Synergistic anti‐tumor effects of combined IL‐1/IFN‐α/β therapy in mice injected with met astatic friend erythroleukemia cells

Belardelli, Filippo; Gabriele, Lucia; Proietti, Enrico; Sestili, Paola; Peretti, M.; Rozera, Carmela

doi:10.1002/ijc.2910490222

Cited by 6 publications

(5 citation statements)

References 21 publications

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“…In an attempt to determine the possible mechanisms responsible for such a powerful antitumor response, studies were performed using 3Cl-8 FLC line because of the extensive information available on the in vivo behavior of these tumor cells and their response to different therapy regimens. This highly metastatic tumor has been used widely by our group for evaluating the antitumor response to type I IFN (44)(45)(46)(47) and other cytokines, as well as to chemotherapy (32,(48)(49)(50). In particular, DBA/2 mice bearing metastatic FLC do not develop a clear antitumor response after treatment with various cytokines or chemotherapeutic agents, with the notable exception of type I IFN, which markedly inhibited tumor growth and visceral metastases (41,48).…”

Section: Resultsmentioning

confidence: 99%

Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice.

Proietti¹,

Greco²,

Garrone³

et al. 1998

J. Clin. Invest.

144

145

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Cyclophosphamide (CTX) increases the antitumor effectiveness of adoptive immunotherapy in mice, and combined immunotherapy regimens are now used in some clinical trials. However, the mechanisms underlying the synergistic antitumor responses are still unclear. The purpose of this study was (a) to evaluate the antitumor response to CTX and adoptive immunotherapy in mice bearing four different syngeneic tumors (two responsive in vivo to CTX and two resistant); and (b) to define the mechanism(s) of the CTX-immunotherapy synergism. Tumor-bearing DBA/2 mice were treated with a single injection of CTX followed by an intravenous infusion of tumor-immune spleen cells. In all the four tumor models, a single CTX injection resulted in an impressive antitumor response to the subsequent injection of spleen cells from mice immunized with homologous tumor cells independently of the in vivo response to CTX alone. Detailed analysis of the antitumor mechanisms in mice transplanted with metastatic Friend leukemia cells revealed that (a) the effectiveness of this combined therapy was dependent neither on the CTX-induced reduction of tumor burden nor on CTX-induced inhibition of some putative tumor-induced suppressor cells; (b) the CTX/immune cells' regimen strongly protected the mice from subsequent injection of FLC, provided the animals were also preinoculated with inactivated homologous tumor together with the immune spleen cells; (c) CD4(+) T immune lymphocytes were the major cell type responsible for the antitumor activity; (d) the combined therapy was ineffective in mice treated with antiasialo-GM1 or anti-IFN-alpha/beta antibodies; (e) spleen and/ or bone marrow cells from CTX-treated mice produced soluble factors that assisted in proliferation of the spleen cells. Altogether, these results indicate that CTX acts via bystander effects, possibly through production of T cell growth factors occurring during the rebound events after drug administration, which may sustain the proliferation, survival, and activity of the transferred immune T lymphocytes. Thus, our findings indicate the need for reappraisal of the mechanisms underlying the synergistic effects of CTX and adoptive immunotherapy, and may provide new insights into the definition of new and more effective strategies with chemotherapy and adoptive immunotherapy for cancer patients.

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Section: Resultsmentioning

confidence: 99%

Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice.

Proietti¹,

Greco²,

Garrone³

et al. 1998

J. Clin. Invest.

144

145

View full text Add to dashboard Cite

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“…On E14.5, pregnant females were i.v. injected with a single dose of 22,700 U [61] or 45,400 U recombinant mouse IFNβ (PBL Assay Science, NJ, USA) dissolved in 100 µl vehicle (PBS supplemented with 0.1% FCS), or an equivalent volume of vehicle as a control.…”

Section: Maternal Treatment With Interferon Beta (Ifnβ)mentioning

confidence: 99%

“…1d), we decided to use this cytokine for our subsequent experiments. Pregnant dams were injected at E14.5 with IFNβ (22,700 U) [61] or vehicle, as a control (see Materials and Methods), and the microglia of newborn offspring were examined (Fig. 3d).…”

