Diapositiva 1

Diapositiva 1

Diapositiva 1


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I dati fanno riferimento al sitoClinicalTrials.gov

Clinical trials of IFN-γ are ongoing…ConditionInterventionPhaseLymphoma, B-CellBreast CancerColorectal CancerKidney CancerLung CancerGeneTransfer: AdenovirusInterferon gammaDrug: allogeneictumor cell vaccineDrug: autologoustumor cell vaccineDrug: cyclophosphamideDrug: interferon alfaPhase IIPhase IIPhase IIPhase IIPhase IIMalignantMesotheliomaPancreatic CancerDrug: interferongammaDrug: sargramostimPhase IIPhase III dati fanno riferimento al sitoClinicalTrials.gov

Marrying Immunotherapy withChemotherapyTryptophanIDOKynurenineIDO =innate defense mechanism limiting growth of viruses bacteria pathogens and malignant cellsTUMORICIDAL CONSEQUENCE OF IFN-γSTIMULATION?

… IDO is overexpressed in most tumorsMuller A.J., “Marrying Immunotherapy with Chemotherapy: why say IDO?”, Cancer Res 65:8065,2005IDO’s deregulation promotes tumorigenicity enabling IMMUNE ESCAPE

IDO inhibitors as anticancer agentswell-defined biochemistrybioactive and orally bioavailable lead inhibitors exist as tools for prenical validationKO mice are viable, useful for toxicity problemspharmacodynamic evaluation by misuring blood levels of triptophan and kynureninelogistical and cost advantages

Science 313: 1960, 2006In clinically detectable CRC adaptive immune response (IFNγ) prevent tumorrecurrence

Multiple S clerosisIt is thought that MS results from attacks by an individual'simmune system on the nervous system and is thereforecategorized as anautoimmune deseaseWHICH IS THE ROLE OF IFNγ?

Mana P., “Deleterious role of IFNgamma in a toxic modl ofcentral nervous system demyelination”, Am J Pathol 168:1464,2006

IFNγR -/- mice show decreased loss of mature oligodendrocytes during cuprizonetreatmentIFNγR-/- mice show increased early appearance of oligodendroglial precursorcells during cuprizone feedingIFNγoligodendrocyte destructioninhibition of recruitment of new precursors

transgenic line of mice that expresses SOCS1 in oligodendrocytes under thetranscriptional control of the gene encoding the myelin protein proteolipid proteinBalabanov R., “Suppressor of cytokine signaling 1 expression protects oligodendrocytes from the deleterious effects of interferonγ”,J Neurosci, 26:5143, 2006

PLP/SOCS1 mice exhibit diminished oligodendrocyte responsiveness toIFN-γWTPLP/S OCS1enforced expression of SOCS1 protects oligodendrocytes against injuriouseffects of IFN-γ

Schering-PloughBiogenBerlexGlaxo-WellcomeHoffmann-La RocheAmgenAres SeronoInterferon Sciences3M PharmaceuticalsViragen

single-chain polypeptide containing 140 amino acidsfermentation of a genetically engineered Escherichia coli bacteriumcontaining DNA that encodes for the human proteinChronic granulomatous diseaseSevere, malignant osteopetrosis

La malattia delle ossa di marmoPerturbation in the balance between the bone matrix formation byosteoblasts and its resorption by osteoclatsINCIDENCE: 1/200000MORTALITY:first 2 years of life

BibliografiaBowers W., Microbiology and Immunology on-line, Immunology chapter 12 fig.8Schroder K., “Interferongamma: an overview of signals, mechanisms,and functions”,Journal of Leukocyte Biology, 75:163, 2004Hanahan D., “The Hallmarks of Cancer”, Cell, 100: 57, 2000Dunn GP, “Interferons, immunity and cancer immunoediting”,Nat Rev Immunol., 6: 836,2006de Visser KE, “Paradoxical roles of the immune system during cancer development”, NatRev Cancer 6:24, 2006Muller A.J., “Marrying Immunotherapy with Chemotherapy: why say IDO?”, CancerRes 65:8065, 2005

Brandacher G., “Antitumoral activity of interferon-gamma involved in impaired immunefunction in cancer patients” Current drug metabolism 7:599, 2006Muller AJ, “Targeting the mechanisms of tumoral immune tolerance with small-moleculeinhibitors” Nat Rev cancer 6:613, 2006Morse MA, “Recent developments in therapeutic cancer vaccines”, Nat Clin Onc 2:108, 2005Galon J., “Type density and location of immune cells within human colorectal tumors predictclinical outcome”, Science 313:1960, 2006Mana P., “Deleterious role of IFNgamma in a toxic model of central nervous systemdemyelination”, AJP 168:1464, 2006Pasquini LA, “The neurotoxic effect of cuprizone on oligodendrocytes depends on thepresence of pro-inflammatory cytokines secreted by microglia”, Neurochem Res, 2006

Balabanov R., “Suppressor of cytokine signaling 1 expression protects oligodendrocytesfrom the deleterious effects of interferon-γ”, J Neurosci, 26:5143, 2006Kantarci OH, “IFN-gamma polymorphisms are associated with gender differences insusceptibility to multiple sclerosis”, Genes and Immunity, 6:153, 2005Frattini, A. et al: “ Defects in Tcirg1 subunit of the vacuolar proton pump areresponsible for a subset of human autosomal recessive osteopetrosis”.Nature Genetics, 25: .343, 2003Blin-Wakkach, “Hematological defects in the oc/oc mouse, a model of infantilemalignant osteopetrosis”, Leukemia 18:1505, 2004Dinauer MC, “Chronic granulomatous disease and other disorders of phagocytefunction”, Hematology pg.89, 2005www.ClinicalTrials.govAbbas, “Immunologiacellulare e molecolare”,Piccin,quarta edizione, 2000Alberts, “Biologia molecolare della cellula”,Zanichelli terza edizione, 1995

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