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PubMed1985

Effect of a thymic factor, thymostimulin, on growth and pulmonary metastases of Lewis lung carcinoma.

The antitumor and antimetastatic activities of a thymic factor, thymostimulin (TP-1), with or without cyclophosphamide (CPA) were examined in C57BL/6 mice inoculated with Lewis lung carcinoma (3LL). Tumor growth was followed by determining the tumor diameter after tumor implantation. TP-1 given to mice every 2 days after tumor implantation significantly inhibited tumor growth without affecting the survival rate. For induction of spontaneous pulmonary metastases, 3LL cells were implanted into the footpads of mice, and the implanted tumor was removed on day 9. The antimetastatic effect of TP-1 on pulmonary metastases after removal of the primary tumor was evaluated by counting the number of pulmonary surface nodules. TP-1 showed antimetastatic activity depending on its time of administration and dose. Combined therapy with TP-1 plus CPA significantly prolonged the survival of mice with pulmonary metastases. The cytolytic activities of spleen cells on 3LL cells were enhanced in mice treated with TP-1 and/or CPA and the cytolytic activity of nonadherent spleen cells, the T-cell population, was enhanced. The role of cytolytic spleen cells in inhibiting and preventing metastases was discussed.

Animals↗
PubMed1985

Immunorestorative properties of thymostimulin (TS) in patients with Hodgkin's disease in clinical remission.

Fifteen Hodgkin's disease patients (8 male, 7 female) aged 19-72 years, who had been in complete unmaintained remission for 1 year or more when the study was initiated, were given 50 mg thymostimulin (TS) IM daily for 60 consecutive days. When compared with 26-30 age- and sex-matched controls, as a group the patients' circulating ENR+, OKT+3, and OKT+4 cells were depressed (0.001 less than or equal to P less than or equal to 0.06), whereas their OKT+8 cell population was not. Low (greater than 1 SD or greater than 2 SD below mean in controls) or borderline (mean value of two subsequent tests greater than 1 SD below mean in controls) values of ENR+, OKT+3, and OKT+4 cells were seen in nine (group I) of the 15 patients tested, while the remaining six patients (group II) had normal T-cell proportions. Following TS treatment, the proportions of ENR+, OKT+3, and OKT+4 cells increased to normal in all group I patients. The T-cell levels, however, decreased to pretreatment values 60-70 days after completion of TS therapy. TS had no effect on the group II patients whose T-cell percentages had initially been normal. Spontaneous cell-mediated cytotoxicity (SCMC) was assessed in 11 patients, and irrespective of the baseline values, there was a significant enhancement (P less than 0.005) by day 15 of TS administration, which was maintained during treatment. SCMC, however, returned to pretreatment levels 60-70 days after TS was discontinued. The delayed skin test reactivity to DNCB was significantly depressed in all cases. Although TS restored the T-cell proportions, it failed to reverse DNCB reactivity from negative to positive in any of the patients tested. TS can thus restore defective T-cell frequencies and can enhance cytolytic functions that are potentially important in host immunosurveillance, but it apparently failed to improve the skin reactivity to neoantigen.

Adult↗
PubMed1988

A randomized trial to evaluate the immunorestorative properties of thymostimulin in patients with Hodgkin's disease in complete remission.

A total of 19 Hodgkin's disease (HD) patients (12 male, 7 female) aged 26-67 years, who had been in complete unmaintained remission for 6 months or more when the study was initiated, were randomly given 50 mg thymostimulin (TS) i.m. daily (G1) or every other day (G2) for 35 days. A third group (G3) was not treated. Then TS, at the same dose was administered twice a week for the following 22 weeks in patients both initially receiving loading or intermittent TS treatment. When compared with age- and sex-matched controls, as a group, the patients' circulating OKT3+, OKT4+, OKT11+ and E-AETR+ cells were depressed (P less than 0.001 for both proportions and absolute numbers), whereas their OKT8+ cell population was not. Following 5 weeks of daily TS administration, the proportions and numbers of all T cell fractions significantly increased in G1 patients (P less than 0.03 for all the comparisons tested), while following intermittent TS treatment (G2) only the proportions of OKT3+ and OKT11+ cells (P less than 0.03), but not of other T cell fractions, significantly increased. In addition, no significant changes in the absolute numbers of T cell fractions were observed in this group of patients. Furthermore, no spontaneous variations in the T cell pool size occurred in untreated patients. TS maintenance therapy did not produce any further improvement in the size of overall T cells and T cell subsets but sustained percentage and absolute numbers of these cells during administration and the absolute number of T cells even after discontinuation of therapy. The TS-induced improvement in the T cell pool was not associated with any change in the size of circulating non-T lymphocytes and monocytes. In vitro phytohemagglutinin-induced interleukin-2 (IL-2) and gamma-interferon (IFN-gamma) synthesis was assessed in 11 patients (3 G1, 4 G2, and 4 G3). Although it was not statistically significant, a rise in IL-2 and IFN-gamma production was observed in TS-treated patients, but not in untreated controls. TS failed to exert any effect on the serum circulating levels of neopterin, type I and II IFN, beta-2 microglobulin (B2-M) and immunoglobulins (Ig). TS can thus improve defective T cell frequences and numbers and may modulate IL-2 and IFN-gamma production.

