The dilemmas of immunotherapy.
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Interleukin-2↗
Biomedical subjects
J Vaage
Publications and source records attributed to J Vaage.
A survey of in vivo growth characteristics and spontaneous metastasizing potentials of C3H mouse mammary tumors.
This investigation examined the relationship between spontaneous metastasizing potential, immunogenicity and growth rate in 34 C3H/He mammary carcinomas. The main purpose of our studies was to examine the hypothesis that a tumor's metastasizing potential is affected by its immunogenicity. The tumors were studied during serial intra-mammary transplantations, starting with tissue from autochthonous, spontaneous pulmonary metastases. The results show that there was no correlation between metastasizing potential and tumor immunogenicity, and no correlation between metastasizing potential and tumor growth rate. Moreover, metastasizing potential was not related to invasive behavior, because histological examination showed that all of the metastases grew extensively within pulmonary vessels and displayed no tendency to active extravasation.
Animals↗
Late sequelae of lung contusion.
Twenty-four patients with severe lung contusion and multiple rib fractures were studied at a mean 4.9 years (range 2-9 years) after injury. All patients had been in good health before the accident. After the accident 15 (63 per cent) patients had respiratory symptoms such as dyspnoea at rest or moderate exercise (4), pain (8), cough or increased expectoration (11) and frequent bronchopulmonary infections (5). Three patients had changed their job because of respiratory disturbance. The average vital capacity, forced expiratory volume in 1 s, maximal voluntary ventilation and CO transfer factor were reduced respectively to 87, 88, 82 and 83 per cent of predicted values (P less than 0.01), while total lung capacity, residual volume and helium mixing time showed no definite changes (P greater than 0.05). Arterial blood gases at rest and at maximum exercise showed slight changes only. Maximal working capacity and ECG, as well as the ventilatory cost of moderate exercise were normal, where as the CO2 recovery time after moderate exercise was slightly increased (P less than 0.05). Overall there was a tendency towards poorer function in patients treated with artificial ventilation. Chest radiographs were normal in 10 patients (42 per cent), and moderate changes were seen in 14 patients. Diaphragmatic movements were essentially normal in all patients. Severe injury to the chest causes frequent respiratory symptoms. However, objective tests were only moderately reduced when compared with normal values. There was no unequivocal association between the subjective symptoms and the pulmonary function.
Adult↗
Functional impairment in isolated rat hearts induced by activated leukocytes: protective effect of oxygen free radical scavengers.
Ischemia-reperfusion activates polymorphonuclear leukocytes (PMN). Depletion of PMN has been shown to reduce the size of experimental myocardial infarction. We have studied whether PMN activated by phorbol myristate acetate (PMA) would depress function of the isolated rat heart, and if this effect was mediated by oxygen free radicals (OFR). Cells and/or drugs were added to the perfusate into the aortic cannula for 10 min, followed by a 30 min recovery period. Oxygen free radicals formation was verified by chemiluminescence (CL). PMA-activated PMN (n = 13) caused CL response of 27,493 +/- 5113 counts (mean +/- S.E.M.) and reduced left ventricular developed pressure (LVDP) to 30 +/- 9% and coronary flow (CF) to 49 +/- 7% of the baseline value at the end of the observation period. Addition of super-oxide dismutase (SOD) and catalase (CAT) (n = 11) reduced the CL response to 5623 +/- 806 counts, but did not influence either LVDP (36 +/- 15%) or CF (51 +/- 18%). Addition of thiourea (TU) to the activated cell suspension (n = 8) further reduced the CL response (3663 +/- 474 counts), and LVDP was 86 +/- 5% and CF was 87 +/- 3%. When TU + SOD + CAT was mixed with PMN + PMA (n = 11), the CL was almost abolished (117 +/- 21 counts) and LVDP was 73 +/- 8% and CF was 94 +/- 6%. When CF was reduced (n = 7) alike the CF reduction in the hearts receiving PMA + PMA, LVDP was not significantly changed at the end of the observation period (75 +/- 6%). Unactivated PMN (n = 8) caused minor response of LVDP and CF, similar to PMN + PMA + TU and PMN + PMA + SOD + CAT + TU. PMA alone (n = 8) was cardiotoxic and caused changes similar to PMN + PMA. This effect was not inhibited by scavengers (n = 6). The supernatant of the PMN + PMA suspension (n = 7) did not impair cardiac function, suggesting that no free PMA was available after mixing with PMN. We conclude that activated PMN in the coronary circulation depressed cardiac function and increased vascular resistance due to OFR production.
Animals↗
Increased microvascular permeability caused by toxic oxygen metabolites is partly reversed by exchanging the perfusate in isolated rat lungs.
