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F Cavallo

Publications and source records attributed to F Cavallo.

At least 55 records · Page 3Linked to original sources
PubMed1995

Local release of IL-10 by transfected mouse mammary adenocarcinoma cells does not suppress but enhances antitumor reaction and elicits a strong cytotoxic lymphocyte and antibody-dependent immune memory.

The cDNA coding for mouse IL-10 (mIL-10) was transduced into the parental cells of a spontaneous adenocarcinoma of BALB/c mice (TSA-pc), and clones secreting small, medium, and large quantities of IL-10 were selected. In vivo, both low and high producer clones do not display an enhanced ability to grow in H-2 and non-H-2 incompatible mice. Instead, the intensity of their rejection increases in function of the amount of mIL-10 released. After an initial growth period in syngeneic mice, high producer clones undergo complete rejection due to the combined action of CD8+ lymphocytes, NK cells, and neutrophils. After this rejection, mice are immune to a subsequent challenge with TSA-pc. This memory rests on a strong lytic activity of CD8+ CTL and granulocytes. Following the rejection, mice also develop anti-TSA Ab that guide the granulocytes in TSA-pc memory reaction. A direct comparison shows that although TSA clones engineered to release IL-2 activate CTL and no anti-TSA Ab, those engineered to release IL-4 activate a strong Ab response but not CTL. The kind of cytokine released by the tumors appears to determine the type of response. However, IL-10 high producer cells do not deviate the immune memory, neither toward a Th1 nor a Th2. Both the CTL activity and the Ab responses induced by IL-10 high producer cells are the strongest so far observed in the TSA system.

Adenocarcinoma↗
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

Systemic effects of cytokines released by gene-transduced tumor cells: marked hyperplasia induced in small bowel by gamma-interferon transfectants through host lymphocytes.

Cells transduced with cytokine genes are currently used to enhance the anti-tumor and immunomodulatory effects of these molecules in cancer therapy. The sustained release of cytokine thus obtained can perturb many homeostatic systems of the host. We have previously shown that the murine mammary adenocarcinoma TS/A transfected with the murine gamma-interferon (IFN-gamma) gene stimulates a strong immune response that impairs tumor growth. Mice bearing tiny tumors have serum IFN-gamma levels constantly exceeding 100 IU/ml. Therefore, we asked which systemic effects can be triggered in mice by such transfectants. BALB/c mice bearing tumors produced by clone 16.6000 cells (which release 6,000 IU/ml of IFN-gamma in culture) were compared to normal mice and to mice with tumors produced by parent cells transfected with the neomycin resistance gene (NEO cells, no IFN-gamma release). Histological studies revealed a marked hyperplasia of small bowel in mice bearing 16.6000 tumors; the villi and crypts of these mice were > 1.5 times longer than those of normal mice and of mice bearing NEO tumors. In vivo administration of bromodeoxyuridine evidenced a 2.5-3 times increase in the proliferative score of the intestinal crypts of mice bearing 16.6000 tumors compared to control mice. No intestinal alterations were observed in nude mice bearing 16.6000 tumors. T lymphocytes thus appear to play a causal role in this phenomenon.

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

Moderate alcohol consumption and spontaneous abortion.

A prospective study was carried out on 546 women interviewed during pregnancy about their drinking habits, in order to evaluate the association between alcohol consumption during pregnancy and spontaneous abortion. Pregnancy outcome (normal or abortion) was analysed as a dependent variable in a multivariate model where different levels of drinking were taken into consideration as independent-effect variables. A significant increase in the risk of abortion was observed in the 30+ age category and in the higher parity category; no significant trend was evidenced for alcoholic variables, even after controlling for the other potentially confounding variables. The possible underestimation of alcohol consumption, due to reluctance in declaring real consumption by the women interviewed, is discussed. It is concluded that, on the basis of these and other data reported in the literature, a low level of alcohol consumption during pregnancy does not appear to be a significant risk for abortion.

Abortion, Habitual↗
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

Immunizing and curative potential of replicating and nonreplicating murine mammary adenocarcinoma cells engineered with interleukin (IL)-2, IL-4, IL-6, IL-7, IL-10, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and gamma-interferon gene or admixed with conventional adjuvants.

