Human immune suppression is inducible by trichosanthin via CD8 cell-mediated pathway

Thichosanthin(Tk), a polypeptide with 249 amino acid residues isolated and purified from a Chinese medicinal herb, showed the capability of inducing abortion and was able to inhibit tumor growth and HIV replication. Owing to sequence homology of the peptide with a ribosomeinactivating protein, the downward activity of Tk was suggested to be related to its cytotoxic property. We report here, however, that Tk could exert potent inhibitory effects on human lymphoproliferative responses in vitro to allogeneic, mitogenic and soluble antigens with 50% inhibition doses ranged between 0.05 and 0.5 μg/ml. The lowresponsiveness caused by Tk was not due to toxic cytolysis. Rather, evidences suggested that, in the dose range adopted, the Tk-induced inhibition was attributable, at least in part, to immune suppression, in view of (1) Tk was more effective in the early stage of alloreactivity; (2)Suppression also occurred if responder cells were pulsetreated with Tk rather than cocultured; (3) Irradiated Tk-pulsed cells were capable of inducing suppression in a Tk-free culture; (4) Suppression could also be transferred by the supernatants of Tk-pulsed cultured cells; (5) Tkinduced immune suppression was diminished by depletion of CD8+ cells from the culture, and, finally; (6) Adding CD8+ cells back to the culture could restore the suppres Trichosanthin-induced humall immune suppression sion. Thus the possibility that Tk might function as a down-regulator by immunological mechanisms in human immune responses is discussed.

Up-regulation of Tim-3 Expression Contributes to Development of Burn-induced T Cell Immune Suppression in Mice

T cell immunoglobulin and mucin domain 3 （Tim-3） is well known to negatively regulate T cells responses, but its role in burn-induced T cells immune suppression remains unclear. In the present study, in order to identify the relationship between Tim-3 expression and post-burn T cells immune suppression, C57BL/6 mice were subjected to burn injury or sham injury, and the liver and spleen were harvested at the day 1 after operation. The expression level of Tim-3 on hepatic or splenic T cells and the functional properties of Tim-3＋ T cells were evaluated. It was found burn injury induced dramatically elevated Tim-3 expression on both hepatic and splenic CD4＋ and CD8＋ T cells in contrast with the post-burn depletion of T cells. Furthermore, Tim-3 expression was correlated with the suppressive phenotype of T cells following burn injury, including increased expression of anti-inflammatory cytokine IL-10, decreased expression of pro-inflammatory cytokines IFN-γ and TNF-α, reduced T cell proliferation and elevated co-expression of Tim-3 and PD-1. Moreover, Tim-3＋ T cells subsets were more prone to spontaneous apoptosis than Tim-3- T cells subsets. Our findings reinforce the idea that the up-regulated expression of Tim-3 on T cells after burn injury plays an important role in the development and maintenance of burn-induced T cell immune suppression.

The Effect of TSH Suppression Therapy on the Efficacy and Immune Function of Postoperative Patients with Thyroid Cancer

Objective:To investigate the efficacy and immune function of thyroid stimulating hormone(TSH)suppression therapy in postoperative thyroid cancer patients.Methods:Sixty thyroid cancer patients admitted from July 2020–July 2022 were recruited and randomly divided into two groups.The control group(30 patients)received hormone replacement therapy,while the study group(30 patients)received TSH suppression therapy.The thyroid function,clinical efficacy,immune function,and tumor markers of the two groups were compared.Results:After treatment,the levels of free triiodothyronine(FT3)and thyroxine(FT4)in both groups increased significantly,while TSH levels decreased significantly.Moreover,the magnitude of change in the study group was greater than that in the control group(P<0.05).The total effective rate in the study group was significantly higher as compared to the control group(P<0.05).After treatment,the levels of CD3+and CD4+cells in both groups of patients increased significantly,with the study group showing significantly higher levels than the control group,whereas the level of CD8+cells decreased significantly,with the study group having lower levels than the control group(P<0.05).After treatment,the levels of Tg and CEA in both groups were significantly lowered as compared to before treatment,and the levels of Tg and CEA in the study group were significantly lower than the control group(P<0.05).Conclusion:TSH suppression therapy in postoperative thyroid cancer patients can improve thyroid function,suppress the levels of tumor markers,and enhance immune function,thereby achieving good clinical outcomes.

