Biotherapy (Dordrecht, Netherlands)最新文献

Rationale and objective: Early long-term treatment with recombinant interferon (IFN) alpha-2b delayed disease progression in asymptomatic Human Immunodeficiency Virus (HIV) carriers in a randomized trial that lasted from October 1987 to February 1992 (14). The aim of the work reported in this paper was to observe if there was also an effect on survival when the same patients were followed-up further.

Design and interventions: IFN alpha-2b was given 3 x 10(6) IU, 3 times weekly. The control group did not receive any treatment. The main end-point for this evaluation was death due to any cause. The deadline was August 1995.

Population: Subjects were anti-HIV-1 seropositive, Western blot-confirmed, asymptomatic (CDC group II), or with generalized lymphadenopathies (CDC group III). The groups had 79 (control) and 83 (IFN) patients.

Main results: Mean survival was longer in the IFN group (95% CI: 127-152 vs. 101-120 months since infection or 80-90 vs. 70-82 months since the start of treatment). Survival rates were higher in IFN-treated individuals (61-77% vs. 24-54% at 10 years of infection or 53-69% vs. 34-52% at 7 years of treatment or follow-up). It was also confirmed that disease progression is significantly slower in IFN-treated patients. There were 23.4 vs. 3.2% long-term survivors in the IFN and control groups, respectively (p = 0.005). IFN-treated patients had fewer AIDS-related malignancies (5 vs. 11), mainly Kaposi's sarcomas (1 vs. 5). This difference was not statistically significant, but clinically interesting. There was no difference in survival if measured since the onset of AIDS.

Conclusion: IFN alpha treatment given from the early stages of infection, but not after the appearance of AIDS symptoms, can prolong survival.

The modulation of cisPlatin cytotoxicity by interleukin-1 (IL-1 alpha) was studied in cultures of SCC-7 tumor cells with and without tumor macrophages to examine potential mechanisms for the synergistic antitumor activity of cisPlatin and IL-1 alpha in SCC-7 solid tumors. Neither IL-1 alpha nor tumor macrophages affected the survival of clonogenic tumor cells and IL-1 alpha had no direct effect on tumor cell growth in vitro. Macrophages had no direct effect on cisPlatin sensitivity (IC90 = 6.0 microM), but, the addition of IL-1 alpha (500-2000U/ml) to co-cultures of cisPlatin pretreated tumor cells and resident tumor macrophages increased cell killing (IC90 = 3.1 microM). Similar responses were seen in primary cultures treated with cisPlatin before IL-1 alpha. The modulation of cisPlatin cytotoxicity by IL-1 alpha exhibited a biphasic dose response that paralleled the IL-1 alpha dose dependent release of H2O2 by resident tumor macrophages. Further, IL-1 alpha modification of cisPlatin cytotoxicity was prompt and inhibited by catalase. CisPlatin and exogenous H2O2 (50 microM) produced more than additive SCC-7 clonogenic cell kill and hydroxyl radicals played an important role in the response. Interleukin-1 modulation of cisPlatin cytotoxicity was schedule dependent. IL-1 alpha treatment for 24 hrs, before cisPlatin, produced drug resistance (IC90 = 11.1 microM). Our study shows that IL-1 alpha can stimulate tumor macrophages to release pro-oxidants that modify cellular chemosensitivity in a schedule and dose dependent fashion. Our findings may also provide a mechanistic explantation for the synergistic antitumor activity of cisPlatin and IL-1 alpha in vivo.

We previously reported that the antitumor effect of OK-432, a streptococcal preparation, was markedly augmented when this agent was injected into tumors together with fibrinogen. In order to elucidate the effect of this treatment on the spleen, we assessed splenic function in gastric cancer patients receiving preoperative local immunotherapy with OK-432 and fibrinogen. Immunohistochemical studies of the spleen at 7 days after intratumoral injection therapy revealed numerous macrophages phagocytizing OK-432 in the splenic sinuses. Phenotypic analysis of splenocytes by flow cytometry revealed an increase in the CD4/CD8 ratio and in the expression of HLA-DR, CD25, and Leu M3 by splenic T cells of the patients treated with OK-432 plus fibrinogen when compared to patients treated with OK-432 alone or untreated patients. Splenic T cells from patients treated with OK-432 plus fibrinogen showed significantly higher cytotoxicity against Daudi and K562 cells than T cells from control patients (p < 0.05), and culture of these splenic T cells with recombinant IL-2 induced the expansion of lymphokine-activated killer cells. These results demonstrate that local immunotherapy with a mixture of OK-432 and fibrinogen effectively augumented splenic antitumor immunity in gastric cancer patients.

