Conveying glycan information into T-cell homeostatic programs: a challenging role for galectin-1 in inflammatory and tumor microenvironments

Summary:  The immune system has evolved sophisticated mechanisms composed of several checkpoints and fail-safe processes that enable it to orchestrate innate and adaptive immunity, while at the same time limiting aberrant or unfaithful T-cell function. These multiple regulatory pathways take place during the entire life-span of T cells including T-cell development, homing, activation, and differentiation. Galectin-1, an endogenous glycan-binding protein widely expressed at sites of inflammation and tumor growth, controls a diversity of immune cell processes, acting either extracellularly through specific binding to cell surface glycan structures or intracellularly through modulation of pathways that remain largely unexplored. In this review, we highlight the discoveries that have led to our current understanding of the role of galectin-1 in distinct immune cell process, particularly those associated with T-cell homeostasis. Also, we emphasize findings emerging from the study of experimental models of autoimmunity, chronic inflammation, fetomaternal tolerance, and tumor growth, which have provided fundamental insights into the critical role of galectin-1 and its specific saccharide ligands in immunoregulation. Challenges for the future will embrace the rational manipulation of galectin-1-glycan interactions both towards attenuating immune responses in autoimmune diseases, graft rejection, and recurrent fetal loss, while at the same overcoming immune tolerance in chronic infections and cancer.     

干预醛固酮逃逸对心血管疾病的意义

醛固酮逃逸现象是指在血管紧张素Ⅱ转化酶抑制剂(angiotensinconvertingenzymeinhibitor,ACEI)应用过程中,血浆醛固酮水平在短期内下降,长期治疗后仍可增高的现象。慢性心力衰竭醛固酮合成和释放增加。钠潴留、电解质紊乱,脂质胶原沉积和纤维化,导致慢性心力衰竭进行性加重。螺内酯的化学结构类似醛固酮,能阻断醛固酮作用。显著降低心力衰竭的总病死率和(或)住院时间,拮抗心律失常,新的选择性醛固酮拮抗剂可作为心力衰竭、高血压病和心肌梗死后强适应症推荐药物。     

肿瘤免疫学在未来面临的挑战

目前，人类肿瘤免疫学已进入了一个全新的的阶段，开始飞速发展。然而，在未来，肿瘤免疫学仍面临着许多挑战，仍有许多问题需要解决，例如人类肿瘤的抗原性问题，尚未阐明的机体对肿瘤免疫应答的细胞分子机制和免疫监视理论等等。     

Plasma volume in acute hypoxia: comparison of a carbon monoxide rebreathing method and dye dilution with Evans' blue

Exposure to acute hypoxia is associated with changes in body fluid homeostasis and plasma volume (PV). This study compared a dye dilution technique using Evans' blue (PV_Evans') with a carbon monoxide (CO) rebreathing method (PV_CO) for measurements of PV in ten normal subjects at sea level and again 24 h after rapid passive ascent to high altitude (4,350 m). Hypobaric hypoxia decreased arterial oxygen saturation to 79 (74–83)% (mean with 95% confidence intervals). The PV_Evans' remained unchanged from 3.49 (3.30–3.68) l at sea level to 3.46 (3.24–3.68) l at high altitude. In contrast PV_CO decreased from 3.39 (3.17–3.61) l at sea level to 3.04 (2.75–3.33) l at high altitude (P < 0.05). Compared with sea level, this resulted in an increase of the mean bias between the two methods [from 0.11 (−0.05–0.27) l at sea level to 0.43 (0.26–0.60) l at high altitude] so that the ratio between PV_Evans' and PV_CO increased from 1.04 (0.99–1.09) at sea level to 1.15 (1.06–1.24) at high altitude (P < 0.05). In conclusion, the two methods were not interchangeable as measures of hypoxia-induced changes in PV. The mechanism responsible for the bias remains unknown, but it is suggested that the results may reflect a redistribution of albumin caused by the combined effects in hypoxia of both an increased capillary permeability to albumin and a decrease in PV. As a result, the small perivascular compartment of albumin beyond the endothelium may increase without changes in the overall albumin distribution volume. Accepted: 31 October 1997     

Stress-induced increases in avoidance responding: an animal model of post-traumatic stress disorder behavior?

One prominent symptom of post-traumatic stress disorder (PTSD) is avoidance of stimuli reminiscent of the traumatic event. We attempted to study this aspect of PTSD in two experiments. Groups of rats received forty 3-s tailshocks, or served as home cage controls (HCC). Twenty-four hours later, all subjects received a 4-h session of leverpress escape/avoidance conditioning. In Experiment 1, shock periods in the absence of a response were 1 s; in Experiment 2 they were 30 s. No group differences were observed in Experiment 1. In Experiment 2, previously shocked animals made more avoidance responses and had a higher percent avoidance during the fourth hour of the session than controls. Further, previously shocked animals had a higher efficiency ratio (the percent of responses that were avoidances). No group differences were observed in leverpresses during the safety period (an index of anxiety) in either study. Results are discussed in terms of the effects of stress on avoidance behavior as a potential model for this important feature of PTSD.     

