Biotherapy (Dordrecht, Netherlands)最新文献

Induction of oral tolerance to antigens that are targets of self-reactive immune responses is an attractive approach to antigen-specific immune therapy of autoimmune diseases. Oral tolerization has indeed proven to be safe and effective in amelioration of autoimmune diseases in animal models. In humans, results have been somewhat controversial. The emphasis given to clinical outcome rather than to immunomodulation, and the difficulty in identifying appropriate candidate antigens contribute to the controversy. Heat shock proteins are promising targets for immune intervention. Immune reactivity to heat shock proteins has indeed been correlated with autoimmune arthritis in animal models, and abnormal immune responses to heat shock proteins have been described in human arthritis as well. Despite significant recent progress, little is known at a molecular level regarding the mechanisms which are responsible for a switch from autoimmunity to tolerance in humans. This is particularly true with respect to sequential analysis of several molecular and immunologic markers during both the course and treatment of disease. Novel approaches are currently under way to fill the gaps. We will briefly detail here the experience gained to date, and identify some of the avenues which future research will explore.

Soluble receptors for hormones and cytokines have been described. They can serve as natural blockers of their respective ligands. The natural soluble interferon gamma receptor (sIFN gamma R) has been isolated and characterized only in urine. Chromatography of human (hu) plasma from rheumatoid arthritis (RA) patients and controls on immobilized hu IFN gamma or antibodies against IFN gamma R alpha chain permitted us to isolate the sIFN gamma R. The receptor isolated from one control is a protein with a molecular weight between 60-67 kDa depending on the presence of reducing agents. We detected a significantly higher level of plasma sIFN gamma R in patients with rheumatoid arthritis than in apparently healthy subjects.

The antitumor effects of adoptive immunotherapy using LAK cells treated with sizofiran (SPG) following in vivo antigen sensitization with EL-4 lymphoma (EsLAK), comparing nonsensitized LAK cells (sLAK), were studied in mice with intraperitoneal implantation of EL-4 lymphoma. EL-4 cells treated with Mitomycin C (100 micrograms/ml) were introduced by inoculation into the peritoneum of C57BL/6 mice for antigen sensitization. Four days later, SPG (100 micrograms) was intramuscularly injected. Three days after SPG administration, mononuclear cells obtained from the spleen were prepared for LAK cells (EsLAK). The following results were obtained: 1) The survival period was significantly greater in the sLAK and EsLAK groups than in the control group. The survival period in the EsLAK group was significantly greater than that in the sLAK group. 2) The number of EL-4 cells in the peritoneal exudate cells 11 days postimplantation was lowest in the EsLAK group, and the number of lymphocytes including LGL was largest in the EsLAK group, compared with the sLAK group and the control group. 3) The EsLAK cells showed significantly more enhanced cytotoxic activity against EL-4 than the sLAK cells. 4) Histopathological findings of metastatic lesions of the liver and spleen stained by HE 11 days postimplantation showed less infiltrating tumor cells and more lymphocytic infiltrations in the sLAK and EsLAK groups compared with the control group. These results suggest that induction of LAK cells by administration of SPG to lymphocytes treated by in vivo sensitization with tumor antigen increases the efficacy of adoptive immunotherapy.

The idea that synthetic chemicals such as DDT are major contributors to human cancer has been inspired, in part, by Rachel Carson's passionate book, Silent Spring. This chapter discusses evidence showing why this is not true. We also review research on the causes of cancer, and show why much cancer is preventable. Epidemiological evidence indicates several factors likely to have a major effect on reducing rates of cancer: reduction of smoking, increased consumption of fruits and vegetables, and control of infections. Other factors are avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. Already, risks of many forms of cancer can be reduced and the potential for further reductions is great. If lung cancer (which is primarily due to smoking) is excluded, cancer death rates are decreasing in the United States for all other cancers combined. Pollution appears to account for less than 1% of human cancer; yet public concern and resource allocation for chemical pollution are very high, in good part because of the use of animal cancer tests in cancer risk assessment. Animal cancer tests, which are done at the maximum tolerated dose (MTD), are being misinterpreted to mean that low doses of synthetic chemicals and industrial pollutants are relevant to human cancer. About half of the chemicals tested, whether synthetic or natural, are carcinogenic to rodents at these high doses. A plausible explanation for the high frequency of positive results is that testing at the MTD frequently can cause chronic cell killing and consequent cell replacement, a risk factor for cancer that can be limited to high doses. Ignoring this greatly exaggerates risks. Scientists must determine mechanisms of carcinogenesis for each substance and revise acceptable dose levels as understanding advances. The vast bulk of chemicals ingested by humans is natural. For example, 99.99% of the pesticides we eat are naturally present in plants to ward off insects and other predators. Half of these natural pesticides tested at the MTD are rodent carcinogens. Reducing exposure to the 0.01% that are synthetic will not reduce cancer rates. On the contrary, although fruits and vegetables contain a wide variety of naturally-occurring chemicals that are rodent carcinogens, inadequate consumption of fruits and vegetables doubles the human cancer risk for most types of cancer. Making them more expensive by reducing synthetic pesticide use will increase cancer. Humans also ingest large numbers of natural chemicals from cooking food. Over a thousand chemicals have been reported in roasted coffee: more than half of those tested (19/28) are rodent carcinogens. There are more rodent carcinogens in a single cup of coffee than potentially carcinogenic pesticide residues in the average American diet in a year, and there are still a thousand chemicals left to test in roasted coffee. This does not mean that coffee is dangerous but r

