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Linea cellulare
NA DD DNANA +NA+ NA+ + NAT21T0 T0 T21NA NA NANAELTHEM cell lineA B(A) Real Time-PCR of tumor markers (OFA, CE,hTERT, Ruas) and interleukin-6(B) Microsatellite instability (MSI) and loss ofheterozygosity (LOH)(C) Immunocytochemistry (CAM 5.2, themitochondrial markers, the vimentin,cytokeratin AE1/AE3, cytokeratin 19, EGF-R, theEMA, CD10 and Ki 67)CELTHEM cell lineA (A) Mixed Lymphocytes Tumorcell Cultures Cytotoxicity test of+CD8 T lymphocytes againstautologous ELTHEM clone (60%lysis, E / T = 60:1).(B) ELISPOT test for IFNgB release. The block of theresponse of class I test showsthe 91% specificity.ELTHEM proteomic profileA BMW150 KDa C10 3 10pH(A) Representative 2-DE map of proteins extracted from ELTHEM clone(B) Biological function and (C) localization of identified protein.Therapeutic vaccines based on the use of autologousdendritic cells as natural cellular adjuvantsPeripheral Blood CytokinesDendriticCellRe-infusion RCC AntigenPatent N. MI2005 A002018 (21.10.05).di carcinoma renale e suo uso".
Brevetto Industriale
Inventors: E. Ranieri, L. Gesualdo, W. Herr, M. Battaglia.
International Patent : PCT/EP2006/06763, 20.10.06
DC MONITORING Immunity
DC phenotyping In induction
RCC tissue and lymph nodes cancer, infectivedisease
RCC PATIENT DC subsetsanalysis by IHCTolerogenicity
InductionDC Phenotyping inPeripheral Blood Transplant,autoimmunity,allergy
Human Dendritic cells
DC comprise two subsets functionally and phenotypically different:
Myeloid DCs
- BDCA-1 /BDCA-3
- potent stimulators of T lymphocyte
- IL-6, IL-12p70, IL-10, TNF-a production
Plasmacytoid DCs
- BDCA-2 /BDCA-4
- generate a Th2 response
- impressive producers of IFN-a in viralinfection
Dendritic cells analysis in RCC peripheral blood
35000 blood
30000 P<0,01 peripheral
25000 BDCA1
20000 BDCA2
15000 of BDCA3 cells/mL
10000
5000
N° 0 Normal RCC
A significant decrease (p<0,01) in the percentage and in the absolute number of myeloid DC and plasmacytoid DC subsets
are observed in RCC pts compared with healthy controls Gigante M. et al, Mol Immunol. 2009
Dendritic cells analysis in RCC tissue
Plasmacytoid DC
Myeloid DC
RCC
Healthy
A significant increase of myeloid DC and plasmacytoid DC infiltrate in RCC biopsies compared to normal kidneys (p<0.001) Gigante M., Ranieri E et al, Mol Immunol. 2009
Dendritic Cells distribution in RCC lymph nodes
+
A significant decrease of mature DC (CD11c , CD83 ) infiltrate in RCC lymph nodes compared to normal (p< 0.001)
Normal
RCC
Green:: CD11c-FITC
Red: CD83-TRITC
16 cells/hpf
1412 *10
CD11c+/CD83+
86420
PATIENTS
CONTROLS
Gigante M. Ranieri E et al, Mol Immunol. 2009
Mechanism of Action
DC subsets
Immature DC
Immature DC
Peripheral
Peripheral blood
Lymphoid tissue
tissues/Cancer
IFN-a-conditioned DC
IFN-a is an important adjuvant for the development of DC-based vaccines with high clinical efficacy.
IFN-a potently enhances both T cell and antibody responses and promote immunological memory by direct action on
DC.IFN-a-conditioned DC preferentially stimulate Type-1 and limit Treg-type in vitro T cell responses in RCC patients
IFNa DC :
- promoted significantly stronger Tc1 effector T cell responses than cytokine cocktail-matured DC as revealed by IFN-g ELISPOT assay
- mDC were more efficient in inducing the generation of suppressor CD8 T cells than mDC
- induced a lower expansion of Treg cells than mDC
- IFN-a-conditioned DC may be candidates for use in novel therapeutic vaccines in the setting of RCC
Gigante M., Ranieri E. J. Immunother 2008
Look Into the Future
DC-based vaccine is still a promising emerging treatment option for patients with RCC
+CD8 T cell – RCC Interaction
IL-2R
RCC +CD8 T cell Cell Cycle
CYTOKINES
INTRACELLULAR SIGNALING
APOPTOSIS
+In vitro CD8 T cells Response analysis
AUTOLOGOUS SYSTEM
ALLOGENEIC SYSTEM
Matched HLA Donor PBL
Patient PBL
Tumor cells
Tumor cells
Resting T cell
Resting T cell
+CD8 T responders
Gene
TCR LYMPHOCYTE survival, development, and differentiation of a variety of cells but are critically important for immune cells and hematopoietic cells.
Jaks exert their effect is through the activation of a relatively small number of latent, cytosolic DNA-binding proteins term the Signal Transducers and Activators of Transcription (STATs).
Ghoreschi K et al. Janus kinases in immune cell signaling. Immunol Rev. 2009
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