Toxic oxygen metabolites (TOM) released from stimulated phagocytes and lung tissue have been shown to injure the pulmonary microcirculation. In the present study we evaluated microvascular injury caused by TOM in rat lungs perfused with plasma. The injury, as indicated by an increase in vascular permeability, was assessed by determining the fluid filtration rate (FFR) after paralysing the pulmonary vascular bed with papaverine (0.1 mg/ml). TOM were generated by adding xanthine oxidase (XO) (0.05-0.125 U/ml) and hypoxanthine (HX) (1 mmol/l) to the perfusate. FFR was measured before, 30 and 60 min after addition of XO and HX. The following interventions were done: 1. the H2O2-scavenger catalase, 2. substitution of the perfusate after 30 min, 3. BW 755 C, a combined lipoxygenase and cyclooxygenase inhibitor, and 4. indomethacin, a cyclooxygenase inhibitor. Addition of XO and HX caused FFR to increase from 14 +/- 4 mg/min (mean +/- s.e. mean) at the onset to 56 +/- 7 mg/min and 86 +/- 10 mg/min after 30 and 60 min, respectively. Replacing the perfusate with fresh plasma after 30 min caused a significant reduction in FFR at 60 min, from 86 +/- 11 mg/min to 58 +/- 10 mg/min. Catalase prevented the increase in FFR. Indomethacin and BW 755 C had no effect on the increase in FFR. We conclude that TOM induced a partly reversible increase in microvascular permeability of isolated rat lungs. From previous studies, the activity of XO was expected to cease after 30 min. Therefore it is suggested that secondary products of TOM propagate the lung injury. The increase in permeability was not mediated by arachidonic acid metabolites.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
Oxygen free radicals decrease survival time of isolated rat hearts.
Effects of oxygen free radicals (OFR), enzymatically generated in the coronary circulation, were studied in isolated rat hearts retrogradely perfused with Krebs-Ringer solution. Control hearts (n = 6) functioned adequately for at least 5 hours. When rat hearts (n = 6) received xanthine oxidase (XOD) and hypoxanthine (HX) in order to generate OFR, survival time was reduced to 31 +/- 0.4 min (mean +/- SEM). Infusion of XOD (n = 8) or HX (n = 5) alone also reduced cardiac survival time, to 32 +/- 6 min and 139 +/- 23 min, respectively. When allopurinol (an inhibitor of XOD) was given together with XOD (n = 6), survival time (277 +/- 30 min) was similar to the control value. The production of OFR did not result in depressed coronary flow or heart rate, but reduced the aortic pulse pressure. OFR thus can depress cardiac function and may ultimately cause cardiac arrest.
Animals↗
Reactive oxygen intermediates reduce inactivation of serotonin in isolated, perfused rat lungs.
Reactive oxygen intermediates such as free radicals have been proposed to mediate lung injury. The present work examined whether or not enzymatically generated oxygen metabolites altered serotonin clearance. Isolated, plasma-perfused rat lungs were exposed to xanthine oxidase (XO) and hypoxanthine (HX). Pulmonary arterial pressure (Ppa) and lung weight were recorded. Fulminant edema was defined as a spontaneous weight increase exceeding 500 mg. Inactivation of serotonin was determined by superfusion bioassay. XO and HX reduced serotonin inactivation from 74 +/- 3% (mean +/- SEM) to 62 +/- 2%. This reduction was inhibited by the scavenger enzymes superoxide dismutase (SOD) and catalase and by allopurinol, an inhibitor of XO. Hydrostatic edema and perfusion per se did not decrease the pulmonary clearance of serotonin. XO and HX did not significantly alter Ppa. Fulminant edema developed in four of six lungs after exposure to XO and HX compared with none in the other groups. It was concluded that reactive oxygen intermediates inhibited serotonin inactivation in isolated rat lungs.
Allopurinol↗
Myocardial reperfusion injury: an inflammatory reaction?
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Coronary Artery Bypass↗
Metastasizing potentials of mouse mammary tumors and their metastases.
This in vivo investigation determined the relative potentials of 7 C3H/He and C3Hf/He mammary tumors and their metastases to metastasize spontaneously from intramammary implants. The purpose of the studies was to examine the hypothesis that metastases derive from distinct sub-populations of cells in primary tumors which have specific inheritable characteristics that predispose the cells to form metastases. By serially transplanting, in parallel tests, tissue from autochthonous metastases and tissue from autochthonous primary tumors, the distinction of tumor-cell populations with different metastatic potentials was anticipated. However, the results of the experiments showed that primary tumors and metastases in autochthonous hosts had similar potentials for spontaneous metastasis. Moreover, the primary tumors and the metastases, transplanted as parallel lines through consecutive generations, maintained similar average metastasizing potentials. Changes in metastatic potential which occurred in 3 of the 7 tumors during serial passage appeared in nearly equal transplant generations in the parallel lines of the primary tumor and the metastases. The data suggest that the spontaneous metastases were not derived from a sub-population of cells with inheritable high metastasizing potential, but developed through stochastic events from the average tumor cells that entered the circulation.