Low dose oral interferon alpha has been shown to be of benefit in viral disease in animals. In a double-blind, placebo-controlled trial, 177 patients seropositive for HIV-1 were randomly assigned to receive placebo or recombinant human interferon alpha 2a (rIFN alpha). Endpoints were survival, alteration of disease classification, performance, and changes in CD4+ T cell numbers. There was a trend for improved survival in the group receiving rIFN alpha at the dose of 1.0 IU/lb. The changes in disease classification or in weight were not significantly different. Performance was improved to a greater extent (p=0.1) in the patients who received the two higher rIFN alpha dosages (1.0 IU/lb and 10.0 IU/lb) at 6 months. In addition, the CD4+ T cell count was improved only in the 1.0 IU/lb dose treatment group at 6 months. Treatment with low dose oral interferon at 1.0 IU/lb was associated with improved CD4+ T cell count, performance and a trend toward enhanced survival in HIV seropositive patients. These differences were, however, not statistically significant. A larger study, with better return rate, will be needed to determine whether low dose, oral interferon alpha is actually beneficial for these patients.

Adoptive immunotherapy using MHC-nonrestricted-lymphocytes, peripheral blood gammadelta T cells and NK cells was devised. Peripheral blood mononuclear cells (3 x 10(7)) were selected by immobilization to anti-CD3 monoclonal antibody for 4 days and cultured for 2 weeks in the presence of IL-2. Thereafter they were reactivated by 500 U/ml of IFN-alpha and 1000 U/ml of IL-2 for 1 hour. Enhancement of NK and LAK activities was confirmed. Peripheral blood gammadelta T cells proliferated in response to immobilized anti-CD3 antibody (3% to 30%). Approximately 6 x 10(9) BRM-activated killer (BAK) cells composed of CD56+ gammadelta T cells and CD56+ NK cells, were dispensed to cancer patients via intravenous drip infusion. Nine patients were treated with BAK cells every 2 weeks or every month on an outpatient basis. During the course of adoptive immunotherapy, the crossed affinity immunoelectrophoresis (CAIE) pattern of serum immunosuppressive acidic protein (IAP) was analysed. Both the production and glycosylation pattern of IAP is changed in response to tumor enlargement and may therefore act as a marker of the disease progression. During the course of BAK therapy, the glycosylation IAP pattern of 6 patients changed from tumor (T) to normal (N). In addition, the performance status of all patients was maintained at 90-100% of the Karnofsky scale and any side effects including fever were not observed during treatments with BAK cells. Moreover, the overall quality of life (QOL) of the patients, scored at the Face scale was favorable. In addition, blood levels of activated gammadelta T cells producing IFN-gamma were assayed as an indication marker of BAK therapy. The normal range of IFN-gamma producing gammadelta T cells comprised 6.9 +/- 0.9% of peripheral blood mononuclear cells (PBMC), according to a single cell FACScan analyses of PBMCs derived from normal individuals. IFN-gamma producing gammadelta T cells of Patients No. 8 and 9, who received extensive chemotherapy before initiation of BAK therapy, comprised only 0.2% and 2% of PBMC, respectively. These patients died 3 and 6 months after beginning BAK therapy. Peripheral blood gammadelta T cells of Patients Nos. 1-7 proliferated in response to immobilized anti-CD3 antibody and the frequency of IFN-gamma producing gammadelta T cells in PBMC preparation of these patients were over 3% before initiation of BAK therapy. Since our data show a positive correlation between survival time and initial gammadelta T cell counts, a low frequency of these cells may contraindicate BAK therapy.