Adjuvants, Immunologic↗
PubMed1984

Enhancement of natural killer cell activity in mice by treatment with a thymic factor.

The administration of a thymic factor, thymostimulin (TP-1), to mice resulted in considerable augmentation of natural killer (NK) cell activity as measured in a short-term assay against 51Cr-labeled YAC-1 target cells. Conditions suitable for detection of the thymostimulin-induced boosting of NK included multiple daily exposures to TP-1 (50 micrograms/kg), and peak levels of reactivity were observed at 2-4 days after discontinuation of treatment. A strict age-dependency of the effect was also observed, with optimal augmentation of NK-cell activity when TP-1 was administered to mice at 4-6 weeks of age. The effect was not limited to TP-1 treatment but was also observed on administration of another thymic factor (thymosin alpha 1). The activated cells responsible for the increased natural cell-mediated cytotoxicity appeared to be typical murine NK cells, judging by both functional and antigenic criteria.

Age Factors↗
PubMed1984

Anti-ribosomal ribonucleoprotein autoantibodies in systemic lupus erythematosus.

Sera from systemic lupus erythematosus (SLE) patients giving a fluorescent ribosomal pattern on tissue and cell preparations also showed precipitating autoantibodies against purified rat liver ribosomes. Ribosomal antigen is also present in rabbit thymus cellular extract (RTE), since the same sera gave precipitin lines against RTE in identity with ribosomes. Immunofluorescent staining was completely inhibited by serum absorption with ribosomes or with RTE. However ribosomal RNA and RNase or trypsin-treated ribosomes failed to react with these autoantibodies as demonstrated in immunoabsorption and immunodiffusion studies. These data suggest that these sera contain autoantibodies directed against some antigenic site composed of a portion of both RNA and ribosomal protein. Ribosomal autoantibodies were detectable at a low frequency in SLE patients characterized by an active disease and renal involvement.

Antigens↗
PubMed1983

Interactions of trichloroethylene with DNA in vitro and with RNA and DNA of various mouse tissues in vivo.

The covalent binding of 14C-1,1,2-trichloroethylene (14C-TRI) metabolites to calf thymus DNA in vitro and to RNA and DNA of mouse brain, lung, liver, kidney, spleen, pancreas, and testis after repeated i.p. injections has been studied. Hydrolysates of DNA reacted with 14C-TRI in vitro and hydrolysates of RNA and DNA from selected organs were separated on Aminex A6 for quantitation of alkylation products. The presence of 3,N4-etheno(deoxy)cytidine, 1,N6-etheno(deoxy)adenosine and 1,N6-ethenoadenine was investigated. No radioactivity could be registered in DNA incubated with 14C-TRI in the absence of liver microsomes. Covalent binding of 14C-TRI to DNA took place in the presence of liver microsomes from control mice. The binding was enhanced by 50% if liver microsomes from phenobarbital pretreated mice were used. The radioactivity in DNA reacted with 14C-TRI and microsomes from control mice was eluted in early fractions and together with thymidine. The same two peaks appeared on chromatography of DNA incubated with 14C-TRI and liver microsomes from phenobarbital pretreated mice. In addition, radioactivity was eluted together with 1,N6-ethenoadenine. Radioactivity was registered in RNA and DNA from all of the studied organs after i.p. injections of 14C-TRI. The radioactivity in RNA increased in the order brain less than testis less than pancreas less than kidney less than liver less than lung less than spleen. The radioactivity in DNA increased in the order brain less than kidney less than testis less than lung less than pancreas less than liver less than spleen. Aminex A6 chromatography revealed that the entire radioactivity in RNA from liver and kidney and in DNA from kidney, testis, lung, pancreas, and spleen was due to metabolic incorporation, particularly into guanine and adenine. This finding indicates that the C-C bond in TRI is split, with the formation of C1-fragments, during biotransformation in vivo. In liver DNA, the metabolic incorporation of radioactivity was insignificant. Instead, the dominant part of the radioactivity in liver DNA was eluted in early fractions. The elution profile of radioactivity in liver DNA gave no direct evidence of the formation of TRI-DNA adducts in vivo. No etheno-derivatives were identified as alkylation products of TRI in vivo, which is consistent with current theories of the metabolic fate of TRI.