Effect of Fuzheng Jiedu granule on immunological function and level of immune-related cytokines in immune-suppressed mice

Fuzheng Jiedu granule exhibits a number of health benefits and it is thought that the mechanisms involved in these effects are due to the modulation of immunity. In this article, we studied the effect of Fuzheng Jiedu granule on immunological function and the expression of immune-related cytokines in immune-suppressed mice. 72 mice were randomly divided into six groups, with 12 in each group. The control groups included an untreated group, a negative control group（Cyclophosphamide） and a positive control group（Astragalus polysaccharide）. There were three treated groups, which were given different doses of Fuzheng Jiedu granule： a low dose（100 mg kg^（–1））, a medium dose（400 mg kg^（–1）） and a high dose（600 mg kg^（–1））. With the exception of the untreated control animals, each group received an intraperitoneal injection of Cyclophosphamide（100 mg kg^（–1）） for 3 days to establish the immune-suppressed model. Mice were then treated for 19 consecutive days and, 24 h after the last treatment, blood was taken for the eyeballs and serum separation was performed. Analysis was made of the levels of related cytokines（IgA, IgG, IgM, IL-6, IFN-γ, C3, C4 and TNF-α）, the transformation of lymphocytes and the immune organ indexes. The results showed that Fuzheng Jiedu granule can improve the levels of cytokines, the rate of proliferation of lymphocytes and the immune organ indexes of immune-suppressed mice.

Does steroid-free immunosuppression improve the outcome in kidney transplant recipients compared to conventional protocols?

Steroids continue to be the cornerstone of immune suppression since the early days of organ transplantation.Steroids are key component of induction protocols,maintenance therapy and in the treatment of various forms of rejection.Prolonged steroid use resulted in significant side effects on almost all the body organs owing to the presence of steroid receptors in most of the mammalian cells.Kidney allograft recipients had to accept the short and long term complications of steroids because of lack of effective alternatives.This situation changed with the introduction of newer and more effective immune suppression agents with a relatively more acceptable side effect profile.As a result,the clinicians have been contemplating if it is the time to abandon the unquestionable reliance on maintenance steroids in modern transplantation practice.This review aims to evaluate the safety and efficacy of various steroid-minimization approaches(steroid avoidance,early steroid withdrawal,and late steroid withdrawal)in kidney transplant recipients.A meticulous electronic search was conducted through the available data resources like SCOPUS,MEDLINE,and Liverpool University library e-resources.Relevant articles obtained through our search were included.A total number of 90 articles were eligible to be included in this review[34 randomised controlled trials(RCT)and 56 articles of other research modalities].All articles were evaluating the safety and efficacy of various steroidfree approaches in comparison to maintenance steroids.We will cover only the RCT articles in this review.If used in right clinical context,steroid-free protocols proved to be comparable to steroid-based maintenance therapy.The appropriate approach should be tailored individually according to each recipient immunological challenges and clinical condition.

Effects of Bortezomib and Dexamethasone combination on treating senile multiple myeloma and influence on immune suppressed factors and immune cell levels

