Biomedical subjects

G Forni

Publications and source records attributed to G Forni.

At least 73 records · Page 4Linked to original sources

PubMed1996

Concomitant factors of decompensation in chronic heart failure.

The concomitant factors implicated in 328 nonfatal decompensations of 304 patients with congestive heart failure were: arrhythmias in 24%, infections in 23%, poor compliance in 15%, angina in 14%, iatrogenic factors in 10%, and other causes in 5% of cases. New York Heart Association class and right atrial pressure significantly related to the occurrence of decompensation. Poor compliance and angina were unpredictable, infection was related to pulmonary wedge pressure, iatrogenic factors were predicted by the more advanced functional classes, whereas arrhythmias were more frequent in patients with renal failure.

Chronic Disease↗

PubMed1996

Interleukin 12 potentiates the curative effect of a vaccine based on interleukin 2-transduced tumor cells.

The purpose of these studies was to determine whether systemic administration of recombinant interleukin 12 (rIL-12) is able to potentiate an initial, but insufficient T-cell antitumor response. Mice challenged with carcinoma cells engineered to release interleukin 2 (IL-2) and displaying such a response received single or multiple i.p. injections of rIL-12. This combination of systemic rIL-12 and local IL-2 increased the percentage of mice that rejected two different IL-2 gene-transduced tumors. In another set of experiments more closely resembling a clinical situation, IL-2 gene-transduced tumors were used as vaccines in an attempt to cure mice bearing wild-type parental tumors. The combination of these vaccines with systemic rIL-12 cured mice more effectively than rIL-12 and IL-2 gene-transduced tumor vaccines alone.

Adenocarcinoma↗

PubMed1996

Heterogeneous effects of B7-1 and B7-2 in the induction of both protective and therapeutic anti-tumor immunity against different mouse tumors.

Experimental mouse tumors are classified as intrinsically immunogenic when, after a single injection into syngeneic mice as nonreplicating cell vaccines, they elicit a protective immune response against a subsequent lethal challenge. Tumors that do not retain this residual immunogenicity are defined as poorly immunogenic or nonimmunogenic. The expression of the B7-1 co-stimulatory molecule on immunogenic tumors can further increase their capacity to induce a T cell-dependent anti-tumor immunity, whereas it has limited effects on nonimmunogenic tumors. Recently, B7-2, a second molecule with an apparently similar co-stimulatory activity, has been cloned. In this report, we compare the efficiency of nonreplicating cells from one immunogenic and two nonimmunogenic mouse tumors transfected with B7-1 or B7-2 in the induction of protective and curative anti-tumor immunity. Immunogenic lymphoma cells expressing B7-1 or B7-2 are equally effective in both protecting against a subsequent challenge and curing established tumors. By contrast, nonimmunogenic adenocarcinoma and melanoma cells expressing B7-2 provide superior protective immunity, and only B7-2+ adenocarcinoma cells induce an efficient curative immunity. CD8+ and polymorphonuclear cells, but not CD4+ T cells, are critically involved in the rejection of the adenocarcinoma elicited by both B7-1+ and B7-2+ vaccines. These data indicate that B7-1 and B7-2 are not redundant co-stimulatory molecules and that, in these experimental models, B7-2 is superior to B7-1 in the induction of an efficient immunity when the immunogenicity of a tumor is a limiting factor.

Adenocarcinoma↗

PubMed1996

Immunotherapy I: Cyclosine gene transfer strategies.

The cytokine approach to gene therapy of cancer stems from early studies of direct, repeated injection of recombinant cytokines at the tumor site, and extension of the bystander effect that enables a few cytokine gene transduced cells in a tumor to bring about its total destruction. This effect can be extended through the immune system, since cytokine-activated regression of a small mass of tumor cells can afford systemic protection. Transduced cells used as a vaccine provide a local concentration of both cytokine and tumor antigens. Cytokines sustain antigen uptake and presentation by increasing the immunogenic potential of the environment through the recruitment of antigen presenting cells and leukocytes, and activation of a cascade of events which amplify and tone up the efficacy of a vaccine. The promises and difficulties of this approach are discussed by considering what is still missing from experimental studies and what can best be done as soon as possible in animals and humans to reach compelling conclusions.

