Biotechnology therapeutics最新文献

The effect of eosinophil cationic protein (ECP) upon proliferation of human B cell lines or purified B cells was studied. ECP inhibited proliferation of the human lymphoblastoid cell lines CBL and GM-1056 at doses of 0.1-5 ng/mL during 2-4 days of culture. The inhibitory effect of ECP was reversible and not due to toxic damage. Moreover, inhibition could be blocked by anti-ECP serum while the control serum failed to do so. Of various cytokines tested--including interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6; interferon (IFN)-alpha or IFN-gamma--IL-4 reduced the inhibition, while other cytokines failed to do so. The reduction of inhibition was specific to IL-4 since reduction by IL-4 was blocked by anti-IL-4 antibody but not by the control antibody. ECP also inhibited proliferation of tonsillar small resting B cells stimulated with anti-mu antibody plus low molecular weight B-cell growth factor (BCGF) or of large activated B cells. In contrast, ECP had no effect on proliferation of unstimulated small resting B cells. This inhibition was also reduced by IL-4 specifically. These results indicate that ECP may also act as a B-cell regulating factor.

In this study we demonstrate that an immunodominant antigen of Giardia lamblia is a heat shock protein. The expression of the antigen was induced not only by heat shock but also when Giardia trophozoites were placed in media more closely resembling the environment in the host, indicating that this antigen may play an important role in host-parasite interactions.

We have used disulfide-linked conjugates of murine anti-TNF antibodies to determine whether TNF binding to the cell surface could be increased by exploiting the Fc receptors present on monocytes and macrophages. Binding and degradation of TNF via Fc receptors may enhance the ability of anti-TNF antibodies to lower the high TNF levels found in several diseases. Conjugated murine anti-TNF antibodies greatly increased the binding of TNF to human U937 cells and had little effect on cells which did not express Fc receptors. U937 cells treated with anti-TNF conjugates also degraded more TNF than untreated cells. Competition analysis indicated that Fc receptors were involved in anti-TNF binding and that conjugated anti-TNF shared binding sites with monomeric anti-TNF. Preincubation of anti-TNF conjugates or monomeric anti-TNF with TNF increased the amount of anti-TNF antibody bound to the surface of cells. These results demonstrate that cross-linking may greatly enhance the ability of anti-TNF antibodies to mediate TNF clearance and degradation by making effective use of Fc receptors.

A total of 22 patients with metastatic renal cell carcinoma or malignant melanoma were treated in a phase II study to assess the safety and efficacy of combination therapy of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). 3 x 10(6) U/m2/day recombinant human (rh)IL-2 was given in repetitive cycles by continuous 24-h infusion from day 1 to day 4; 6 x 10(6) U/m2/day rhIFN-alpha was given subcutaneously on days 1 and 4. There was one complete remission and two partial remissions in the renal cell carcinoma group and two partial remissions in the malignant melanoma group, giving an overall response rate of 24% in 21 evaluable patients with a median response duration of 5+ months. Toxicity was moderate, with hypotension, fever, chills, nausea, neurotoxicity, and dermatitis as prominent side effects. Measurement of circulating cytokine levels showed increased serum tumor necrosis factor-alpha (TNF), interferon-tau, and soluble interleukin-2 receptor levels during each cycle with a tendency to higher concentrations of TNF in responders as compared to nonresponders. With regard to therapeutic efficacy and tolerance, our approach might represent an alternative to the high-dose protocols and the labor- and cost-intensive strategies of adoptive immunotherapy.

The human immunodeficiency virus (HIV-1) envelope glycoprotein gp160 was produced in large-scale microcarrier cultures of Vero cells, using a system involving coinfection with two recombinant vaccinia viruses. The immunogenicity of this material was studied in conjunction with a number of different adjuvant formulations, and chimpanzees were then immunized with gp160 in conjunction with Al(OH)3, Al(OH)3 and sodium deoxycholate, and a lipid-based adjuvant. The Al(OH)3-gp160 vaccine formulation elicited very poor immune responses in two chimpanzees, and these animals were further immunized with gp160 in conjunction with a lipid-based adjuvant. Immunization with the latter formulation lead to induction of high-titer neutralizing antibodies, and, following challenge with HIV-1, one chimpanzee demonstrated no evidence of virus infection over a period of 3 years. The second chimpanzee, which had previously been infected with non-A, non-B hepatitis, and two animals immunized with gp160 with Al(OH)3 and deoxycholate were not protected against challenge.

CSFs may be useful in improving the clinical effectiveness of cytosine arabinoside (ara-C). In vitro studies have indicated that GM-CSF may be capable of specifically increasing the sensitivity of leukemic cells to this agent. Other studies have indicated that IL-3 may enhance the ability of ara-C to kill leukemic cells by cytokinetic and pharmacologic mechanisms. While the effects of GM-CSF and IL-3 on ara-C-induced differentiation appear limited, the combination of ara-C and leukemia inhibitory factor (LIF) may appear to be useful in overcoming the block in differentiation characteristic of leukemic myeloblasts. On the basis of in vitro studies, clinical trials with ara-C are underway that are examining the usefulness of GM-CSF and IL-3 in cell cycle recruitment of leukemic myeloblasts. These cytokines are also under study in supportive therapy of ara-C-induced myelosuppression. While certain results appear promising, further controlled studies are needed to determine the role of CSFs in improving ara-C therapy.