Immunotherapy in Hodgkin and non-Hodgkin lymphoma: Innate,adaptive and targeted immunological strategies

Since the clinical introduction of anti-CD20 monoclonal antibodies into lymphoma treatment, immunologic approaches in lymphoma have made substantial progress. Advances in our understanding of tumor immunology have led to the development of strategies to overcome immunologic barriers responsible for an ineffective immune response. Specifically, therapeutic agents have been developed and tested against molecules that are responsible for T-cell exhaustion. The use of monoclonal antibodies against immune checkpoints in the adaptive immune system, such as programmed cell death-1 and cytotoxic T-lymphocyte-associated protein 4, has changed the landscape of cancer therapy including the treatment of lymphoma. This achievement has recently been accompanied by the development of novel immune checkpoint inhibitors targeting the innate immune system, including the CD47-SIRPα signaling pathway, and this approach has yielded promising results. To overcome impaired antigen presentation, antibody-based cytotoxic strategies, namely antibody-drug conjugates (polatuzumab vedotin and brentuximab vedotin) and bispecific T-cell or NK-cell engagers (blinatumomab, REGN1979, RG6206, and AFM13), have rapidly evolved with promising clinical activity. As additional tools become available for lymphoma treatment, formulation of safe, rational combination strategies to combine them with standard therapy will be of paramount importance. A successful approach to the treatment of lymphoma may require both an optimized anti-tumor immune response as well as effective depletion of malignant lymphoid cells.     

Isolation of isoguanosine fromCroton tiglium and its antitumor activity

This paper describes the isolation of isoguanosine from Croton tiglium L. and its cytotoxic effect against several tumor cell lines in culture and newly reports that isoguanosine has an antitumor activity against implanted S-180 ascitic tumor mice. Isoguanosine is effective at the dose of 24 mg/kg/day x 5, with T/C value of 168%. Isoguanosine inhibits the growth of S-180 and Ehrlich solid tumor in mice at the optimal doses of 96 mg/kg/day x 12 and 48 mg/kg/day x 12, with 1-T/C values of 65% and 60%, respectively.     

Anti-Tumor Activity of Four Ayurvedic Herbs in Dalton Lymphoma Ascites Bearing Mice and Their Short-Term In Vitro Cytotoxicity on DLA-Cell-Line

The anti-tumor activity and chemopreventive potential of four Ayurvedic herbs viz. Curcuma longa L., Ocimum sanctum L., Tinospora cordifolia (Wild) Miers ex Hook.f & Thomas and Zizyphus mauritiana Lam. were evaluated using Dalton Lymphoma ascites (DLA) tumor model in Swiss Albino mice. The outcome was assessed using survival time, peritoneal ascitic fluid (Tumor volume) and hematological indices as parameters. Animals were divided into five groups (n = 6) viz. one DLA control and four Herb + DLA treated groups. All the four herb + DLA groups were pre-treated with respective herbs for 7 days and hematological indices were measured for entire five groups. On day-8 animals were inoculated with 1×10⁶ DLA cells i.p., and Herb + DLA groups were continued with oral herbal treatment for 21-days. Hematological parameters and tumor volume were assessed to find the effects of herbs. Short term in vitro cytotoxicity was determined by Trypan Blue exclusion method and LDH leakage assay using different concentrations of herbal extracts and 5-FU as a positive control and IC₅₀ for each herbal extract and 5-FU were determined. Oral administration of crude herb increased the survival time and decreased the peritoneal ascitic fluid content significantly. Hb, RBCs and total WBC which were altered by DLA inoculation were restored significantly by all the herbs except O. sanctum. All the four herbs showed in vitro cytotoxic activity against DLA cell-line. Moreover inter group comparison of all the four herbs for anti-tumor activity showed efficacy in the following order- T. cordifolia > Z. mauritiana ≥ C. longa > O. sanctum respectively.     