Animals↗

PubMed1996

Mitral flow velocity changes after 6 months of optimized therapy provide important hemodynamic and prognostic information in patients with chronic heart failure.

Transmitral flow velocity patterns evaluated by Doppler echocardiography provide important hemodynamic and prognostic information in various cardiac conditions. However, these patterns may change over time, and so far the hemodynamic and prognostic significance of these changes has not been established. Accordingly, we performed this study to determine the hemodynamic and prognostic value of changes in transmitral flow velocity patterns after 6 months of optimized medical treatment in patients with chronic heart failure due to ischemic or nonischemic dilated cardiomyopathy. Ninety-eight consecutive patients with chronic heart failure underwent a clinical examination, a cardiopulmonary exercise test, and simultaneous Doppler echocardiographic and hemodynamic studies at baseline and after 6 months, patients were followed up for 12 +/- 7 months. Cardiac death and heart transplantation while patients were in critical condition were considered events. A restrictive pattern was defined by an early-to-late peak diastolic velocity ratio > 1 and an early diastolic deceleration time < or = 130 msec. Patients were grouped according to their mitral flow pattern at baseline and its changes after chronic optimized therapy. No significant changes in clinical, ergometric, and hemodynamic variables were found after 6 months in the 49 patients who had a persistent restrictive transmitral flow pattern or the 24 patients who had a persistent nonrestrictive transmitral flow pattern. In the 19 patients who had a restrictive pattern at baseline that reverted into a nonrestrictive pattern, this change was accompanied by a highly significant reduction in pulmonary wedge pressure (from 25 +/- 7 mm Hg to 11 +/- 3 mm Hg) and by an increase in exercise capacity, whereas in the 6 patients who had a nonrestrictive pattern that became restrictive, hemodynamic features markedly deteriorated. Seventeen of the 21 events occurred in the 49 patients (event rate 35%) with a persistent restrictive pattern, whereas the event rate was much lower in the 19 patients with a reversible restrictive pattern (5%) and in the 24 patients with a persistent nonrestrictive pattern (4%). Two (33%) of the 6 patients in whom a restrictive pattern developed had events. Cox analysis revealed that a restrictive transmitral flow pattern (p = 0.0068) and peak rate of oxygen consumption (p = 0.0056) detected at the late examination were significantly related to cardiac events. These results show that in patients with chronic heart failure, changes in transmitral flow patterns after chronic optimized therapy are correlated with changes in pulmonary wedge pressure, are accompanied by changes in functional capacity, and provide relevant independent prognostic information.

Blood Flow Velocity↗

PubMed1996

Therapy of murine mammary carcinoma metastasis with interferon gamma and MHC gene-transduced tumour cells.

Gene-transfected tumour cells were used to cure mice bearing lung metastases by the parental, non-transduced mammary adenocarcinoma (TSA-pc). Repeated subcutaneous (s.c.) administrations of mitomycin C (MitC)-treated interferon gamma (IFN-gamma) transfectants induced a 90% inhibition in the number of lung metastases. Therapeutic effect required an intact T-cell response, as shown by the lack of efficacy in nude mice. Autocrine stimulation by IFN-gamma induces specific modifications in the phenotype of transfectants that acquire a high metastatic ability and show a high expression of IFN-responsive genes; these two features were exploited to design two experimental protocols to obtain an improvement of the therapeutic effect. The increased metastatic ability of IFN-gamma transfectants was used to deliver IFN-gamma selectively to the lungs of mice bearing TSA-pc pulmonary metastases. A significant therapeutic effect was obtained when TSA-pc experimental metastases were treated by repeated intravenous (i.v.) injections of MitC IFN-gamma transfectants. Since i.v. administrations of IFN-gamma transfectants did not induce immune memory, the therapeutical effect appeared to depend on the inflammatory-like response activated by local IFN release. To exploit the autocrine stimulation of IFN-sensitive genes an IFN-gamma transfectant clone was subjected to a second transfection with an allogeneic class I MHC gene (H-2K(b) or H-2D(h)). IFN-gamma plus MHC double transfectants maintained IFN-gamma release, showed a very high expression of the MHC gene products, stimulated both macrophages and T cells, and were less tumorigenic in immunocompetent mice than the parent IFN-gamma clone. Therapeutic efficacy of double transfectant IFN-gamma plus H-2D(b) cells against TSA-pc was superior to single transfectants, showing that the reaction elicited by genetically engineered cells can be selectively tuned to increase therapeutic efficacy.