Objective:To investigate the effects of Bortezomib and Dexamethasone combination on treating senile multiple myeloma and influence on immune suppressed factors and immune cell levels.Methods:A total of 80 cases of patients with multiple myeloma treated in our hospital from Oct 2013 to Jul 2015 were selected as investigate subjects. They were randomly divided to be observation group consisted of 43 cases and control group consisted of 37 cases. For observation group, treatment of Bortezomib and Dexamethasone combination was provided. For control group, Vincristine + Epirubicin + Dexamethasone treatment was provided. After three courses, effects on two groups of patients were compared, and immune suppressed factors and immune cell levels before and after treatment in different periods were compared.Results:After three courses of treatment, the total effective rate in observation group was significantly higher than control group. Before treatment, IL-6, IL-17, TGF-β, CD3+CD4+, CD3+CD8+ and CD3+CD4+/CD3+CD8+ between the two group of patients were compared, no significant difference showed;After treatment for 6 weeks, IL-6, IL-17 levels in observation group were significantly decreased comparing with the same group before treatment;After treatment for 12 weeks, IL-6, IL-17 and TGF-β levels in observation group were significantly decreased comparing with the same group before treatment;After treatment, IL-6, IL-17 levels in observation group were significantly lower than control group at the same phase. After treatment for 12 weeks, CD3+CD4+, CD3+CD4+/CD3+CD8+ in observation group were significantly higher than the same group before treatment, and significantly higher than control group at the same phase;CD3+CD8+ in observation group was significantly lower than the same group before treatment, and significantly lower than control group at the same phase. Conclusion:Compared with Vincristine + Epirubicin + Dexamethasone treatment, Bortezomib and Dexamethasone combination on treating senile multiple myeloma had more significant effects, which deserves further clinical researches.

Innate-like CD4 T cells selected by thymocytes suppress adaptive immune responses against bacterial infections

We have reported a new innate-like CD4 T cell population that expresses cell surface makers of effector/memory cells and produce Th1 and Th2 cytokines immediately upon activation. Unlike conventional CD4 T cells that are selected by thymic epithelial cells, these CD4 T cells, named T-CD4 T cells, are selected by MHC class II expressing thymocytes. Previously, we showed that the presence of T-CD4 T cells protected mice from airway inflammation suggesting an immune regulatory role of T-CD4 T cells. To further understand the function of T-CD4 T cells, we investigated immune responses mediated by T-CD4 T cells during bacterial infection because the generation of antigen specific CD4 T cells contributes to clearance of infection and for the development of immune memory. The current study shows a suppressive effect of T-CD4 T cells on both CD8 and CD4 T cell-mediated immune responses during Listeria and Helicobacter infections. In the mouse model of Listeria monocytogenes infection, T-CD4 T cells resulted in decreasedfrequency of Listeria-specific CD8 T cells and the killing activity of them. Furthermore, mice with T-CD4 T cells developed poor immune memory, demonstrated by reduced expansion of antigen-specific T cells and high bacterial burden upon re-infection. Similarly, the presence of T-CD4 T cells suppressed the generation of antigen-specific CD4 T cells in Helicobacter pylori infected mice. Thus, our studies reveal a novel function of T-CD4 T cells in sup-pressing anti-bacterial immunity.

Aiming to immune elimination of ovarian cancer stem cells

Ovarian cancer accounts for only 3% of all cancers in women, but it causes more deaths than any other gynecologic cancer. Treatment with chemotherapy and cytoreductive surgery shows a good response to the therapy. However, in a large proportion of the patients the tumor grows back within a few years. Cancer stem cells, that are less responsive to these treatments, are blamed for this recurrence of disease. Immune therapy either cellular or humoral is a novel concept to treat cancer. It is based on the notice that immune cells invade the tumor. However, the tumor invest heavily to escape from immune elimination by recruiting several immune suppressive mechanisms. These processes are normally in place to limit excessive immune activation and prevent autoimmune phenomena. Here, we discuss current knowledge about the immune(suppressive)status in ovarian cancer. Moreover, we discuss the immunological targets of ovarian cancer stem cells.

Immune phenotypes of prostate cancer cells: Evidence of epithelial immune cell-like transition?

Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-like Transition’’(EIT)by expressing molecules conventionally associated with immune cells(e.g.,a variety of cytokines/receptors,immune transcription factors,Ig motifs,and immune checkpoint molecules),which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment.Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development,thus leading to the development of novel immunotherapeutic approaches.Here,we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells,with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa.Furthermore,we summarize current advances in anti-immune checkpoint therapies,and provide perspectives on their potential applicability.

