are regulatory T cells (Tregs) that suppress both autoimmunity and alloimmunity. We have previously shown that CD8+CD122+PD-1+ Tregs not only suppress allograft rejection, but also are more potent in suppression than conventional CD4+CD25+ Tregs. However, the mechanisms underlying their suppression of alloimmunity are not well understood. In an adoptive T-cell transfer model of mice lacking lymphocytes, we found that suppression of skin allograft rejection by CD8+CD122+PD-1+ Tregs was mostly dependent on their expression of Fas ligand as either lacking Fas ligand or blocking it with antibodies largely abolished their suppression of allograft rejection mediated by transferred T cells. Their suppression was also mostly reversed when effector T cells lacked Fas receptor. Indeed, these FasL+ Tregs induced T cell apoptosis in vitro in a Fas/FasL-dependent manner. However, their suppression of T cell proliferation in vitro was dependent on IL-10, but not FasL expression. Furthermore, adoptive transfer of CD8+CD122+PD-1+ Tregs significantly extended allograft survival even in wild-type mice if Tregs lacked Fas receptor or if recipients received recombinant IL-15, as these two measures synergistically expanded adoptively-transferred Tregs in recipients. Thus, this study may have important implications for Treg therapies in clinical transplantation.
A transplanted organ is always rejected in the absence of any immunosuppressive treatment due to vigorous alloimmunity. However, continuously global immunosuppression with a conventional immunosuppressant may result in severe side effects, including nephrotoxicity, tumors and infections. Tregs have been widely used to inhibit allograft rejection, especially in animal models. However, it's well accepted that administration of Tregs alone is not satisfactory in immune-competent wild-type animals. Therefore, it's imperative to promote Treg therapies under the cover of other approaches, including costimulatory blockade. In the present study, we demonstrated that administration of in vitro-expanded CD8+CD122+PD-1+ Tregs synergized with costimulatory blockade of CD40/CD154, but not B7/CD28, to prolong skin allograft survival in wild-type mice and to reduce cellular infiltration in skin allografts as well. Treg treatment and blockade of CD40/CD154, but not B7/CD28, also exhibited an additive effect on suppression of T cell proliferation in vitro and pro-inflammatory cytokine expression in skin allografts. Importantly, blocking B7/CD28, but not CD40/CD154, costimulation decreased the number of transferred CD8+CD122+PD-1+ Tregs and their expression of IL-10 in recipient mice. Furthermore, it's B7/CD28, but not CD40/CD154, costimulatory blockade that dramatically reduced IL-10 production by CD8+CD122+PD-1+ Tregs in vitro, suggesting that B7/CD28, but not CD40/CD154, costimulation is critical for their production of IL-10. Indeed, infusion of IL-10-deficient CD8+CD122+PD-1+ Tregs failed to synergize with anti-CD154 Ab treatment to further prolong allograft survival. Our data may explain why blocking B7/CD28 costimulatory pathway does not boost IL-10-dependent Treg suppression of alloimmunity. Thus, these findings could be implicated in clinical organ transplantation.
Traditional Chinese Medicine (TCM) has been traditionally used to treat patients with cancers in China. It not only alleviates the symptoms of tumor patients and improves their quality of life, but also controls the size of tumors and prolongs the survival of tumor patients. While some herbs of TCM may exert therapeutic effects by directly targeting cancer cells or reducing side effects caused by antitumor drugs, others can control tumor growth and metastasis via enhancing antitumor immunity. In particular, TCM can exert antitumor effects by upregulating immune responses even in immunosuppressive tumor microenvironment. For instance, it reduces the number of M2-type macrophages and Treg cells in the tumor tissue. Although extensive reviews on directly killing cancer cells by TCM have been conducted, a review of anticancer activity of TCM solely based on its immunity-enhancing capacity is unusual. This review will summarize research progress of antitumor TCM that regulates the immune system, including both innate immunity, such as macrophages, dendritic cells, natural killer cells and MDSCs, and adaptive immunity, including CD4+/CD8+ T lymphocytes, regulatory T cells (Tregs) and B cells. As cancer immunotherapy has recently achieved certain success, it is expected that the clinical applications of immunity-enhancing TCM or traditional medicine for treating various cancer patients will be expanded. Further studies on the mechanisms by which TCM regulates immunity will provide new insights into how TCM controls tumor growth and metastasis, and may help improve its therapeutic effects on various cancers in clinic.
Zhen-Wu-Tang (ZWT), a conventional herbal mixture, has been recommended for treating lupus nephritis (LN) in clinic. However, its mechanisms of action remain unknown. Here we aimed to define the immunological mechanisms underlying the effects of ZWT on LN and to determine whether it affects renal tissue-resident memory T (T
Abstract The mechanisms responsible for the generation and maintenance of T cell memory are unclear. In this study, we tested the role of IL-2 in allospecific CD8+ T cell memory by analyzing the long-term survival, phenotype, and functional characteristics of IL-2-replete (IL-2+/+) and IL-2-deficient (IL-2−/−) CD8+ TCR-transgenic lymphocytes in an adoptive transfer model. We found that IL-2 is not essential for the in vivo generation, maintenance, or recall response of CD8+ memory T cells. However, IL-2 increased the size of the CD8+ memory pool if present at the time of initial T cell activation but reduced the size of the pool if present during memory maintenance by inhibiting the proliferation of CD8+ memory T cells. Thus, IL-2-based vaccine strategies or immunosuppressive regimens that target IL-2 should take into account the divergent roles of IL-2 in CD8+ T cell immunity.
Background. Immune responses are tempered in immunologically privileged sites including the testis. Previous studies have shown that islet transplantation in the testis significantly prolongs islet allograft survival. However, mechanisms underlying testicular immune privilege and intratesticular allograft survival remain unclear. Methods. Allogeneic murine islets were transplanted in the testis. Programmed death-1 ligand-1 (PD-L1) expression was detected by immunohistochemstry and real-time polymerase chain reaction. Infiltrating T-cell proliferation was measured by bromodeoxyuridine uptakes, whereas their apoptosis was quantified by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling methods. Transgenic T cells were used to track allospecific memory T-cell generation. Results. We found that programmed death-1 (PD-1):PD-L1 negative costimulation is essential for prolonged survival of intratesticular islet allografts, as blocking PD-L1 or PD-1, but not PD-L2 and cytotoxic T-lymphocyte antigen 4, abrogated long-term survival of intratesticular islet allografts. As controls, blocking PD-1 or PD-L1 did not significantly accelerate the acute rejection of islet allografts transplanted under the renal capsule, a conventional islet-grafting site. We also found for the first time that PD-L1 is constitutively expressed mainly by spermatocytes and spermatids in seminiferous tubules of the testis. Moreover, infiltrating T cells underwent less vigorous proliferation but faster apoptosis in the testis than in the kidney. Blocking PD-1:PD-L1 costimulation largely abolished the suppression of T-cell proliferation and acceleration of T-cell apoptosis. Importantly, testicular immune privilege significantly suppressed the generation and proliferation of donor-specific memory CD8+ T cells. Conclusions. The constitutive expression of PD-L1 in the testis is an important mechanism underlying testicular immune privilege and long-term survival of intratesticular islet allografts.
Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell-originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.
<p>Continuous treatment with HI-TOPK-032 increases the expression of effector molecules but reduces some of the exhaustion molecules in CAR-T cells in vitro.</p>
<p>HI-TOPK-032 decreases the expression of LAG-3 and TIM-3 and frequencies of CCR7+PD-1+ subset in CD8+ CAR-T cells of mice bearing subcutaneous Huh7-HCC.</p>
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