The effect of Z-100, an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis, on cecal ligation and puncture (CLP)-induced sepsis in mice bearing Meth-A fibrosarcoma was investigated. When normal BALB/c mice were subjected to the CLP procedure, their mortality rate was 17%. On the other hand, an increased mortality was observed in tumor-bearing mice subjected to CLP 10 days after tumor inoculation, and then all mice died when tumor-bearing mice were subjected to CLP 20 days after tumor inoculation. However, the increased percent mortality was decreased by 50% when these mice were injected intraperitoneally with a 10 mg/kg dose of Z-100. When splenocytes (5 x 10(7) cells), obtained from Meth-A tumor-bearing mice 20 days after tumor inoculation, were transferred intravenously to normal mice (recipient mice), mortality of these recipient mice were increased by 62% as compared with that of the control (22%). However, no increased mortality (25%) was observed in recipient mice which were transferred with splenocytes from tumor-bearing mice injected intraperitoneally with Z-100 (10 mg/kg). In addition, suppressor cell activity was demonstrated in splenocytes from Meth-A tumor-bearing mice at 20 days after tumor inoculation using one-way mixed lymphocyte reaction. However, the suppressor cell activity was significantly decreased by the intraperitoneal administration of a 10 mg/kg dose of Z-100 (p < 0.01). The increase of mortality in recipient mice by adoptive transfer of mononuclear cells (MNCs) from tumor-bearing mice was not detected when these MNCs were treated with anti-Thy 1.2 monoclonal antibody (mAb), anti-Lyt 2.2 mAb or anti-CD11b mAb, but an increase was seen with anti-Lyt 1.2 mAb or anti-immunoglobulin antiserum treated MNCs. These results suggest that the suppressor cells affect the mortality of CLP-induced sepsis and Z-100 may have a therapeutic activity against opportunistic infections in immunocompromised hosts through the regulation of suppressor T-cells.

The modulation of NK activity by muramyl dipeptides derivatives against Ab (amelanotic) Bomirski melanoma and human erythroleukemia K562 cells was studied in vitro. The stimulatory effect was observed for 3 of 7 muramyl dipeptides: MDP(L-Ala)C921, MDPC857 and L18-MDP(Ala) in relation to cytotoxic activity of NK cells obtained from peripheral blood and spleen of healthy and Ab Bomirski melanoma bearing hamsters. An increased of cytotoxic activity NK cells isolated from animals before and during the transplantable phase of the tumor against K562 was found. A similar stimulation was received for NK cells obtained from animals against their own melanoma cells. The most significant influence of examined MDP derivatives on the cytotoxic activity of NK cells were obtained from animals between 10 to 12 days of tumor growth. The extent of the modulation of cytotoxic activity of NK cells was dependent on its initial value both in healthy control and Ab Bomirski melanoma bearing hamsters. If natural cytotoxic activity was high the stimulatory effect of the examined MDP derivatives was only slightly expressed.

IFN-gamma is an important regulator of immune responses and inflammation. Studies in animal models of inflammation, autoimmunity, cancer, transplant rejection and delayed-type hypersensitivity have indicated that administration of antibodies against IFN-gamma can prevent the occurrence of diseases or alleviate disease manifestations. Therefore, it is speculated that such antibodies may have therapeutical efficacy in human diseases. Since animal-derived antibodies are immunogenic in patients several strategies are being developed in order to reduce or abolish this human anti-mouse antibody (HAMA) response. In our laboratory, we have constructed a single-chain variable fragment (scFv) derived from a mouse antibody with neutralizing potential for human IFN-gamma. A scFv consists of only variable domains tethered together by a flexible linker. The scFv was demonstrated to neutralize the antiviral activity of HuIFN-gamma in vitro and therefore might be considered as a candidate for human therapy.

Natural antibodies to interferon (IFN)-gamma were detected in the serum of virus-infected patients and also, at a low titre, in the serum of healthy subjects. The increased titre of antibodies to IFN-gamma in the sera of virus-infected patients, and its decrease with clinical resolution, indicate that these antibodies are related to viral infection and probably reflect IFN-gamma production as a result of antigenic stimulation in vivo. Natural antibodies to IFN-gamma were affinity purified and studied for their capability to interfere in vitro with the multiple activities of the lymphokine. Data obtained show that these human anti-IFN-gamma antibodies have no inhibitory effect on the antiviral and antiproliferative activity of IFN-gamma and do not interfere with the binding of the lymphokine to its specific cell receptor. Instead, they can inhibit the expression of HLA-DR antigens induced by IFN-gamma on U937 cells and interfere, in mixed lymphocyte culture, with the proliferation of lymphocytes and the generation of cytotoxic lymphocytes. Experiments in animal models suggest that natural antibodies to IFN-gamma may have a role in the immunoregulatory process limiting the intensity and/or duration of immune response. As they can interfere only with the immunomodulating activities of IFN-gamma, these antibodies might open up new therapeutic approaches to diseases with evidence of activated cell-mediated immunity.

Interferons (IFNs) are generally recognized as the most important therapeutic agent in some infectious diseases such as chronic hepatitis B and C. Since the early clinical trials it was documented that the therapeutic use of IFNs could be complicated by the development of antibodies able to neutralize or to bind to the IFN molecule. After several years of research it is now widely accepted that the presence of circulating anti-IFN antibodies may affect the response to IFN. Here we summarize what is currently know on the clinical significance of antibodies to IFN in IFN-treated viral diseases patients.

Natural antibodies to human interleukin-2 are present in sera of patients infected with human immunodeficiency virus and also, at a lower titre, in sera of healthy individuals. These antibodies could be purified by affinity-chromatography. Purified human anti-hIL-2 antibodies can interfere with lymphocyte proliferation both in the lymphokine activated killer cell assay and in the mixed lymphocyte culture. The neutralizing activity observed in vitro suggests that these antibodies play a role in the elaborate cytokine network by which the immune system regulates its response.