Chimeric immune receptor T cells bypass class I requirements and recognize multiple cell types relevant in HIV-1 infection

Transduction of T cells with a chimeric immune T cell receptor (CIR) has been proposed as a strategy to generate cellular immunity against viral pathogens such as HIV-1. In the case of the CD4-CD3-zeta chain (CD4-zeta) CIR, specificity for HIV-1 is conferred by binding of the CD4 moiety to gp120 on the surface of infected cells. However, it is unclear whether CD4-zeta-T cells may differ from naturally derived CD8(+) cytotoxic T cells (CTL) in their susceptibility to viral escape mechanisms or ability to recognize different cell types that support viral replication. We demonstrate that CIR-T cells can mediate antiviral activity against HIV-1 in cells that are resistant to class I-restricted CTL-mediated activity. Furthermore, CIR-T cells can suppress virus in multiple cell types, including monocytes, dendritic cells, and lymphocyte-dendritic cell clusters. These results provide evidence that T cells can be redirected against novel targets, and that independence from the class I pathway may have distinct advantages.     

MHC class I-deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components

Previous reports from our group indicated that the MHC class I phenotype of metastatic lung colonies produced by a mouse fibrosarcoma tumor clone (B9) were, depending on the immune status of the host, MHC class I negative in immunocompetent mice and MHC class I positive in immunodeficient athymic nude/nude mice. Now we report the identification of the molecular alterations responsible for the changes of MHC class I molecules in both situations. Metastatic nodes were analyzed for the mRNA level of H-2 class I and beta2-microglobulin genes, and several gene components of the major histocompatibility complex (MHC) class I antigen-processing machinery (APM). These included the genes coding for the low-molecular-weight proteins LMP2, LMP7, LMP10, the transporter associated with antigen processing (TAP-1, TAP-2), and calnexin, calreticulin, tapasin, PA-28-alpha, PA-28-beta, ERP-59 and ER-60. Analyses with RT-PCR showed that TAP-1, TAP2, LMP-2, LMP7, LMP10, tapasin and calnexin mRNA specific for these genes was absent in metastases produced in immunocompetent mice. In contrast, similar techniques with mRNA preparations obtained from metastatic nodes from immunodeficient mice showed that the mRNA expression level of these genes was highly positive. Interestingly, the MHC class I-positive or negative phenotypes of the metastatic colonies correlated with in vivo immunogenicity. H-2 positive metastasis grew more slowly than the H-2 negative ones when injected intrafootpat in syngeneic immunocompetent animals and were finally rejected. These results provide evidence of the role of T cells in immune surveillance against tumors and identify a mechanism targeted by antitumor T lymphocytes to generate MHC class I-negative tumor escape variants.     

Potential mechanisms underlying CDK5 related Osteosarcoma progression

Objectives: Identification of new prognostic biomarkers and therapeutic targets is of crucial importance for patients with osteosarcoma. Cyclin-dependent kinase 5 (CDK5) is overexpressed in several tumor types. However, the exact role CDK5 plays in osteosarcoma is still unknown.

Methods: In this study, we explored the association between CDK5 expression and the prognosis of osteosarcoma patients using publicly available gene expression datasets. Potential molecular mechanisms underlying its pro-malignant role in cancer progression were also discussed.

Results: We demonstrated that tricarboxylic acid (TCA) cycle is activated while antigen presentation is repressed in patients with CDK5 overexpression and poor survival. This results indicated that sufficient energy production and tumor immune escape are important characteristics and potential therapeutic targets for this subgroup of osteosarcoma patients. Furthermore, several critical hub genes that are associated with CDK5 related osteosarcoma progression such as MELK were identified.

Conclusion: This study discussed the pro-malignant role of CDK5 and potential mechanisms involved. Further preclinical and clinical studies to develop CDK5 based treatments are warranted.     

Dual antiretroviral therapy for HIV infection

Introduction: For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens.

Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naïve and in treatment-experienced patients with viral suppression (switch strategy).

Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions.

The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction-maintenance.     

吲哚胺2,3-双加氧酶在肿瘤及肿瘤耐药中的研究现状

吲哚胺2,3-双加氧酶(IDO)是一种肝外催化色氨酸沿犬尿氨酸途径降解的限速酶。IDO抑制药被用在不同恶性肿瘤及耐药肿瘤治疗的相关实验中,特别是与放疗和化疗相结合时取得了良好的效果。本文将对IDO及其抑制药对肿瘤及肿瘤耐药的影响进行综述。