<i>Leishmania donovani</i>-Induced Immune Dysregulation among Sudanese Patients with Visceral and Post Kala-Azar Dermal Leishmaniases: Possible Roles in Pathogenesis

L. donovani infections (visceral and post kala-azar dermal leishmaniases) are characterized by infection-induced reversible immune suppression. Autoimmunity is a well-documented phenomenon among patients with primary immune deficiencies. This study aimed to study auto-immune phenomena accompanying L. donovani infections. In a prospective case-controlled study and following informed consent, 155 individuals with visceral leishmaniasis (VL;n = 62), post kala-azar dermal leishmaniasis (PKDL;n = 31) and apparently healthy volunteers (n = 62) were recruited. Sera antinuclear (ANA), anti-dsDNA, anti-thyroid peroxidase (TPO), anti-smooth muscles (ASMA) and F-actin auto-antibodies were measured using ELISA and indirect immune-fluorescence assay. The mean ages of VL, PDKL patients and apparently healthy volunteers were: 17.5 ± 12.5, 15.0 ± 7.0 and 17.5 ± 9.5 years with Male:Female ratios of 2:0, 1:2 and 1:5 respectively. Significantly high frequencies of F-actin (74.2%;46/62) and ASMA (50%;31/62) auto-antibodies were seen among VL patients (p = 0.003, p = 0.001) compared to apparently healthy volunteers. Likewise, significantly high frequencies of F-actin (64.5%;20/31;p = 0.001), ASMA (42%;13/31;p = 0.003), ANA (36%;11/31;p = 0.001) and anti-dsDNA (16%;5/31;p = 0.01) auto-antibodies were seen among PKDL patients. Development of tissue-based autoantibodies in L. donovani infections probably indicates loss of peripheral tolerance with activation of circulating auto-reactive T and B cells probably contributing to disease pathogenesis (increased bilirubin/liver enzymes, prolonged QT interval/arrythmias and blood cytopenias). In conclusion, L. donovani infection-induced immune suppression with development of tissue-based auto-antibodies is prevalent among Sudanese patients with VL and PKDL leishmaniases and contributes to some aspects of the disease pathogenesis.

Converting“cold”to“hot”:epigenetics strategies to improve immune therapy effect by regulating tumor-associated immune suppressive cells

Significant developments in cancer treatment have been made since the advent of immune therapies.However,there are still some patientswithmalignant tumors who do not benefit from immunotherapy.Tumors without immunogenicity are called“cold”tumors which are unresponsive to immunotherapy,and the opposite are“hot”tumors.Immune suppressive cells(ISCs)refer to cells which can inhibit the immune response such as tumor-associated macrophages(TAMs),myeloid-derived suppressor cells(MDSCs),regulatory T(Treg)cells and so on.The more ISCs infiltrated,the weaker the immunogenicity of the tumor,showing the characteristics of“cold”tumor.The dysfunction of ISCs in the tumor microenvironment(TME)may play essential roles in insensitive therapeutic reaction.Previous studies have found that epigeneticmechanisms play an important role in the regulation of ISCs.Regulating ISCs may be a new approach to transforming“cold”tumors into“hot”tumors.Here,we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs.In addition,we summarized the mechanisms by which the epigenetic drugs convert immunotherapy-insensitive tumors into immunotherapy-sensitive tumors which would be an innovative tendency for future immunotherapy in“cold”tumor.