Adenocarcinoma↗
Local interleukin 2 therapy of mouse mammary tumors of various immunogenicities.
The local and systemic therapeutic effects of multiple injections of recombinant human interleukin 2 (IL-2), at doses of 5,000 to 100,000 units each, were tested against intramammary implants of 12 syngeneic C3H mouse mammary tumors of various immunogenicities. Among 5 tumors with transplantation-type immunogenicity and with mononuclear leukocyte infiltration, 4 tumors were affected by IL-2 therapy. A fast-growing, moderately immunogenic tumor was not affected. Among 7 tumors which did not display transplantation-type immunogenicity, 4 tumors did, nevertheless, attract mononuclear leukocytes. Among these 4 tumors, the 2 slowest growing tumors were affected by IL-2 therapy. Local and systemic therapeutic effects resulted from peritumor IL-2 injections, but not from injections 2 cm from a tumor. The results indicate that the therapeutic effectiveness of IL-2 depends on the ability of a tumor to attract IL-2 responsive immune effector cells and that therapeutic effectiveness is reduced by faster tumor growth.
Animals↗
Local and systemic effects during interleukin-2 therapy of mouse mammary tumors.
The therapeutic effects of 12 daily peritumor injections of from 100 to 300,000 units of recombinant human interleukin-2 were tested against the syngeneic, immunogenic mammary carcinoma MC2 implanted s.c. into C3H/He mice. Local therapeutic effect on injected tumors was observed down to 300 units of interleukin-2 per injection. Cures of injected tumors were obtained with 1,000 units and more per injection. Systemic therapeutic effect on contralateral, uninjected tumors in treated mice was discernible at 5,000 units and more per injection. Hepatic periportal cellular swelling with mononuclear infiltration, and renal tubular edema were observed at 7,000 units or more per injection. Hepatic and renal repairs were rapid and complete with 50,000 units and less per injection. Hepatic necrosis developed above 50,000 units per injection. Deaths resulted from 100,000 units and more per injection. It is concluded that interleukin-2 can be a safe and effective therapeutic agent at a wide range of doses well below those that may be expected to have serious negative side effects.
Animals↗
Influence of the administration schedule on the therapeutic effect of interleukin-2.
The local and systemic therapeutic effects of multiple peritumoral injections of recombinant human interleukin-2 (IL-2) were tested against the syngeneic, immunogenic mammary carcinoma MC2 implanted subcutaneously into C3H/He mice. Multiple (12) low-dose injections had a greater local therapeutic effect than the same total amount of IL-2 given in 2 injections. Peri-tumoral injections were equally effective in inhibiting the growth of the injected tumors in normal and in immunized mice. The systemic therapeutic effect was manifested by the inhibition of tumors implanted contra-laterally to the injected tumors, and was only discernible in non-immunized mice.
Animals↗
Spontaneous metastasis from primary C3H mouse mammary tumors.
The normal incidence of metastasis was determined in 207 C3H/He and 42 C3Hf/He mice with spontaneous mammary tumors. The effects of early versus delayed surgical removal of the tumors on the incidence of metastasis were studied in the C3H/He mice. The presence of metastases was determined by histological examination, primarily of the lungs. The incidence of metastasis was proportional to the size the primary tumors were allowed to reach before surgery, with the highest incidence in mice not surgically cured. Tumors that developed early in the life of the mice had the greater tendency to metastasize. Immunogenic and non-immunogenic tumors occurred with similar frequency among 16 metastasizing tumors tested. Primary tumors and their metastases were equally immunogenic. All of 95 metastasizing adenocarcinomas grew extensively within pulmonary vessels with no tendency for active extravasation. In contrast, each of six metastasizing mammary sarcomas extravasated actively and probably extravasated early because intravascular growth was never observed.
Adenocarcinoma↗
Effects of liposome-entrapped doxorubicin on liver metastases of mouse colon carcinomas 26 and 38.
The effects of doxorubicin (DOX) and DOX entrapped in standardized liposomes [mean diameter, 0.15 micron; (DOX-Lip)] on the survival of mice bearing liver metastases of mouse colon carcinoma CT38LD (C57BL/6J mice) or CT26 (BALB/c mice) were investigated. In vitro cultured CT38LD cells were more sensitive to DOX than CT26. In vivo DOX and DOX-Lip, administered iv 10 mg/kg weekly to a maximum of five injections, increased the life-spans of mice bearing CT38LD liver metastases 32% (P less than .05) and 64% (P less than .05), respectively. DOX-Lip was more effective than DOX in prolonging survival (P less than .05). Free DOX did not significantly increase the life-spans of mice bearing CT26 liver metastases (P greater than .5), whereas DOX-Lip increased the life-spans 35% (P less than .05). The results suggest that liposomal delivery of agents to the liver can enhance therapeutic activity and could be used as an arm of protocols for adjuvant therapy of liver metastases.
