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PubMed2001

Expression of inducible nitric oxide synthase in the liver of bile duct-ligated Wistar rats with modulation by lymphomononuclear cells.

BACKGROUND: The current study evaluated whether biliary tract obstruction stimulates inducible nitric oxide synthase (iNOS) protein expression in the liver and analyzed the implication of lymphomononuclear cells and interleukin-4 (IL-4). METHODS: Male Wistar rats were used. Bile flow interruption was achieved by a complete division of the extrapancreatic common bile duct. iNOS expression was determined by both the Western blot technique and immunohistochemistry. RESULTS: iNOS protein was markedly expressed in the liver 7 days after bile duct obstruction. Treatment with thymostimulin (TP-1), a partially purified thymic extract, reduced the intensity of the expression of iNOS protein in the liver after bile duct ligation. Recent data have suggested that IL-4 attenuates iNOS protein expression. We then analyzed the involvement of this anti-inflammatory cytokine on the modulation of iNOS expression in the liver. The liver from rats that underwent bile duct ligation (BDL) showed a lower content of IL-4 than that of sham-operated (SO) rats. TP-1 treatment increased the content of IL-4 in the liver. Liver slices incubated in vitro with Escherichia coli lipopolysaccharide (LPS, 10 microg/mL) stimulated the expression of iNOS protein. The level of LPS-induced iNOS expression was reduced by lymphomononuclear cells obtained from sham-operated animals. However, lymphomononuclear cells isolated from BDL rats potentiated the induction of iNOS expression by LPS-stimulated liver. However, lymphomononuclear cells from TP-1-treated BDL rats failed to modify LPS-stimulated iNOS expression. The different effect of lymphomononuclear cells on the modulation of iNOS expression in the liver was associated with their ability to generate IL-4. CONCLUSIONS: The liver of jaundiced rats markedly expressed iNOS protein, which was associated to modifications in the content of IL-4 in the liver. Furthermore, lymphomononuclear cells modulate iNOS protein expression in the liver by a mechanism in which IL-4 is involved.

Animals↗
PubMedDate not supplied

Thymostimulin enhancement of T-cell infiltration into head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) produces immunosuppressive low-molecular-mass factors (LMMFs) responsible for defects in the cell-mediated immune system. These defects include impaired monocyte chemotaxis and an impaired capability of dendritic cells (DC) to form cellular clusters. It has been shown previously that the immunomodulating drug thymostimulin (TP1) restores these defects in vitro. METHODS: An immunohistochemical study was performed on tumors of 18 patients with HNSCC who had preoperatively been treated with TP1 in one of three dosages (0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg body weight). Additionally, tumors of 4 patients who had been treated with a placebo and 12 patients who had not received any preoperative treatment were studied. A relative surface area of infiltration, meaning the percentage of stromal or epithelial tissue covered by infiltrating cells in histological sections, was calculated using an image analysis system (VIDAS RT) for CD3+ T-cells, CD14+/CD68+ monocytes/macrophages and L25+/CD1a+ dendritic cells for each tumor. RESULTS: A highly significant, denser T-cell infiltration into the stromal tissue area of tumors of patients who had been treated with TP1 when compared with tumors of non-TP1-treated patients was observed for all three dosages. None of the other tumor-infiltrating cell types was affected by TP1. In addition, a correlation was found between the tumor T-cell infiltration and capability of DCs in the peripheral blood to form clusters with T-cells. No correlation existed between CD3+ T-cell numbers in peripheral blood and T-cell infiltration into the tumor; nor were monocyte chemotactic functions in peripheral blood correlated with tumor infiltration by monocytes or monocyte-derived macrophages and DCs. CONCLUSIONS: Preoperative treatment of HNSCC patients with TP1 appears to strongly enhance tumor--T-cell infiltration. The number of tumor-infiltrating DCs was not affected by TP1, but a positive correlation between tumor--T-cell infiltration and DC clustering capability suggests that the functional status of DCs is important in improved cell-mediated immunity.

