γ-干扰素转基因对过敏原导致的小鼠肺嗜酸性粒细胞浸润的抑制作用

目的 :探讨腺病毒介导的小鼠γ 干扰素在小鼠哮喘模型肺上皮细胞内的转基因表达对过敏原所致的嗜酸性粒细胞浸润的作用。方法 :C5 7小鼠经卵蛋白 (ovalbumin ,OVA)腹腔致敏和气道吸入激发建立哮喘模型 ,48h后收获小鼠肺泡灌洗液 (bronchoalveolarlavage ,BAL)和小鼠肺 ;哮喘模型在OVA激发前 48h ,在其气道内给予带有γ 干扰素的复制缺陷腺病毒 (replication deficientadenoviruswithIFN γgene,AdCMVmIFNγ) 5× 10 8空斑形成单位 (pfu) ,同上在OVA激发 48h后收获其肺泡灌洗液和肺。结果 :在卵蛋白所致的哮喘模型中 ,肺组织病理可见支气管周围、血管周围及部分肺泡内明显的嗜酸粒细胞浸润 ,肺泡灌洗液中的嗜酸粒细胞平均占 (75 .13±6 .85 ) % ,而在阴性对照组中则未见嗜酸粒细胞 ;小鼠哮喘模型气道内给予AdCMVmIFNγ后 ,肺内嗜酸粒细胞浸润的程度明显减少 ,肺泡灌洗液中的嗜酸粒细胞占 (9.0 0± 4.5 8) % (P <0 .0 0 1) ,二者均显著低于哮喘模型组。结论 :小鼠的IFN γ经腺病毒介导在小鼠肺上皮细胞内的表达可明显抑制过敏原所致的肺内嗜酸性粒细胞浸润 ,从而为进一步利用细胞因子的体内转基因免疫治疗过敏性哮喘探索了新的治疗途径     

Combinations of interferon with platinum complexes: synergistic and antagonistic effects on growth inhibition of MCF-7 and MDA-MB231 breast cancer cells

The growth-inhibitory effects of combining interferons (IFN) with platinum(II) complexes were tested with the aim of comparing these in cultures of estrogen-receptor(ER)-negative MDA-MB₂₃₁ and ER-positive MCF-7 breast cancer cell lines. Another aim was to test whether IFN as a biological response modifier could enhance the effect of the Pt complexes in vitro in an attempt to find an explanation for their more potent antitumor effects in in vivo models. Here it is shown that in both cell lines the combinations of different IFN with all three Pt complexes generally resulted in additive growth inhibition, as calculated by the product of the fraction of surviving cells obtained with each compound alone. Moreover, in MCF-7 cells natural IFN (nIFN) combined with aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) (meso-6-Pt) resulted in synergistic inhibition. This synergy could be attributed to the estrogenic property of meso-6-Pt, since the ligand and estradiol also enhanced the inhibitory effect of nIFN. In contrast, the combination of recombinant IFN and meso-6-Pt was antagonistic in MDA-MB₂₃₁ cells. These results show that, in spite of the similar responses of the ER-negative and ER-positive cells to each compound alone, these cells show unexpected differences in their sensitivity to combinations of IFN and the new Pt complex meso-6-Pt.Abbreviations ER estrogen receptor - IFN interferon(s) - nIFN natural interferon - rIFN recombinant interferon - meso-4-Pt aqua[meso-1,2-bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) - meso-6-Pt aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]sulfatoplatinum(II)     

Local interferon therapy for lip carcinoma

In a prospective non-randomized study 21 patients with lower lip squamous cell carcinoma were treated with human natural leukocyte interferon (HNLI). The response rate was measured by a size reduction of more than 25% and was 81%. A complete response rate was considered to be a cure according to histopathological and clinical findings and was 48%. The response rate of six lower lip squamous cell carcinoma cases treated with recombinant interferon alpha 2c was 67% and the complete response rate was 17%. Three patients with basal cell carcinoma of the upper lip were also treated with HNLI. All three patients were cured, as determined by histopathological and clinical findings. These findings indicate that interferon can be a useful alternative therapy for lip carcinoma either with or without surgery.     

用LDH释放法判断细胞病变程度确定干扰素生物活性

目的：应用ＬＤＨ释放法测定干扰素生物活性。方法：通过检测ＷＩＳＨ细胞裂解后释放出的ＬＤＨ活性判断细胞病变的程度,确定干扰素效价。对ＬＤＨ释放法进行改进,与结晶紫染色法和ＭＴＴ比色法进行灵敏度、重复性和相关性比较。结果和结论：该法减少了实验步骤和时间,成本低,敏感性高,重复性好,与其他方法所测结果无显著差异,简便实用,优于结晶紫染色法和ＭＴＴ比色法。     

大剂量干扰素治疗慢性丙型肝炎50例临床观察

目的：探讨使用大剂量干扰素（ＩＦＮα）治疗慢性丙型肝炎（ＣＡＨ）的效果。方法：使用大剂量ＩＦＮα,每天６００万Ｕ,连续投药３周,以后每周３次间断投药２１周,共计２４周,治疗ＣＡＨ５０例。观察治疗前后血清ＨＣＶＲＮＡ与ＡＬＴ的变化,以此作为ＩＦＮ疗效的判定指标。结果：ＩＦＮ治疗ＣＡＨ有效率为６８％,停药６个月后有３４％复发。结论：ＩＦＮ的疗效与ＣＡＨ的基因亚型有关（Ⅲ型疗效显著,Ⅱ型较差）,与ＩＦＮ的剂量无明显关系。     

Adoptive Immunotherapy With Tumor-Infiltrating Lymphocytes and Subcutaneous Recombinant Interleukin-2 Plus Interferon Alfa-2a for Melanoma Patients With Nonresectable Distant Disease: A Phase I/II Pilot Trial