To evaluate the efficacy of vaccinations with cytokine-gene-transduced tumor cells, BALB/c mice were challenged with 1 x 10(5) parental cells of a syngeneic adenocarcinoma cell line (TSA-pc). No protection was observed in mice immunized 30 days earlier with 1 x 10(5) nonreplicating mitomycin-C-treated TSA-pc alone, or with Corynebacterium parvum or Complete Freund Adjuvant (CFA). Ten to 30% of mice immunized with nonreplicating cells engineered to produce interleukin (IL)-2, IL-4, IL-6, IL-7, IL-10, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and gamma-interferon gene were protected. Fifty % of mice immunized with replicating TSA-pc admixed with C. parvum and 80-100% of mice immunized with replicating tumor cells transduced with IL-2, IL-4, IL-7, IL-10, or gamma-interferon gene were protected. No cure was afforded by TSA cells admixed with C. parvum or CFA, nor by TSA cells engineered with IL-6, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha gene injected starting 1 day after TSA-pc challenge. Complete tumor regression, however, was obtained in 10-20% of mice treated with TSA cells transduced with IL-2, IL-4, IL-7, or IL-10 and in 30% of those treated with TSA cells transduced with gamma-interferon gene.

Adenocarcinoma↗
PubMed1993

Protective and curative potential of vaccination with interleukin-2-gene-transfected cells from a spontaneous mouse mammary adenocarcinoma.

The potential of interleukin 2-gene-transfected tumor cells to prevent tumor growth and cure established tumors was evaluated using cells from a spontaneous, invasive, and metastasizing mouse mammary adenocarcinoma. Tumor cells engineered to secrete interleukin 2 initially trigger a local inflammatory reaction that leads to inhibition of established parental adenocarcinomas, as well as an antigenically unrelated fibrosarcoma. The ensuing systemic immunity selectively inhibits subsequent parental cell challenges and cures established parental adenocarcinomas and their lung metastases, although less effectively as the neoplastic mass increases. Multiple injections of interleukin 2-gene-transfected tumor cells may thus be considered a new form of vaccination in the management of minimal residual disease and incipient metastases.

Adenocarcinoma↗
PubMed1993

Inhibition of tumor growth and enhancement of metastasis after transfection of the gamma-interferon gene.

Cells from the spontaneous metastatic TS/A mammary adenocarcinoma of a BALB/c mouse were transfected with the murine gamma-interferon (IFN-gamma) gene. Six clones (IFN-gamma clones) releasing between 2 and 6,000 international units (IU) of IFN-gamma/ml culture medium, were compared to TS/A parental cells (TS/A-pc) and to cells transfected with neomycin resistance gene only (NEO cells). Autocrine IFN-gamma up-regulated membrane expression of H-2 class-I and Ly-6 glycoproteins, but did not alter cellular proliferation in vitro. All IFN-gamma clones gave rise to progressive tumors with a growth rate significantly slower than that of tumors induced by TS/A-pc and NEO cells, and inversely correlated with the amount of IFN-gamma secreted. TS/A-pc and NEO tumors displayed a marginal reactive infiltrate, whereas those formed by IFN-gamma clones were massively infiltrated mostly by macrophages. In T- and NK-deficient mice the growth of tumors formed by IFN-gamma clones was not enhanced. In vitro tests showed that IFN-gamma clone cells were markedly more lysed by macrophages than TS/A-pc and NEO cells, while they remained poorly sensitive to NK and LAK cells. These data as a whole suggest that the development of solid tumors by IFN-gamma clones is primarily hampered by macrophages and not by T-lymphocytes or NK cells. When spontaneous metastatic ability was compared, 2 IFN-gamma clones releasing 2-4 IFN-gamma IU/ml were significantly more metastatic, while most IFN-gamma clones appeared to be as metastatic as NEO cells. By contrast, following intravenous challenge, all IFN-gamma clones produced 5-10 times more experimental metastases than NEO cells. The higher metastatic ability of IFN-gamma clones was attributed to increased resistance to NK cells since, in NK-depleted BALB/c mice, metastatic spread of IFN-gamma clones was not enhanced, whereas a 50-fold increase in the number of metastases was found upon injection of NEO cells.

Adenocarcinoma↗
PubMed1993

Strategies for cytokine utilisation in tumor therapy.