Adjuvants, Immunologic↗
PubMed1975

Thymosin-induced increase in E-rosette-forming capacity of lymphocytes in patients with malignant neoplasms.

Thymosin, a thymic hormone, restores decreased cellular immunity under various experimental conditions. The purpose of this study was to evaluate the effect of thymosin on the E-rosette-forming capacity in cancer patients. Peripheral blood lymphocytes obtained from eight patients with various malignant neoplasms were examined. One of these patients received thymosin intramuscularly; his E-rosette formation was examined serially. Eight normal adults served as controls. Patients with advanced stages of malignant tumors showed decreased E-rosette-forming capacity, which increased significantly under the influence of thymosin. Patients with less-advanced tumors, as well as normal adults, demonstrated normal E-rosette formation without further effects by thymosin. The in vivo administration of thymosin to one patient was followed by a marked increase of the E-rosette-forming capacity. These results suggest that the administration of thymosin, both in vivo and in vitro, significantly increases the circulating T-lymphocyte levels and/or functions in patients with advanced malignant neoplasms.

Adult↗
PubMed1976

The effect of thymosin on human T-cells from cancer patients.

The effect of thymosin on in vitro reactivity of peripheral lymphocytes to phytohemagglutinin, concanavalin A, and the formation of spontaneous E-rosettes in 54 patients with metastatic carcinomas has been studied. Thymosin increased lymphocyte responses to PHA and Con A in only 10 patients, with predominant effect seen with Con A. Twenty patients showed depressed baseline levels of E-rosettes which were increased to normal or subnormal levels after incubation with thymosin. No distinct correlation was noted between the clinical stage of the disease and the ability of lymphocytes to form E-rosettes. Although the exact mechanism by which the thymus exerts its influence on host resistance is not clearly defined, present evidence supports the concept that the thymic hormone, thymosin, may be an important addition in treatment of cancer patients by increasing cell-mediated immunity.

Adolescent↗
PubMed1984

Characterization of a new antigen-antibody system (Su) in patients with systemic lupus erythematosus.

A new antigen (Su) from calf thymus nuclear extract that reacts with sera from patients with systemic lupus erythematosus (SLE) is described. Antibodies to Su, demonstrated by immunodiffusion, were most frequently found in patients with a diagnosis of probable or definite SLE. Thirty-seven percent of patients with Su antibodies and a diagnosis of SLE were positive for antinuclear antibodies by indirect immunofluorescence, but lacked specific antibodies previously associated with SLE. Patients with Su antibodies exhibited a higher frequency of Raynaud's phenomenon, but exhibited a lower frequency of malar rash, alopecia, and arthritis when compared with SLE patients in previously published reports. The Su antigen is weakly acidic, heat-stable at 37 degrees C, heat-sensitive at 56 degrees C, resistant to DNase and RNase, but sensitive to trypsin. Its molecular weight approximated 154,000 daltons by Sepharose chromatography. The Su antibody may be associated with a subset of SLE patients with distinct clinical features, and may serve as a serologic marker for patients who are positive for fluorescent antinuclear antibodies but have no other detectable SLE-associated antibodies.

Antigens↗
PubMed1986

Biotherapy: the fourth modality of cancer treatment.

Biotherapy represents a new modality of cancer treatment. It utilizes biologicals and biological response modifiers in the treatment of cancer. Many of these substances are of "natural" origin emanating from mammalian cells as physiologic mediators of immune response and as substances active in the regulation of growth and maturation. With the advent of molecular biological techniques, hybridoma technology, and computer applications, it is now possible to prepare these biological substances in highly purified form and in large quantities for use as medicinals. The expertise required to apply these biotherapeutic approaches to the treatment of cancer often involves the use of immunological and/or molecular biological capabilities. Because of the rather specialized expertise needed to understand and apply these substances as anticancer approaches, those individuals with expertise in the application of chemotherapy to patients with cancer are not necessarily well prepared for the translation of biotherapy to the clinic. Biotherapeutic approaches are broad and involve a whole range of physiological responses inherent in cancer biology. The approaches necessary to bring these biotherapeutic capabilities to the clinic need to be considered carefully, and the use of new techniques and new methods of application should be encouraged so as not to inhibit these potentially powerful anticancer approaches. As natural mediators, many biologicals have much less inherent toxicity than the drugs previously used in systemic cancer therapy. Therefore, the systems for translating these substances from the laboratory to the clinic should be restructured for the rapid translation of biotherapy to the patient.