Contribution of myeloid-derived suppressor cells to tumor-induced immune suppression,angiogenesis,invasion and metastasis

Growing evidence suggests that myeloid-derived suppressor cells （MDSCs）,which have been named ＂immature myeloid cells＂ or ＂myeloid suppressor cells＂ （MSCs）,play a critical role during the progression of cancer in tumor-bearing mice and cancer patients.As their name implies,these cells are derived from bone marrow and have a tremendous potential to suppress immune responses.Recent studies indicated that these cells also have a crucial role in tumor progression.MDSCs can directly incorporate into tumor endothelium.They secret many pro-angiogenic factors as well.In addition,they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases （MMPs）,chemoattractants and creating a pre-metastatic environment.Increasing evidence supports the idea that cancer stem cells （CSCs） are responsible for tumorigenesis,resistance to therapies,invasion and metastasis.Here,we hypothesize that CSCs may ＂hijack＂ MDSCs for use as alternative niche cells,leading to the maintenance of stemness and enhanced chemo-and radio-therapy resistance.The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis.Therefore,the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.

Immunological properties of embryonic and adult stem cells

The possibility of treating degenerative diseases by stem cell-based approaches is a promising therapeutical option.Among major concerns for the clinical application of stem cells,some derive from the possibility that stem cells may be rejected by the immune system as a consequence of histoincompatibility and that stem cells themselves may interfere with the normal functions of host immune response.Therefore,the immunogenicity and the immunomodulatory properties of stem cells must be carefully addressed.Although these properties are common features of different stem cell types,some peculiarities can be recognized and characterized for their proper clinical use.

Emerging roles of plasmacytoid dendritic cell crosstalk in tumor immunity

Plasmacytoid dendritic cells(pDCs)are a pioneer cell type that produces type I interferon(IFN-I)and promotes antiviral immune responses.However,they are tolerogenic and,when recruited to the tumor microenvironment(TME),play complex roles that have long been a research focus.The interactions between p DCs and other components of the TME,whether direct or indirect,can either promote or hinder tumor development;consequently,p DCs are an intriguing target for therapeutic intervention.This review provides a comprehensive overview of p DC crosstalk in the TME,including crosstalk with various cell types,biochemical factors,and microorganisms.An in-depth understanding of p DC crosstalk in TME should facilitate the development of novel p DC-based therapeutic methods.

Maternal Bias of Immunity to Her Offspring: Possibility of an Autoimmunity Twist out from Maternal Immunity to Her Young

The major interest in materno-foetal relation is why fetus is not rejected by the mother, even in a different genetic background. But in this article we have been investigating about the effect(s) of maternal antigenic stimulation or infection upon the active immune responses in her offspring. The results of various researchers have certainly pose significant problems as to the defense of infants against infectious agents, especially those introduced by their mothers. But we have already reported that maternal antigenic stimulation greatly suppresses the specific immune response of the offspring in a system of mouse vs. heterologous erythrocytes and other T-dependent antigens. This suppression was antigen specific and effective on 1/6 life of rodents. The mechanisms that concerned in this suppression were not antigen administered nor antibody produced in the mother. The supporting evidences were that this suppression was MHC restricted and limited in during pregnancy for induction between mother and her young. The system examined was separating genetic backgrounds that the haplotype was different in F2 family where half of the young were identical but not in remainder to the F1 mother mouse. From this backcross system, this suppression was MHC restricted, suggesting cell to cell contact with mother to her young. Moreover, cytokine level in both mother and her young, IFN-g levels was up-regulated in such a young whose mother was immunized with antigen. The significance of this phenomenon were accessed as biological and medical intervention especially for the mother and infant health care and prevention of hypersensitivities, autoimmune syndrome for her young after delivery.

Myeloid derived suppressor cells in breast cancer:A novel therapeutic target?