Long-Term Follow-Up of the Changes in Circulating Cytokines, Soluble Cytokine Receptors, and White Blood Cell Subset Counts in Patients with Rheumatoid Arthritis (RA) After Monoclonal Anti-TNFα Antibody Therapy

To investigate the mechanism of the long-lasting efficacy of chimeric monoclonal anti-TNF antibody (cA2) therapy for rheumatoid arthritis (RA), eight patients with refractory RA were treated with a single infusion of cA2 and the changes in circulating cytokines (IL-1, IL-6, TNF, and IL-10), soluble cytokine receptors (TNF-RI, RII, and sIL-6R) and peripheral white blood cell (WBC) subset counts were followed up long-term (12 weeks) after cA2 therapy in them. Significant clinical responses (>20% improvement according to Paulus' criteria) were observed just after cA2 infusion and lasted more than 4 weeks in all patients, as reported elsewhere. Moreover, five of the eight patients showed prolonged clinical responses (>12 weeks). The elevated serum IL-6 and sTNF-RI (or RII) levels before treatment rapidly decreased after treatment. The serum IL-10 levels also significantly elevated before treatment. The elevations of serum IL-10 levels were augmented after treatment and stayed higher than the baseline in four patients with prolonged clinical responses. No significant TNF, IL-1 and -, or sIL-6R were detected in the sera of the patients before treatment and during the whole study period. On the other hand, peripheral lymphocytes as well as total WBC and neutrophils increased for 4 weeks after treatment. However, thereafter, only the lymphocyte count decreased gradually and stayed below the baseline long-term (12 weeks). FACS analysis revealed the predominance of T lymphocytes in the decrease in lymphocyte counts. These results suggest that the augmentation of IL-10 production and the decrease in T cells might partly contribute to the long-lasting efficacy of cA2 treatment in RA.     

Melanosomes and MHC class II antigen-processing compartments

Melanosomes are specialized intracellular compartments within melanocytes and retinal pigment epithelial cells that function in the synthesis, storage, and secretion of melanins, which are the major pigments made by mammals. The mechanisms that regulate the formation of melanosomes, and the pathways by which constituent proteins are targeted to them, are related to those involved in the biogenesis of major histocompatibility complex (MHC) class II antigen-processing compartments. Consequently, diseases that affect pigmentation may also affect antigen presentation to T cells. Moreover, many of the tissue-specific proteins that localize to melanosomes and participate in melanin formation double as tumor-associated antigens that are targets for T cells in patients with melanoma. Our studies on melanosome biogenesis are providing new ways of thinking about antigen-processing compartments and the mechanisms regulating presentation of tumor-associated antigens.     

古草生机汤对H22荷瘤小鼠体内抑瘤及免疫调节作用的初步研究

目的：探究古草生机汤对H22荷瘤小鼠体内实体瘤的抑瘤功效和对机体的免疫调节作用机制。方法：本研究采用H22实体瘤动物模型,随机分为空白组、模型组、阳性药组、古草生机汤低、高剂量组,灌胃给药7 d,计算各组小鼠的体质量增长率、肿瘤抑制率、胸腺及脾指数,小鼠实体瘤病理切片苏木精-伊红（HE）染色观察瘤体组织和细胞形态,酶联免疫吸附试验法检测小鼠血清中γ干扰素（IFN-γ）、肿瘤坏死因子-α(TNF-α)、白细胞介素-2（IL-2）、Fas、Fas配体、天门冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）的含量,实时荧光定量PCR测量小鼠瘤组织中Bax和Bcl-2mRNA的相对表达量。结果：古草生机汤有促进H22荷瘤小鼠体质量增长、抑制体内实体瘤增长和促进肿瘤凋亡坏死的作用,可提高小鼠的胸腺指数同时降低脾脏指数,可显著提高小鼠血清中IFN-γ、TNF-α、IL-2的含量并降低Fas、Fas配体、AST、ALT的含量（均P<0.01）,能够上调小鼠瘤组织中Bax mRNA的表达并下调Bcl-2mRNA的表达。结论：古草生机汤具有明显的体内抗肝肿瘤药效,在抑制肿瘤生长、促进肿瘤细胞凋亡、调节机体免疫方面有一定作用。     