Antibodies, Monoclonal↗
PubMed1976

Regulation of immune balance by thymosin: potential role in the development of suppressor T-cells.

Studies in a variety of animal and human models indicate that thymosin plays a role in the differentiation of a number of T-cell subpopulations. The hypothesis presented is that a normal immune balance depends heavily upon the presence of thymosin-activated suppressor or regulator T-cells. A major thrust in our present research program is to determine whether or not the various disorders discussed here are causally related to abnormal thymosin production by the thymus gland. We are also assessing in animal models the potential value of thymsin in the treatment of specific autoimmune diseases. This information may yield new insights for the management of autoimmune type disorders such as SLE. Results from clinical trials to date suggest that thymosin will have a role in boosting the immune responses of patients with specific thymic malfunctions and may indeed exert an influence via the production of suppressor or regulator T-cells.

Animals↗
PubMed1976

Augmentation of cell mediated lysis (CML) by THF.

The in-vitro model of cell mediated lysis (CML) was used to study whether a thymic hormone (THF) participates in the processes which lead to generation of effector cells. It was found that THF increases the capacity of effector cells from spleens of intact mice in the CML assay. This effect of THF on generation of effector cells was manifested when THF was present during the mixed lymphocyte culture. On the other hand, addition of THF to the effector (CML) phase did not elevate the lytic capacity of killer cells. Moreover, THF compensated the impaired lytic capacity of effector cells from adult thymectomized mice and raised it to the level of intact mice. The results are compatible with the hypothesis that THF acts on the generation of CML effector cells of both intact and adult thymectomized mice.

Animals↗
PubMed1995

In vivo effects of thymostimulin treatment on monocyte polarization, dendritic cell clustering and serum p15E-like trans-membrane factors in operable head and neck squamous cell carcinoma patients.

Head and neck squamous cell carcinoma patients have been characterized by impairments in their cell-mediated immune system, particularly by decreased chemotactic function of monocytes and impairments in the function of the monocyte-derived dendritic cells (viz, a decreased capability to form cell "clusters"). These impairments are thought to be due to immunosuppressive factors of low molecular mass released by tumor, the so-called p15E-like factors. These suppressive effects of p15-like factors can be neutralized in vitro by thymic peptides, such as thymostimulin (TP1). In a randomized double-blind, placebo-controlled multicenter trial in the Netherlands, 41 patients with operable head and neck squamous cell carcinomas (HNSCC) were treated for 10 days prior to surgery with intramuscular TP1 in one of three dosages (0.5 mg/kg; 1.0 mg/kg or 2.0 mg/kg body weight) or treated with placebo. Assessment of monocyte chemotaxis, the capability of dendritic cells to form clusters and the presence of p15E-like low-molecular-mass factors (LMMFs) in serum was performed before TP1 treatment and on the day of surgery. Findings demonstrated that TP1 in a dose of 1.0 mg/kg and 2.0 mg/kg resulted in normalization of impaired monocyte chemotactic capability. Although the cluster capability of dendritic cells after TP1 treatment improved, values only reached statistical significance for the 0.5 mg/kg group. Serum p15E-like LMMF levels were not affected by TP1 treatment in any of the patient groups. Contrary to expectations we found no correlation between elevated immunosuppressive LMMFs and defective monocyte chemotaxis or cluster capability of dendritic cells. We conclude that treatment with TP1 can improve monocyte chemotaxis in HNSCC patients but an effect on the production of p15E-like factors by carcinoma cells could not be demonstrated.

Adjuvants, Immunologic↗