Adenocarcinoma↗

PubMed1996

Systemic thromboembolism in chronic heart failure. A prospective study in 406 patients.

In patients with heart failure the risk of systemic thrombo-embolism and the benefit of anticoagulation are uncertain. To assess the incidence of systemic thromboembolism and the factors associated with an increased risk, 406 consecutive patients with chronic heart failure were prospectively investigated. Their left ventricular ejection fraction was 23 +/- 8%, pulmonary wedge pressure 19 +/- 10 mmHg and cardiac index 2.3 +/- 1.41. min-1.m-2 of body surface area. Two hundred patients were in NYHA functional class III-IV. Two hundred and thirty-two patients were receiving oral anticoagulants. Over a follow-up period of 16 +/- 11 months, thromboembolism occurred in 11 patients (2.7%), seven of whom were on anticoagulants. Among clinical, echocardiographic and haemodynamic variables, atrial fibrillation, more severe haemodynamic impairment and low exercise capacity were associated with increased thromboembolic risk. No echocardiographic findings, including the presence of intracavitary thrombi, either at baseline or during follow-up, were related to subsequent thromboembolic events. The rate of embolism did not differ in patients receiving anticoagulants (4%) compared with those who did not receive anticoagulants (1%). No major bleeding occurred during follow-up. Thus, in patients with chronic heart failure and sinus rhythm the incidence of systemic thromboembolism is low regardless of anticoagulant treatment. Atrial fibrillation, particularly when associated with low cardiac index, identifies a subgroup of patients at high risk of events. In this subgroup, a moderate-intensity anticoagulant regimen provides unsatisfactory protection against thromboembolism.

Adult↗

PubMed1996

Treatment of oral cavity and oropharynx squamous cell carcinoma with perilymphatic interleukin-2: clinical and pathologic correlations.

We describe the correlations between the clinical and histologic findings in an initial series of 60 patients with T2-4, N0-3, M0 squamous cell carcinoma (SCC) of the oral cavity or oropharynx enrolled in a randomized trial set up to evaluate whether the disease-free interval and survival are extended when perilymphatic injections of recombinant interleukin-2 (rIL-2) are combined with routine surgery and radiotherapy. Twenty-nine patients were operated on only (controls). The other 31 received two daily injections of 2,500 U rIL-2, one near the mastoid process on the same side as the tumor and the other under the chin, for 10 days before surgery, and further injections on the nonoperated-on side on a monthly basis for 1 year starting 4 weeks after surgery (or radiotherapy, where necessary) in an effort to upregulate the immune system and delay recurrence. Their surgical specimens displayed a significantly greater inflammatory reaction, larger areas of necrosis, and more intense sclerosis. The inflammatory tumor infiltration consisted of eosinophils, plasma cells, and CD25+ and human leukocyte antigen (HLA)-DR+ lymphocytes. However, no correlations were apparent with regard to the intensity of necrosis, eosinophil infiltration, and the number of DR+ cells and the clinical outcome. By contrast, the correlation between CD25+ cells and a significantly longer disease-free survival suggests that induction of T-cell reactivity, and perhaps specific immunity, is the only important aspect of rIL-2-induced antitumor reactivity.

Adult↗

PubMed1996

Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-alpha, IFN-gamma, and TNF-alpha.