The relationship of the immune system and tumour cells is complex; although recognised that the immune system can protect the host against tumour development, the immune system also facilitates tumour progression through immune suppression. Pro-inflammatory mediators associated with chronic inflammation are responsible for the expansion and activation of myeloid derived suppressor cells(MDSCs); a heterogeneous group of cells that originates from myeloid progenitor cells but does not complete the final stages of differentiation. A causal relationship between chronic inflammation and tumour progression relies on the accumulation and maintenance of MDSCs as its linchpin; responsible for immunosuppression through the down-regulation of antitumour responses. MDSCs cause immunosuppression through a number of mechanisms; inhibiting the proliferation of CD4^+ and CD8^+ T cells, blocking natural killer cell activation and limiting dendritic cell maturation and function. As well as using various mechanisms to inhibit adaptive and immune responses, MDSCs also have non-immunological functions that aid tumour spread; including directly promoting tumour proliferation and metastasis by having an important role in tumour angiogenesis, secretion of matrix metalloproteinases and induction of epithelial-mesenchymal transition. Breast cancer is the most common cancer among women in the United Kingdom with 44540 new cases of invasive carcinoma in 2013 and results in the second highest cancer mortality rate in women, with 11600 deaths in 2012. Considering this, the need for novel therapeutic interventions is higher than ever. This review summarises the rationale for the targeting of MDSCs in breast cancer as a realistic avenue to increase survival from breast cancer.

Tricking the tumour microenvironment into becoming our best rational drug design factory:reversal of immune suppression

The immune cellular components of the tumour microenvironment are a diverse group of cells that paradoxically are now appreciated to have a coordinated opposing duality of either promoting or retarding tumour growth.Manipulating this seemingly dynamic interaction for therapeutic benefit is a hotbed of much research.Recent findings in tumour immunology(both preclinical and clinical)build on more than a century of insights and provide a way forward to improving patient outcomes,long term survival and the predictability of“cures”.This opinion piece attempts to summarise some of these historical and contemporary insights with a view to describing eminently testable therapeutic solutions.

Immunity

970239 The effect of interleukin 6 against cytopeniaand suppressed phagocytosis of macrophage caused bychemotherapy. ZHANG Lichao(张利朝), et al.Tangdu Hosp, 4th Milit Med Univ, Xian, 710038. ChinJ Clin Oncol 1997; 24(4): 252-255. Objective: To explore The effect of interleukin 6against cytopenia and suppressed phagocytosis ofmacrophage caused by chemotherapy. Methods:Inter-

HBeAg诱导的免疫激活和免疫抑制在慢性乙型肝炎中的作用

HBV感染诱导的慢性乙型肝炎是导致肝硬化和肝癌的重要危险因素。半个世纪前,HBeAg在HBV感染者血清中首次被发现,尽管HBeAg并不参与HBV在肝细胞中的感染或复制,但其已被证实可干扰宿主先天性和适应性免疫反应,在慢性HBV感染的过程中发挥着重要的免疫激活和免疫抑制作用。HBV对于感染的肝细胞并没有细胞毒性,免疫应答介导的抗病毒作用和炎症反应决定HBV是否被清除或者诱导肝脏炎症相关疾病。因此,本文对HBeAg的形成及其在慢性HBV感染中引起的免疫激活和免疫抑制机制进行综述,重点论述HBeAg对先天免疫和适应性免疫细胞所引起的不同免疫效应,阐述了其诱导免疫反应的两面性,并探讨HBeAg在慢性HBV感染不同阶段间的转换作用。

Exosome regulation of immune response mechanism:Pros and cons in immunotherapy

Due to its multiple features,including the ability to orchestrate remote communication between different tissues,the exosomes are the extracellular vesicles arousing the highest interest in the scientific community.Their size,established as an average of 30-150 nm,allows them to be easily uptaken by most cells.According to the type of cells-derived exosomes,they may carry specific biomolecular cargoes used to reprogram the cells they are interacting with.In certain circumstances,exosomes stimulate the immune response by facilitating or amplifying the release of foreign antigens-killing cells,inflammatory factors,or antibodies(immune activation).Meanwhile,in other cases,they are efficiently used by malignant elements such as cancer cells to mislead the immune recognition mechanism,carrying and transferring their cancerous cargoes to distant healthy cells,thus contributing to antigenic invasion(immune suppression).Exosome dichotomic patterns upon immune system regulation present broad advantages in immunotherapy.Its perfect comprehension,from its early biogenesis to its specific interaction with recipient cells,will promote a significant enhancement of immunotherapy employing molecular biology,nanomedicine,and nanotechnology.