The state of the art with regard to the employment of various cytokine-based tumor immunotherapy strategies and their mechanisms of action are critically reviewed. As matters now stand, adoptive transfer of LAK cells or tumor infiltrating lymphocytes together with high doses of IL-2 constitutes the only immunologic way to hinder tumor growth in advanced stages of cancer. On the other hand, many experimental data show that the local presence of cytokines, either injected repeatedly at tumor site or released by cytokine-gene engineered tumor cells, arouses immunogenicity in apparently nonimmunogenic spontaneous tumors. By strengthening the notion that most tumors are potentially immunogenic, these findings offer substantial evidence to stress the potential use of cytokines as a component of new tumor vaccines.

Animals↗
PubMed1993

Cytokine-induced tumor immunogenicity: from exogenous cytokines to gene therapy.

The local presence of cytokines can drastically alter tumor host immune relations and activate a nonspecific reaction that in some cases leads to induction of specific responses to otherwise nonimmunogenic tumors. The employment of cytokines in the creation of new antitumor vaccines is thus a tempting prospect. Analogous effects have been obtained with cytokines inoculated locally and cytokines released from tumor cells engineered to produce them. An account is given of some mechanisms whereby this cytokine-induced reaction results in increased tumor immunogenicity. However, the real value of this potential form of vaccine in inducing the regression of incipient or established tumors remains to be established.

Animals↗
PubMed1993

Cytokine mRNA expression by cultured rat mesangial cells after contact with environmental lectins.

We previously demonstrated that gliadin, a lectinic component of gluten, induces IgA mesangial deposits in orally immunized mice, binds in vitro polymeric IgA and cultured rat mesangial cells modulating their arachidonic acid metabolism. We investigated the effects of gliadin and other environmental lectins on some mesangial cell functions, including synthesis and release of cytokines and lipid mediators. Several lectins, particularly gliadin, affected the mRNA expression of c-myc and c-fos, two proto-oncogenes involved in the transcriptional enhancement of the gene cascade, which are markers of cell growth, differentiation and mitosis. Lectins modulated the ability of cultured rat mesangial cells to express mRNA for cytokines involved in the inflammation and in the regulation of the immune response. TNF-alpha and IL-6 mRNA transcription were enhanced by gliadin and other lectins, and TNF release was variably increased. Conversely, IL-1 production was less affected or slightly depressed. PAF production was not detectable while PGE2 was generally reduced and TXB2 enhanced. Gliadin was one of the lectins most active on the mesangial cells, and its effects were reversed by the addition of N-Acetylglucosamine, a sugar specific for some lectinic bindings, suggesting a carbohydrate interaction. The effects of the various lectins were distinct and only partially convergent, ruling out an aspecific mesangial cell activation. These data suggest that lectins might interfere with mesangial cell functions and modify the mesangial cell homeostasis.

Animals↗
PubMed1992

Role of neutrophils and CD4+ T lymphocytes in the primary and memory response to nonimmunogenic murine mammary adenocarcinoma made immunogenic by IL-2 gene.

TS/A is a spontaneous adenocarcinoma, apparently not immunogenic in BALB/cnAnCr mice. TS/A cells are unable to stimulate a syngeneic antitumor response either in vitro or in vivo. To evaluate the immunogenic potential of IL-2-releasing neoplastic cells, we used an expression vector to introduce the cDNA coding for murine IL-2 into TS/A cells. Six clones releasing between 30 and 6800 U of IL-2/10(5) cells/ml/48 h have been isolated. Both low (30 U, B1.30) and high (6000 U, B4.6000) IL-2-releasing clone are capable of stimulating a proliferative and cytotoxic response in syngeneic cultures. While the B1.30 clone grows in 60% of syngeneic mice with a delayed pattern, the five clones that release higher levels of IL-2 are promptly rejected. Rejection is associated with neutrophil infiltration, the intensity of which is directly proportional to the amount of IL-2 released. NK cells and CD4+ lymphocytes are uninfluential, whereas CD8+ lymphocytes play only a minor role. This neutrophil-dominated rejection leaves a long-lasting, tumor-specific, T lymphocyte-mediated immune memory. For its induction, CD4+ lymphocytes are required. Their specific activation appears to depend on both the amount of IL-2 released and the granulocyte-mediated reaction that may lead to a more efficient presentation of tumor-associated Ag. These data support the notion that, after transduction of IL-2 gene, cancer cells may elicit an immune antitumor response, and stress the potential use of IL-2 as a component of new tumor vaccines.

Adenocarcinoma↗