Impressive inhibition of tumor growth has been observed after transduction of cytokine genes into tumor cells. Secreted cytokines do not affect the proliferation of a tumor directly but activate a host immune reaction strong enough to overcome its oncogenic capacity. However, the reaction mechanisms activated are difficult to interpret; because these mechanisms have been derived from experiments with different tumors, comparisons are hindered. To compare the reactive mechanisms induced by each cytokine, BALB/c mice were challenged with the parental cells of the syngeneic spontaneous mammary adenocarcinoma TSA, or with TSA cells engineered to release IL2, IL4, IL7, IL10, IFN alpha, IFN gamma, and TNF alpha, and the tumor growth area was studied histologically, ultrastructurally, and immunohistochemically. These observations were integrated with data on the growth and rejection patterns of TSA cells in mice depleted of natural killer (NK) cells, granulocytes, CD4+, or CD8+ lymphocytes. The rejection of TSA-IL2 and TSA-TNF alpha cells was associated with the massive presence of neutrophils, that of TSA-IL4 and TSA-IL7 cells with neutrophils and very small areas of colliquative necrosis, and that of TSA-IFN alpha and TSA-IL10 cells with extensive areas of ischemic-coagulative necrosis and some neutrophils. TSA-IFN gamma cells displayed a delay in growth, but were not rejected. Their growth areas comprised necrotic zones of ischemic necrosis devoid of neutrophils. The selective depletion experiments demonstrated that rejection of engineered TSA cells depends on several leukocyte populations. The weight of each population varied with the secreted cytokine, although neutrophils and CD8+ lymphocytes constantly played the major role. Employment of the same tumor line engineered with the genes of different cytokines showed that each cytokine evokes a distinct reaction and that tumor inhibition results from a complex mechanism in which neutrophils and CD8+ lymphocytes and ischemic necrosis are of primary importance.

Adenocarcinoma↗

PubMed1996

Adriamycin-induced proteinuria in nude mice: an immune-system-mediated toxic effect.

BACKGROUND: The renal minimal lesion disease induced in rats by adriamycin (ADR) is generally thought to be consequent to a direct cytotoxic effect of this drug on glomerular epithelial cells. Only recently an altered synthesis of mediators, including reactive oxygen species and monocyte-macrophage cytokines, has been hypothesized. METHODS: A mouse strain (nude) bearing a congenital thymic aplasia is a suitable experimental animal to evaluate the role of immune reactions in the development of the ADR nephropathy, provided mouse susceptibility to its toxic effect. Therefore, experimental mice were divided into three groups (G) each receiving adriamycin 7.5 mg/kg b.w.: GA (15 heterozygous nu/O mice with normal immune system); GB (15 homozygous nu/nu athymic mice); GC (15 homozygous nu/nu mice which were also splenectomized, irradiated, and treated with anti-asialo Gm1 antibody to abolish NK and decrease macrophage activity). All animals were maintained under pathogen-free conditions. Urinary proteins, albumin and TNF-alpha excretion were measured. RESULTS: After 14 days the proteinuria was 43.8+/-1.7 microg/min in GA, 30.2+/-2.9 microg/min in GB (P<0.05) and 12.2+/-2.8 microg/min in GC (GA vs GC, P<0.0001; GB vs GC, P<0.05). Albuminuria gave a similar profile. TNG-alpha urinary excretion was significantly higher in GA (17.3+/-3.2 mU/min) than in GB (5+/-0.6 mU/min, P<0.001) and GC (3.2+/-0.9 mU/min, P<0.001). A significant correlation was found in GA between urinary TNF-alpha and protein losses (r2=0.63 P<0.0001). Kidney tissue homogenates failed to show in each experimental group any evidence of mRNA encoding for TNF-alpha, which was detectable in peripheral mononuclear cells from GA and GB, but undetectable in GC mice. Segmental effacements of glomerular epithelial cell foot process were observed by electron-microscopy in GA only, while they were minimal in GB and absent in GC. Iron colloidal staining for anionic sites on frozen sections always showed a normal pattern. CONCLUSIONS: Nude mice bearing cellular immunity deficiency are protected from proteinuria following ADR toxicity. An impaired synthesis and release of lymphomonocyte mediators including TNF-alpha could be envisaged.

Animals↗

PubMed1996

Marigenol-concentrates comprising Taxol and/or Taxan esters as active substances.