Section: Maternal Ifnβ Signaling Downregulates Newborn's Microglial Pmentioning

confidence: 99%

Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress

et al. 2019

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Viral infection during pregnancy is often associated with neuropsychiatric conditions. In mice, exposure of pregnant dams to the viral mimetic poly(I:C), serves as a model that simulates such pathology in the offspring, through a process known as Maternal Immune Activation (MIA). To investigate the mechanism of such effect, we hypothesized that maternal upregulation of Type-I interferon (IFN-I), as part of the dam's antiviral response, might contribute to the damage imposed on the offspring. Using mRNA sequencing and flow cytometry analyses we found that poly(I:C) treatment during pregnancy caused reduced expression of genes related to proliferation and cell cycle in the offspring's microglia relative to controls. This was found to be associated with an IFN-I signature in the embryonic yolk sac, the origin of microglia in development. Neutralizing IFN-I signaling in dams attenuated the effect of MIA on the newborn's microglia, while systemic maternal administration of IFNβ was sufficient to mimic the effect of poly(I:C), and led to increased vulnerability of offspring's microglia to subsequent stress. Furthermore, maternal elevation of IFNβ resulted in behavioral manifestations reminiscent of neuropsychiatric disorders. In addition, by adopting a "two-hit" experimental paradigm, we show a higher sensitivity of the offspring to postnatal stress subsequent to the maternal IFNβ elevation, demonstrated by behavioral irregularities. Our results suggest that maternal upregulation of IFN-I, in response to MIA, interferes with the offspring's programmed microglial developmental cascade, increases their susceptibility to postnatal stress, and leads to behavioral abnormalities.

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“…mL -1 ) within their respective groups. Both cytokines share the ability to produce fever, lethargy, somnolence and anorexia; additive and synergistic interactions theoretically occur between them at several levels [15]. It is thus plausible that the combination of IFN-α and IL-1 somehow contributes to the systemic signs of the dual PRRSV-PRCV infection.…”

Section: Dual Infections With Respiratory Virusesmentioning

confidence: 99%

Proinflammatory cytokines and viral respiratory disease in pigs

2000

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-Swine influenza virus (SIV), porcine respiratory coronavirus (PRCV) and porcine reproductive and respiratory syndrome virus (PRRSV) are enzootic viruses causing pulmonary infections in pigs. The first part of this review concentrates on known clinical and pathogenetic features of these infections. SIV is a primary respiratory pathogen; PRCV and PRRSV, on the contrary, tend to cause subclinical infections if uncomplicated but they appear to be important contributors to multifactorial respiratory diseases. The exact mechanisms whereby these viruses cause symptoms and pathology, however, remain unresolved. Classical studies of pathogenesis have revealed different lung cell tropisms and replication kinetics for each of these viruses and they suggest the involvement of different lung inflammatory responses or mediators. The proinflammatory cytokines interferon-α (IFN-α), tumour necrosis factor-α (TNF-α) and interleukin-1 (IL-1) have been shown to play key roles in several respiratory disease conditions. The biological effects of these cytokines and their involvement in human viral respiratory disease are discussed in the second part of this review. The third part summarises studies that were recently undertaken in the authors' laboratory to investigate the relationship between respiratory disease in pigs and bioactive lung lavage levels of IFN-α, TNF-α and IL-1 during single and combined infections with the above viruses. In single SIV infections, typical signs of swine "flu" were tightly correlated with an excessive and coordinate production of the 3 cytokines examined. PRCV or PRRSV infections, in contrast, were subclinical and did not induce production of all 3 cytokines. Combined infections with these 2 subclinical respiratory viruses failed to potentiate disease or cytokine production. After combined inoculation with PRCV followed by bacterial lipopolysaccharide, both clinical respiratory disease and TNF-α/IL-1 production were markedly more severe than those associated with the respective single inoculations. Taken together, these data are the first to demonstrate that proinflammatory cytokines can be important mediators of viral respiratory diseases in pigs. respiratory coronavirus, PRCV), et le virus du syndrome dysgénésique et respiratoire porcin (porcine reproductive and respiratory syndrome virus, PRRSV) sont des virus enzootiques provoquant des infections pulmonaires chez le porc. Les caractéristiques cliniques et pathogénétiques de ces infections sont données dans la première partie de cette revue. Le SIV est un agent pathogène respiratoire primaire ; les PRCV et PRRSV, en revanche, ne causent que des infections subcliniques en l'absence de complications, mais ils contribuent de manière importante aux maladies respiratoires multifactorielles. Cependant, les mécanismes précis par lesquels ces virus provoquent des symptômes et une pathologie demeurent inconnus. Les études classiques de pathogenèse ont révélé un tropisme pour les cellules pulmonaires et des cinétiques de réplication différents pour...

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Synergistic anti‐tumor effects of combined IL‐1/IFN‐α/β therapy in mice injected with met astatic friend erythroleukemia cells

Cited by 6 publications

References 21 publications

Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice.

Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice.

Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress

Proinflammatory cytokines and viral respiratory disease in pigs

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