苏木的药理作用及临床应用研究进展

苏木是常用的具有活血疗伤、祛瘀通经功效的中药材。近年来研究发现,苏木药理作用多样,具有抗炎、免疫抑制、抗肿瘤、抗氧化等作用。苏木在糖尿病并发症、心血管疾病、伤科疾病等疾病治疗方面应用广泛,临床前景广阔。现对苏木的药理作用和临床应用文献进行收集整理,以期为深入开展研究和临床开发应用提供参考。     

慢性髓性白血病来源的树突状细胞诱导的CTL体外作用研究

 目的　研究慢性髓性白血病来源的树突状细胞的免疫功能。方法　分离慢性期CML患者外周血单个核细胞 (PBMNC) ,用细胞因子GM CSF及IL 4在体外诱导培养DC ,检测细胞表型 ,并观察其诱导的CTL体外抗肿瘤效应。用酶联免疫 (ELISA)方法测定CML DC混合淋巴细胞反应 (MLR)上清液中IL 12及IFN γ的量 ,并与正常DC进行比较。结果　联合GM CSF及IL 4可诱导CML细胞分化为CML DC ,CML DC的CD1a、CD80、CD83表达率均低于正常DC ;CML DC混合淋巴细胞反应上清IL 12及IFN γ含量均低于正常DC ;CML DC能诱导出对自身CML细胞有特异性杀伤作用的CTL。结论　CML DC具有抗原提呈细胞的免疫功能 ,能诱导抗白血病CTL反应。     

白花蛇舌草提取物的体外抗肿瘤活性

目的　探讨白花蛇舌草乙醇提取物 (SCD)的体外抗肿瘤活性。方法　以MTT法测定SCD对体外培养的肿瘤细胞增殖的抑制作用、对人外周血单个核细胞的增殖促进作用及增强自然杀伤细胞杀伤肿瘤细胞的作用。结果　 10 0 μg/mlSCD对KB、BGC、B16、HBL 6 0、SMMC 772 1、HELA、A5 4 9的增殖仰制率分别为 30 .5 3%、4 2 .82 %、2 3.77%、6 3.93%、39.4 0 %、4 6 .33%、4 2 .5 6 % ;2 5 0 μg/mlSCD可促进PBMC增殖 97.33% ;联合ConA或者LPS作用时 ,在 0 .2 5 μg/ml的低浓度下增殖率分别达 344 .13%和 15 2 .18% ;高浓度SCD未明显增强NK的杀伤作用。结论　SCD对体外培养的肿瘤细胞有明显的抑制作用 ,SCD可以显著促进PBMC增殖。     

中药三叶青提取物抗肿瘤机制初探

目的:通过对三叶青提取物小鼠免疫调节功能的评价,初步确定其抗肿瘤作用的基本机制。方法:从细胞免疫、体液免疫、单核-巨噬细胞吞噬作用和自然杀伤细胞的攻击作用4个方面观察三叶青提取物对小鼠免疫功能的影响。结果:三叶青提取物5.0、15.0、25.0 g/kg.BW剂量组均能提高ConA诱导的小鼠脾淋巴细胞的增殖能力和小鼠左后足跖部厚度差24 h测量值;2.5、5.0 g/kg.BW剂量组均能提高小鼠溶血空斑数;2.5、5.0、15.0和25.0 g/kg.BW剂量组均能提高小鼠碳廓清的能力;15.0 g/kg.BW剂量组能提高小鼠腹腔巨噬细胞吞噬鸡红细胞的吞噬指数。结论:三叶青提取物具有增强小鼠免疫力作用,为其抗肿瘤作用机制之一。