Marigen is a Swiss Research Company based in Riehen (Canton of Basle). It has developed and tested a Solubilization System for its phytosteryl ester compounds having antitumor and antiviral/virucidal activity. By formulating spontaneously dispersible concentrates, which comprise such compounds, it is now possible to produce thermodynamically stable, aqueous ultramicroemulsions which achieve outstanding bioavailability and bio-reactivity for the active principles comprised in these Marigenol-Concen-trates. As a consequence, unwanted side-effects are drastically reduced in therapeutical use or even completely absent, and the economy of the system permits a remarkable optimization of the dose-efficacy relationship and hence also of drug safety.

Alkaloids↗

PubMed1995

5-Fluorocytosine-induced eradication of murine adenocarcinomas engineered to express the cytosine deaminase suicide gene requires host immune competence and leaves an efficient memory.

The nonmammalian cytosine deaminase (CD) enzyme converts the nontoxic prodrug 5-fluorocytosine (5-FC) to the toxic metabolite 5-fluorouracil. Parental cells of a mammary adenocarcinoma (TSA-pc) of BALB/c mice were transfected with the CD gene (TSA-CD), and the ability of 5-FC to hamper their growth was evaluated. A quantity amounting to 0.5 mg of 5-FC/0.3 ml of medium inhibits the proliferation of TSA-CD cells, but not that of TSA-pc, nor that of TSA-pc transfected with neomycin-resistance gene only (TSA-neo). In BALB/c mice, 800 mg 5-FC/kg of body weight injected daily i.p. for 30 days causes total regression of incipient (1-day-old), and established (3- and 7-day-old) TSA-CD tumors, and of 3-day-old experimental lung metastases, but does not impair TSA-pc nor TSA-neo cell growth. Because in CD8+ T lymphocyte- and granulocyte-depleted mice 5-FC no longer impairs TSA-CD growth, immune mechanisms appear to play an important role in this regression. Following, regression, all mice are resistant to subsequent s.c. or i.v. lethal challenges with TSA-pc. The induction of this immune memory is dependent on CD4+ lymphocytes, whereas its effector phase depends on both CD4+ and CD8+ lymphocytes. The memory elicited in tumor-bearing mice by the 5-FC-dependent regression of TSA-CD tumors cures a significant number of mice with 4-day-old TSA-pc metastases, but does not impair the growth of 4-day-old solid s.c. tumors. The reliability of this regression and the subsequent establishment of an efficient immune memory against poorly immunogenic TSA-pc offer the prospect that CD-transduced tumor cells and 5-FC can be used as components of a live antitumor vaccine.

Adenocarcinoma↗

PubMed1995

Co-expression of B7-1 and ICAM-1 on tumors is required for rejection and the establishment of a memory response.

Although the transfection of B7-1 cDNA into a few mouse tumor cell lines can induce anti-tumor T cell immunity, its expression alone is ineffective in many other tumor cell lines tested. We were interested to study what factors limit B7-1 co-stimulatory activity, and decided to investigate whether B7-1 requires the cooperation of ICAM-1 to provide the minimal co-stimulatory signal for establishing an efficient anti-tumor immunity. We show that the transfection of B7-1 cDNA into three ICAM-1+ (plasmocytoma J558L, T lymphomas EL-4 and RMA), but not into two ICAM-1- tumors cell lines (adenocarcinoma TS/A and melanoma B16.F1), is sufficient to induce their complete rejection in syngeneic mice. The expression of ICAM-1 is necessary for the rejection of the B7 expressing tumors, since the primary response elicited by B7-1+ EL-4 and RMA clones expressing reduced levels of ICAM-1 is severely reduced. Furthermore, super-transfection of ICAM-1 cDNA into B7-1+ adenocarcinoma and melanoma clones optimizes their primary rejection. Histologic examination of transfected tumors reveals that B7-1 and ICAM-1 exert a potent pro-inflammatory activity. The intra-tumor infiltration is composed of both eosinophils and lymphomonocytes, and is already massive 5 days after the tumor challenge. The primary rejection of the B7-1+ ICAM-1+ tumors depends critically on CD8+ T cells, natural killer cells and granulocytes, but is independent of CD4+ T cells. Remarkably, in addition to its effects on the early phases of the immune response, the co-expression of ICAM-1 and B7-1 on tumors is also necessary for the efficient induction of a memory response. In fact, only the primary challenge with B7-1+, ICAM-1+ tumor cells protects the majority of the mice from a second injection of parental tumor cells. Collectively, our findings indicate that B7-1 and ICAM-1 are fundamental components for triggering the primary rejection of tumors and establishing a protective memory response. These findings may help to define new strategies for the rational application of co-stimulation in tumor immunotherapy.

