Demonstration And Identification Of Cytotoxic Antibodies And Antibodies Blocking The Cell-Mediated Antitumor Immunity Against Adenovirus Type 12 Induced Tumors

Hyperimmune mouse antisera against syngeneic adenovirus type 12 induced tumors and their 7 S and 19 S fractions of immunoglobulins obtained after combined diethylaminoethyl cellulose and Sephadex G-200 separation were tested against a rat adenovirus type 12 induced tumor by 51 Cr release technique. The same sera and their fractions were investigated with the colony inhibition technique for ability to abrogate the inhibitory effect of mouse lymph node cells specifically immunized against syngeneic adenovirus type 12 induced tumors on rat adenovirus 12 target tumor cells. It was found that (a) hyperimmune antisera from mice which had received many immunization doses were cytotoxic to rat adenovirus 12 induced tumor cells at 37° in the presence of complement; (b) the same hyperimmune antisera abrogated specifically the inhibitory effect of specifically immune mouse lymph node cells on rat adenovirus 12 tumor cells; (c) the cytotoxic activity of the hyperimmune antisera at 37° in the presence of complement was found in 19 S fractions of γ-globulins; and (d) the serum factors causing abrogation of immune lymph node cells in vitro were found in 7 S fractions of immunoglobulins

Long duration of airway but not systemic effects of inhaled formoterol in asthmatic patients.

RATIONALE: Formoterol is approved as asthma rescue medication in many countries. The exact duration of the airway vs. systemic effects of formoterol compared with another rescue medication, salbutamol, has not been evaluated. OBJECTIVE: To assess the duration of airway bronchodilatory effects vs. systemic effects of inhaled formoterol and salbutamol in asthmatic patients. METHODS: Twenty-six patients with stable and reversible asthma were given single doses of formoterol dry-powder inhaler (OxisTurbuhaler) 2x9 microg (lower dose; LD) and 6x9 microg (higher dose; HD), salbutamol (VentolinDiskhaler) 3x400 microg (LD) and 9x400 microg (HD), and placebo in a randomized, double-blind, crossover trial. Airway and systemic effects were assessed by forced expiratory volume in 1s (FEV1), serum potassium, blood pressure, corrected QT-interval (QTc), and palpitation and tremor scores. Time with clinically relevant bronchodilation (FEV1 increase 12%) without clinically relevant markers of systemic effects (serum potassium suppression 0.2 mmol/L, QTc-prolongation 20 ms, or heart rate increase 8 beats per minute) was evaluated. RESULTS: Bronchodilation was maintained for 24h with both formoterol doses and for 7-11h with salbutamol. Maximum bronchodilation and systemic effects were similar after formoterol and salbutamol, except for statistically significantly larger maximum heart rate and palpitation and tremor scores after salbutamol. Systemic responses were similarly brief for formoterol and salbutamol (7 h). CONCLUSIONS: The airway effects of inhaled formoterol are of long duration, whereas the systemic effects are of a similarly short duration as salbutamol. Thus, the time with clinically relevant bronchodilation without systemic effects is substantially longer after formoterol than after salbutamol

Studies on adenovirus type 9‐induced mammary fibroadenomas in rats and their malignant transformation

After inoculating newborn W/Fu rats with adenovirus type 9,27 of 27 females developed mammary fibroadenomas with a latency period of 14–25 weeks. No tumors were observed after inoculation with adenovirus type 5 or in males with the type 9 inoculation. After persistence of the tumors for 3–14 months, malignant transformation of the stroma resulted in different types of sarcoma in three rats: fibrosarcoma, round‐cell liposarcoma, osteosarcoma and malignant mes‐enchymoma. In another animal the stroma of a fibroadenoma was highly cellular, suggesting a transition into fibrosarcoma. Malignant transformation of the epithelial component was not observed. Tumor cells contained adenovirus type 9‐specific T‐antigen, and rats with transplanted tumors were immunized to T‐antigen. Mammary fibroadenomas without signs of malignant transformation developed in eight of nine female rats inoculated with adenovirus type 9 at an adult age. Neonatal thymectomy and total body x‐irradiation neither significantly shortened the induction time of adenovirus 9‐induced fibroadenomas nor increased the frequency of malignant transformation in females. One lipoma and one highly differentiated liposarcoma, however, appeared in two male rats. The results provide an example of the progression of a virus‐induced benign tumor into a malignant neoplasm

Cytotoxicity of Adenovirus-Antibody Aggregates: Sensitivity to Different Cell Strains, and Inhibition by Hexon Antiserum and by Complement