Animals↗
Mammary tumorigenesis and tumor morphology in four C3H sublines with or without exogenous mammary tumor virus.
Mammary tumorigenesis was surveyed in retired breeding females in four sublines of the C3H strain: in standard milk-transmitted early oncogenic mouse mammary tumor virus (MMTV)-infected C3H/He and C3H/Ki mice, and in standard milk-transmitted early oncogenic MMTV free C3Hf/He and C3Hf/Ki mice. All of 58 C3H/Ki mice and 98% (306 of 309) of the C3H/He mice developed palpable mammary tumors at average ages of 276 and 284 days, respectively. Thirty-one % (47 of 152) of the C3Hf/Ki mice and 77% (168 of 218) of the C3Hf/He mice developed palpable mammary tumors at average ages of 798 and 757 days, respectively. The mammary tumors removed from C3H/He and C3H/Ki mice were all adenocarcinomas of epithelial origin, and all contained MMTV. The mammary tumors removed from C3Hf/He and C3Hf/Ki mice were either adenocarcinomas or sarcomas. The carcinomas were of epithelial origin and all expressed the late oncogenic endogenous MMTV. The sarcomas were of histiocyte or fibrocyte origin and contained neither virus particles nor MMTV antigenic markers. It is concluded that exogenous standard milk-transmitted oncogenic MMTV oncogenesis in C3H mice is not modified by host genetic factors. In contrast, late oncogenic endogenous MMTV oncogenesis is influenced both by host genetic control of the expression of the late oncogenic MMTV provirus and by the location of the proviral genes in the germline DNA.
Adenocarcinoma↗
Prognostic factors in blunt chest trauma. Analysis of 652 cases.
All records of 652 patients treated for blunt chest trauma at Ullevål Hospital, Surgical Department 3, during the period 1973-1981 were analyzed for factors predictive of prognosis. Mortality for the whole group was 7.7%. Age, blood pressure on admission, the number of fractured ribs, the need for blood transfusions and the need for artificial ventilation were the most important predictors of prognosis. Mortality increased significantly when at least two extrathoracic injuries were present (22.6%). Intrathoracic injuries did not increase mortality in cases of isolated thoracic injuries. Combined thoraco-abdominal injuries carried a high mortality (25%), especially when the injury had resulted in rupture of the diaphragm (57.1%). There were no sex-related differences. The majority of the patients could be handled adequately with oxygen support, chest drainage, physiotherapy and pain relief. The incidence of bronchial infection, septicaemia and hypercoagulability was significantly higher for patients on ventilators than for patients breathing spontaneously. Mortality increased when septicaemia or bronchial infection was present (30.8 and 21.9%, respectively). The injury severity score (ISS) for the 50 patients who died in the hospital was similar to that of some other reports.
Abdominal Injuries↗
Immunospecific eosinophil infiltration of a mouse mammary carcinoma.
In histological examinations of intramammary implants of mammary carcinoma MC2, it was found that eosinophils began appearing at the implants in numbers well above normal after 3 to 4 wk of immunization. Massive invasion of tumor tissue by eosinophils did not become evident until the mice were strongly immunized, after at least 5 wk. Eosinophilia developed after 5 wk of immunization, with blood counts reaching an average high of 530 per mm3 (5.8%) compared to a normal count of 90 to 100 per mm3 (1.1%). By implanting MC2 and a second, immunologically distinct mammary carcinoma into the same mice, it was shown that the attraction of eosinophils to MC2 was immunospecific. By passive transfer of immune plasma, it was shown that the local eosinophil response was promoted by specific immune plasma factors.
Animals↗
Mammary tumor immune enhancement in mice by local hyperemia.
The mammary carcinoma MC2 causes a strong immune response in syngeneic, female C3H/He mice, and growing s.c. implants will regress spontaneously in about 20% of untreated hosts. Hyperemia is part of the local immune reaction against MC2 implants. An accelerated local hyperemic reaction at MC2 implants could be created in normal mice by the i.p. injection of blood or plasma from MC2 hosts at an early (Day 17) stage of immunization. In these mice given injections, MC2 growth was enhanced, and the incidence of spontaneous regressions was reduced. Local hyperemia caused by heat also promoted the growth of MC2 implants. In contrast, injections of blood or plasma from MC2 hosts at an advanced (Day 35) stage of immunization reduced the growth of MC2 implants and increased the incidence of their spontaneous regression. It is concluded that increased blood supply to a tumor in the absence of adequate systemic immunity favors tumor growth, and that this represents a new, additional mechanism in the immune enhancement phenomenon.
Animals↗