Adenocarcinoma↗

PubMed1995

Transduction of genes coding for a histocompatibility (MHC) antigen and for its physiological inducer interferon-gamma in the same cell: efficient MHC expression and inhibition of tumor and metastasis growth.

The mouse mammary carcinoma TS/A, of BALB/c (H-2d) origin, was transfected with the murine interferon-gamma (IFN-gamma) gene (Int. J. Cancer 55: 320, 1993). We used IFN-gamma transfectants as recipients for a second round of transfections with murine allogeneic class I histocompatibility (H-2b) genes that are modulated by IFN. Transfectants with either gene alone, as well as parent TS/A cells (TS/A-pc), were used as controls. Only double transfectants expressed high levels of the allogeneic H-2b genes, while in H-2b single transfectants the expression was very low (but was induced by treatment with exogenous IFN-gamma). The tumorigenic potential of IFN-gamma or H-2b single transfectants was reduced in comparison to TS/A-pc. IFN-gamma+H-2Kb double transfectants were almost nontumorigenic, while IFN-gamma+H-2Db clones gave rise to tumors in about one-half of mice. The experimental metastatic ability of all IFN-gamma+H-2b double transfectants was very low. IFN-gamma single transfectants were known to induce a strong macrophage response in the host. The expression of allogeneic H-2 antigens added a T-lymphocyte-mediated response that accounted for the lower tumorigenicity of double transfectants. These results show that it is possible to steer the immune response evoked by tumor cells for therapeutic purposes. Moreover, the high H-2 expression obtained in IFN-gamma+H-2b double transfectants suggests that single IFN-gamma transfectants are ideal recipients for all IFN-sensitive genes. This approach can be used also for other general-purpose inducers of gene expression.

Animals↗

PubMed1995

Cardiac and vascular sources of peripheral thromboembolism in patients with atrial fibrillation. A combined transesophageal and vascular ultrasonographic study.

Atrial fibrillation is associated with an increased risk of peripheral thromboembolism. Although emboli arising from the left atrium are the most probable causes of peripheral ischemic events, coexistent vascular mechanisms may play a role in the genesis of thromboembolism. To assess the prevalence and the relative role of cardiac and vascular sources of thromboembolism in patients with atrial fibrillation 101 consecutive patients with (group 1: 47 patients) and without (group 2: 54 patients) recent thromboembolism were studied by transesophageal echocardiography and ultrasound duplex scanning of carotid arteries. Left atrial thrombosis was found in 19 (40%) group 1 patients and in 3 (5%) group 2 patients. Left atrial thrombosis and/or spontaneous echocardiographic contrast were significantly more frequent in group 1 patients than in group 2 (70% vs 20%, p < 0.001). Stepwise regression analysis revealed that they were the only independent predictors of thromboembolism (p = 0.018, p = 0.0003 respectively). Among clinical and transthoracic echocardiographic variables, left atrial diameter (p = 0.022), rheumatic mitral stenosis (p = 0.0058) and absence of significant mitral regurgitation (p = 0.027) emerged as independent predictors of left atrial thrombosis and/or spontaneous echocardiographic contrast. When transesophageal parameters were also entered into the analysis, the only independent predictor was low blood flow velocity within the left atrial appendage (p = 0.0001). Vascular sources (obstructive carotid arteries plaques, non-obstructive ulcerated carotid plaques and thoracic aortic atherosclerotic debris) were found in 30.6% of patients. Their prevalence was not significantly different in the two groups (34% in group 1, 27% in group 2). Vascular and cardiac sources coexisted in 23% of patients with thromboembolism. Seven of the 10 patients with more severe vascular lesions (i.e., obstructive carotid artery lesions or pedunculated mobile aortic debris) were from group 1 and 5 of them had negative cardiac results. In conclusion, these results indicate that a cardioembolic mechanism due to blood stasis within the left atrium is involved in most of the atrial fibrillation-related thromboembolic events. In patients with atrial fibrillation vascular sources are not infrequent and may be involved in the genesis of ischemic events in some patients. Transesophageal echocardiography may be useful in identifying subgroups of patients with atrial fibrillation who are at high thromboembolic risk.