Adenovirus-antibody aggregates under defined conditions are cytotoxic in vitro. All members of adenovirus groups I, II, and III caused toxicity upon aggregation. The toxicity of the clusters is exerted by the virions. Toxicity is temperature dependent and may be caused by a mechanism similar to that used in viral penetration. Cells permitting direct viral penetration were all sensitive to the toxic aggregates. The toxicity seems to be related to hexon antigens on the surface of the virions since antihexon sera neutralized the toxicity. No evidence was obtained showing that pentons are required for this kind of cytotoxicity. Adenovirus types 3, 5, and 9 were used in the experiment. Cytotoxicity was estimated by the (51)Cr release assay. Complement factors could be excluded as mediators of the cytolytic reactions. Instead, complement was shown to prevent the formation of toxic aggregates or to neutralize the toxicity of preformed ones

Adenovirous type 9-induced tumorigenesis in the rat mammary gland related to sex hormonal state

Adenovirus type 9 was inoculated sc into newborn Wistar/Furth rats, divided into four groups: (1) six male rats, not treated further; (2) 11 male rats, castrated at 4 weeks of age; (3) 12 male rats, castrated at 4 weeks of age and subsequently treated repeatedly with estrogen; and (4) 12 female rats, not treated further. All of the rats in group 3 developed mammary hyperplasia and tumors (fibroadenomas and lipomas), in some cases with malignant histologic structure. Rats in group 4 developed similar mammary tumors, but with later appearance and significantly slower growth. A fifth group of rats, not virus inoculated but castrated and estrogen treated as in group 3, did not develop any demonstrable mammary lesions. The results show that the effects of the virus on the mammary gland are dependent upon an estrogenic background, which by itself cannot cause tumor development in males. It is suggested that viral DNA is incorporated into the cellular DNA in such a way that it influences the synthesis and/or activity of steroid receptors, triggering tumor development

Demonstration of two group‐specific TSTAs in adenovirus‐induced tumors

Infection of mice and rats with any one of five tested human adenovirus types belonging to groups A and B (types 3, 7, 12, 18 and 31) induced an immunity to the TSTAs of type 12 tumors as detected by the colony inhibition (CI) test. No immunity was found against an adenovirus type 1 tumor. Two adenovirus types belonging to group C (types 1 and 5) were similarly tested and found to induce a clear‐cut immunity to the adenovirus type 1 tumor but not to tumors induced by adenovirus of groups A and B. The only tested virus type of group D (type 4) did not induce any clear‐cut immunity to either adenovirus 12 tumors or the adenovirus 1 tumor. Immunization of rats with rat adenovirus 12 tumor cells induced a cellular immunity to adenovirus 12 mouse tumor cells but not to a mouse polyoma tumor. Adenovirus 1 rat tumor cells induced no such immunity. Immunization of rats with syngenic adenovirus 12 tumor cells induced a cellular immunity to adenovirus 12 rat and mouse tumors and an adenovirus 7 hamster tumor, but not to an adenovirus 1 rat tumor or BHK‐C13 control hamster cells. The result of a tumor prevention experiment is consistent with the existence of a common TSTA induced by types 7 and 12 and a different TSTA induced by type 5 virus. It is concluded that the highly oncogenic group A and the weakly oncogenic group B adeno virus types all induce a common TSTA. Another TSTA is induced by the group C viruses, while no evidence has been obtained for the existence of any TSTA induced by a group D virus type

Effect of BCG and allogeneic tumour cells on adenovirus type 12 tumorigenesis in mice

HAMSTERS and mice inoculated at birth with tumour viruses have been used in studies of the prophylactic effects of various treatments during the latent period. The incidence of primary tumours in hamsters infected at birth with SV40 is reduced if the virus is inoculated during the latent period1-3. Similar administration of adenovirus type 12 also inhibited the induction of tumours by SV404; this was taken as an indication of a cross-reaction between the tumour-specific transplantation antigens (TSTA) of SV40 and adeno 12 virus tumours. X-irradiated SV40 tumour cells which did not contain infectious virus were also effective in reducing the frequency of primary SV40 tumours when given at various times before tumour development2,5

Effect of selenium on the induction of breast fibroadenomas by adenovirus type 9 and 1,2‐dimethylhydrazine‐induced bowel carcinogenesis in rats

Selenium in its organic and inorganic forms has been shown to inhibit the development of chemically induced, spontaneous and transplanted tumors. The present investigation was performed to study the effect of selenium (4 μg per ml of drinking water) on tumorigenesis of adenovirus‐type‐9‐induced breast fibroadenomas and on 1,2‐dimethylhydrazine‐induced bowel carcinogenesis in WF rats. It was found that identical treatment with Se under identical conditions and with no obvious toxic effects on the rats (I) resulted in inhibition of DMH‐induced large‐bowel carcinogenesis; (2) facilitated induction of small‐bowel cancer by the same carcinogen in the same animals, and (3) greatly facilitated induction of breast fibroadenoma by adenovirus type 9 in the same strain of rats. The effect of Se treatment on DMH‐induced largebowel carcinogenesis confirms previous findings and proves that the opposite effect on fibroadenoma development is not due to differences in e.g. effective dose, animal strains or condition of the animals. It is not yet clear through which mechanisms Se exerts these effects