Background: On the basis of our previous experience, we designed this study to determine the activity and toxicity of outpatient treatment with autologous tumor-infiltrating lymphocytes (TIL) together with intermediate-dose recombinant interleukin-2 (rIL-2) and low-dose recombinant interferon alfa-2a (rIFN-2a), for patients with metastatic melanoma.Methods: Between April 1992 and October 1994, we processed 38 melanoma samples derived from 36 patients with metastases. Proliferative cultures of expanded lymphocytes (TIL) were infused only once into patients with metastatic melanoma. rIL-2 was administered subcutaneously for 1 month, starting on the day of TIL infusion, at an escalating dose of 6–18 × 10⁶ IU/m²/day for the first week and at the maximum-tolerated dose for the subsequent 3 weeks and then, after a 15-day interval, for 1 week/month for 3 months. rIFN-2a was administered subcutaneously at 3 × 10⁶ IU three times each week until progression.Results: Of 38 melanoma samples, 19 (50%) resulted in proliferative cultures and were infused. The median number of expanded lymphocytes was 18 × 10⁹ (range, 1–43 × 10⁹), and the median period of culture was 52 days (range, 45–60). rIL-2 was administered at doses ranging between 6 and 18 × 10⁶ IU/m²/day. Toxicity was mild or moderate, and no life-threatening side effects were encountered. Two of 19 treated patients experienced complete responses of their metastatic sites (soft tissue), 10 had stable disease, and 7 showed progressive disease. The response rate was 11% (95% confidence interval, 2–35%).Conclusions: Outpatient treatment with TIL plus rIL-2 and rIFN-2a is feasible, although, within the context of the small sample size, the activity of the combination was no different from the reported activity of any of the components used alone.     

T-lymphocyte immunointerferon receptors in patients with multiple sclerosis

Multiple sclerosis (MS) is a T-cell-mediated autoimmune demyelinating disease of the central nervous system (CNS), associated with an altered immunoregulation. Interferon (IFN)-, also known as immune IFN, is a cytokine with several effects on the immune system. Specific IFN- receptors have been found on human lymphocytes, as well as on other cell types (e.g. gliocytes), even in the CNS. The aim of the present study was to evaluate IFN- binding on peripheral blood T-lymphocytes from MS patients, compared with those from healthy subjects. Thirty-two patients were selected according to the classical criteria for definite MS; as controls, 21 healthy subjects were studied. We have found that T-lymphocytes from MS patients bear a significantly smaller amount of IFN- receptors than those from controls [B _max: 568, 18 vs 708, 14 (mean, SE) receptors/cell]. Such IFN- binding sites are of the same type in patients and healthy subjects [K _d: 1.0, 0.05 vs 0.9, 0.02 (mean, SE) nM]. These findings are discussed in terms of immunopathogenesis of MS, since it has been reported that activated T-lymphocytes have decreased amounts of IFN- receptors.     

Role of endogenous interferon gamma in murine tumor growth and tumor necrosis factor alpha antitumor efficacy

Background: The anticancer role of tumor necrosis factor-alpha (TNF-) has been limited by toxicity. These experiments evaluate blocking endogenous interferon-gamma (IFN-) activity to abrogate TNF- toxicity. Methods: C57Bl/6 mice bearing MCA 105 tumor were treated with TNF- and anti-IFN- antibody (Ab) to evaluate the effect on the acute lethality of TNF- and their efficacy as evaluated by tumor growth rate, tumor histology, and survival. Results: Anti-IFN- Ab decreased TNF- lethality. Anti-IFN- Ab alone increased tumor growth significantly more than did nonimmune IgG (p₂<0.0001). Tumor-bearing mice that received nonimmune IgG and TNF- had slower tumor growth (p₂<0.02) and a trend toward improved survival (p=0.07) compared with saline-treated controls. Anti-IFN- Ab abrogated the antitumor effect of TNF-, prevented acute tumor necrosis histologically, and resulted in tumor growth rate and host survival similar to that of controls. The findings in mice that received anti-IFN- Ab and high-dose TNF- were comparable with those in mice that received a lower, equitoxic dose of TNF- alone. Conclusions: Blocking endogenous IFN- accelerates tumor growth in this model and partially abrogates the toxic and antitumor activity of exogenous TNF- equally. This suggests that blocking endogenous IFN- activity is not a useful strategy for limiting TNF- treatment toxicity.Presented in part at the 45th Annual Cancer Symposium of The Society of Surgical Oncology, New York, New York, March 15–18, 1992.     

In vivo induction of HLA molecules in patients with myeloproliferative syndrome during IFNα treatment

Summary Eighteen patients with myeloproliferative syndrome (14 with chronic myeloid leukemia, four with essential thrombocytosis) were investigated for modulation of HLA antigens on peripheral blood lymphocytes, monocytes, and hematopoietic precursors during IFN therapy as a sign of potentially increased immune recognition of malignant cells. After 1 month of IFN therapy, an increased number of monocytes and hematopoietic precursor cells, but not of lymphocytes, expressed HLADQ antigens. In addition, a strong induction of HLA class-I antigens was found on both hematopoietic progenitors and normal peripheral blood mononuclear cells. With daily injections of IFN in the first month of therapy stimulation continuously increased, suggested a major effect of IFNa on hematopoietic progenitors with sustained enhanced expression of HLA class-I antigens during differentiation of myelomonocytic cells. HLA class-I antigen expression was consistently augmented by IFN in all patients, irrespective of their hematological response.This work was supported by theElse Übelmesser Stiftung and theDeutsche Forschungsgemeinschaft, Sonderforschungsbereich 120, projects A3 and D4