Adult↗

PubMed1995

Molecular approaches to cancer immunotherapy.

The use of cytokines and costimulatory molecule gene-engineered tumor cells to enhance tumor immunogenicity and elicit curative responses against established tumors and tumor recurrences has become an attractive prospect. The immunotherapy data obtained in many experimental tumor systems using these engineered cells are reviewed here to provide a realistic assessment of the potential and limits of this technique.

Animals↗

PubMed1994

An efficient Th2-type memory follows CD8+ lymphocyte-driven and eosinophil-mediated rejection of a spontaneous mouse mammary adenocarcinoma engineered to release IL-4.

A retroviral infection was used to introduce the cDNA coding for mouse IL-4 into the parental cells of a spontaneous adenocarcinoma of BALB/c mice (TS/A-pc). Four clones releasing between 5 to 40 U of IL-4 (10(5) cells) in 48 h culture were selected. The secretion of IL-4 does not affect their in vitro growth, whereas their ability to form tumor in vivo inversely correlates with the amount of IL-4 secreted. Although morphologic observation suggested that the rejection of clone D5.40 cells (releasing 40 U of IL-4) depends on eosinophil cytolysis, lymphocyte depletion experiments showed that this required CD8+ lymphocyte guidance. Mice that had rejected D5.40 cells were immune to a subsequent challenge with TS/A-pc. This memory rests on the interaction between noncytotoxic lymphocytes, eosinophils, and IgG1 and IgE anti-TS/A Abs. Comparison of these memory mechanisms with those elicited by IL-2 gene-transduced TS/A cells shows that the kind of cytokine released by the tumor cells determines the type of response. This Th2 memory seems to be more efficient in protecting against a subsequent challenge of TS/A-pc than the Th1-type memory elicited by IL-2 gene-transduced TS/A cells.

Adenocarcinoma↗

PubMed1994

IFN-alpha 1 gene expression into a metastatic murine adenocarcinoma (TS/A) results in CD8+ T cell-mediated tumor rejection and development of antitumor immunity. Comparative studies with IFN-gamma-producing TS/A cells.

Cells from a spontaneous, invasive, and metastasizing mouse mammary adenocarcinoma (TS/A-pc) were transfected with a retroviral vector containing the mouse IFN-alpha 1 gene. TS/A clones secreting varying amounts of IFN-alpha 1 were isolated and their tumorigenicity was evaluated after s.c. or i.v. injection into immunocompetent BALB/c mice. Almost all of the IFN-alpha-secreting TS/A clones failed to grow in a high percentage of mice or formed small tumors after a long latency time, whereas TS/A-pc or transfection control cells always grew into large s.c. tumors. Rejection was mainly mediated by CD8+ T lymphocytes and partially by polymorphonuclear cells, as demonstrated by selective immunosuppression experiments and histologic and ultrastructural data. After rejection, a significant portion of mice displayed an immune resistance to the subsequent challenge with TS/A-pc. When the metastatic ability of IFN-alpha-secreting clones was compared with that of previously characterized IFN-gamma-secreting TS/A clones, it was found that the expression of IFN-alpha into TS/A tumor cells resulted in a potent inhibition of metastases formation, whereas IFN-gamma expression either did not affect or even enhanced the metastatic behavior of TS/A cells. These results provide strong evidence for the usefulness of IFN-alpha-producing tumor cells for the development of gene therapy strategies and vaccines against metastatic tumors.

Adenocarcinoma↗