Alkylation↗
PubMed1991

Immunomodulators interfere with angiopathy but not vasospasm after subarachnoid haemorrhage in rabbits.

The present study deals with the effects of immunomodulators on the morphology of intracerebral arterial walls in rabbits with experimental subarachnoid haemorrhage (SAH). Immunostimulators:thymostimuline and inosine dimethylamino-isopropanol-p-acetamido-benzoate were found to aggravate the angiopathic changes, whereas immunosuppressive drugs-cyclosporine A and azathioprine appeared to prevent the damage. The authors consider the possibility of using immunosuppressive drugs in patients with ruptured intracranial aneurysms.

Animals↗
PubMed1994

Antibiotic treatment of burned patients: an Italian multicentre study.

Antibiotic therapy in burn centres with highly specialized ICUs has reduced the mortality and morbidity in burn and trauma but, in spite of constantly improving supportive surgical and resuscitation methods, infection remains a major problem. Indeed, the clinical experience, as recorded in Europe and the USA, using different antimicrobial drugs and regimens, emphasizes a constantly evolving pattern of pathogenic microorganisms in the wound and in the rest of the patient's body, and their increasing chemoresistance. We report the preliminary results of 559 patients in a large controlled multicentre clinical study (mean age 41.4 +/- 17.8 years and burns covering a mean body surface area of 35.7%), with the collaboration of 13 of the 15 major Italian burn centres. The antibiotic treatment consisted of prophylactic administration of pefloxacin (800 mg i.v. OD for 4 days) for all patients as a first treatment while waiting for an antibiogram, and chemotherapy with teicoplanin (800 mg i.v. OD) together with netilmicin (300 mg i.m. OD) in one or more cycles. At random, half of the patients received thymostimulin (70 mg i.m. OD pro die for the first month and every other day thereafter until discharge from hospital). Of the bacterial pathogens involved in septic complications, 63.3% were Gram-positive (Staphylococcus spp. and Streptococcus spp.). The mortality rate was 15.5%. Pefloxacin chemoprophylaxis was successful in 19.4% of patients and cure or improvement was seen with combination chemotherapy in 66.7% of patients, mainly with only one treatment cycle. The incidence of mortality and sepsis was not significantly influenced by treatment with thymostimulin.

Adolescent↗
PubMed1993

Depressed monocyte polarization and clustering of dendritic cells in patients with head and neck cancer: in vitro restoration of this immunosuppression by thymic hormones.

The in vitro restoring effects of a thymic hormone preparation, TP-1, on defective monocyte and dendritic cell function in patients with head and neck squamous cell carcinoma (HNSCC) have been examined. The N-formylmethionyl-leucyl-phenylalanine (fMLF)-induced polarization of monocytes isolated from the peripheral blood was significantly lower (a mean of 19%) than the polarization of monocytes isolated from healthy controls (a mean of 33%). After the in vitro addition of TP-1 this defective polarization was improved to the normal value of 33% polarized monocytes. The capability of dendritic cells prepared from the blood to form cellular clusters with allogeneic cells was impaired in 26/44 patients. In vitro addition of TP-1 again had restoring effects. The original defective dendritic cell clustering of 97 clusters/six microscopic fields (mean) was improved to a value of 121 clusters. The defects in monocyte polarization and clustering of dendritic cells could be ascribed to the presence in serum of a tumor-derived low-molecular-mass factor low-M(r) factor; < 25 kDa) sharing structural homology with p15E, the capsular protein of murine and feline leukemogenic retroviruses. The incubation of low-M(r) factor from the serum of HNSCC patients with healthy donor monocytes resulted in a significantly higher inhibition of fMLF-induced monocyte polarization than did incubation with control low-M(r) factor (a mean of 42 versus 16% inhibition). This suppressive effect of patient low-M(r) factor was abrogated with a mixture of two monoclonal antibodies against p15E as well as with TP-1. The observations here reported on the in vitro effects of TP-1 on depressed monocyte and dendritic cell function in HNSCC have provided one of the rationales for a TP-1 therapeutic pilot trial recently started in HNSCC patients.

Adjuvants, Immunologic↗
PubMed1991

Characteristics of histamine and serotonin release from rat mast cells induced by thymic peptides.

Thymopoietin peptides release histamine and serotonin from rat mast cells. The release has the characteristics of other basic secretagogues in that it occurs rapidly, does not require extracellular Ca2+ ions, and is inhibited by benzalkonium chloride (BAC). These similarities indicate that chemically different basic compounds have common mechanisms for histamine and serotonin release from rat mast cells.

Amino Acid Sequence↗
PubMed1997

Activation of human Kupffer cells by thymostimulin (TP-1) to produce cytotoxicity against human hepatocellular cancer.

BACKGROUND: In a small pilot study, thymostimulin (TP-1) produced tumor regression in almost 50% of patients with hepatocellular cancer (HCC) who were treated with TP-1 alone. However, the mechanism of the TP-1-mediated antitumor effect against HCC is unknown. METHODS: Human hepatocytes and Kupffer cells were isolated from liver biopsy specimens by collagenase infusion and counterflow elutriation. Hepatocytes and Kupffer cells were incubated in vitro with clinically relevant doses of TP-1. Cell-free supernatant levels for a panel of growth factors and monokines were determined by enzyme-linked immunosorbent assay. The cytotoxic activity of TP-1 alone of TP-1-stimulated hepatocyte and Kupffer cell supernatants against Hep G2 and Hep 3B human HCC cells in vitro was measured by MIT assay. RESULTS: Doses of TP-1 up to 100 micrograms/ml produced no cytotoxicity against Hep G2 or Hep 3B cells. Furthermore, supernatants from TP-1-treated hepatocytes produced no cytotoxicity against Hep G2 or Hep 3B cells, and TP-1 did not stimulate the release of transforming growth factor (TGF)-alpha, TGF-beta, or hepatocyte growth factor. TP-1-treated Kupffer cell supernatants produced significant cytotoxicity against Hep G2 cells but produced no cytotoxicity against Hep 3B cells. Kupffer cells stimulated by TP-1 released significant amounts of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 alpha, and IL-6 compared with control Kupffer cells (p < 0.01). The activity of TP-1-treated Kupffer cell supernatants against Hep G2 cells was blocked by anti-TNF-alpha antibodies, whereas neither anti-IL-1 alpha nor anti-IL-6 antibodies blocked cytotoxicity. CONCLUSIONS: These results demonstrate that TP-1 cytotoxicity against human HCC cells is not mediated directly or through hepatocytes, but occurs through activation of Kupffer cells and release of TNF-alpha. Understanding the mechanism of TP-1 cytotoxicity against human HCC has been used to plan a phase 1 trial of TP-1 combined with regional infusion of doxorubicin to treat unresectable HCC.

Adjuvants, Immunologic↗
PubMed1989

Thymomodulin: biological properties and clinical applications.

Thymomodulin (Ellem Industria Farmaceutica s.p.a., Milan, Italy) is a calf thymus acid lysate derivative, composed of several peptides with a molecular weight range of 1-10 kD. Thymomodulin did not exhibit any mutagenic effect. Furthermore, thymomodulin used in animal studies showed no toxicity even when used at high concentrations. Of major significance are the observations in murine and human systems that thymomodulin remains active when administered orally. In vitro and in vivo administered thymomodulin was able to induce the maturation of T-lymphocytes. Additionally, studies in vitro showed that this thymic derivative can enhance the functions of mature T-lymphocytes with cascading effects on B-cell and macrophage functions. Extensive human clinical trials with thymomodulin showed that this agent can improve the clinical symptoms observed with various disease processes, including infections, allergies and malignancies, and can improve immunological functions during ageing.

Humans↗
PubMed1986

Small nuclear ribonucleoprotein antigens are absent from 10S translation inhibitory ribonucleoprotein but present in cytoplasmic messenger ribonucleoprotein and polysomes.

A cytoplasmic 10S ribonucleoprotein particle (iRNP), which is isolated from chick embryonic muscle, is a potent inhibitor of mRNA translation in vitro and contains a 4S translation inhibitory RNA species (iRNA). The iRNP particle shows similarity in size to the small nuclear ribonucleoprotein (snRNP) particles. Certain autoimmune disease patients contain antibodies directed against snRNP antigenic determinants. The possibility that iRNP may be related to the small nuclear particles was tested by immunoreactivity with monospecific autoimmune antibodies to six antigenic determinants (Sm, RNP, PM-1, SS-A (Ro), SS-B (La), and Scl-70). By Ouchterlony immunodiffusion assays, the cytoplasmic 10S iRNP did not show any immunoreactivity. Also, a more sensitive hemagglutination inhibition assay for detecting Sm and RNP antigens failed to show reactivity with the 10S iRNP. Thus, the 10S iRNP particles are distinct from the similarly sized snRNP. However, free and polysomal messenger ribonucleoprotein (mRNP) particles and polysomes also isolated from chick embryonic muscle and analyzed by Ouchterlony immunodiffusion and hemagglutination inhibition for the presence of the antigenic determinants showed reactivity to Sm and RNP autoantibodies, but were not antigenic for the other four antibodies. Some of the Sm antigenic peptides of mRNP particles and polysomes were identical to those purified from calf thymus nuclear extract, as judged by Western blot analysis. The association of Sm with free and polysomal mRNP and polysomes suggests that Sm may be involved in some cytoplasmic aspects of mRNA metabolism, in addition to a nuclear function in mRNA processing.

Animals↗