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Medicina Traslazionale

Appunti di Medicina di laboratorio - Patologia Clinica. Argomenti trattati: Medicina traslazionale: patogenesi molecolare e risposta immune nel carcinoma renale.Istopatologia del carcinoma renale a cellule chiare, a cellule cromofobe, a cellule cromofile, dei dotti collettori, meccanismi di invasione del tumore, mediatori della difesa immunitaria. Cellule dendritiche.

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  • 20-11-2012
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Medicina Traslazionale
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Anteprima Testo:
Patogenesi molecolare e risposta immune nel carcinoma renale : un esempio applicativo di medicina traslazionale Prof.ssa Elena Ranieri Cattedra di Patologia Clinica Dipartimento di Scienze Biomediche Universita’ degli Studi di Foggia
Renal Cell Carcinoma : a Model of Study  Renal cell carcinoma accounts for approximately 3% of adult malignancies and is the sixth leading cause of cancer death  Renal cell carcinoma may remain clinically occult for most of its course. The classic triad of flank pain, hematuria, and flank mass is uncommon (10%) and is indicative of advanced disease.  25-30% of patients are asymptomatic, and their renal cell carcinomas are found on incidental radiologic study
 It is characterized by, resistance to radiation and chemotherapy, and infrequent but reproducible responses to immunotherapy agents such as interferon alpha and interleukin-2.
Istopatologia del RC  Ritenendo che il tumore renale originasse da residui della ghiandola surrenale, in passato veniva definito ipernefroma  Agli inizi degli anni 60, la dimostrazione della sua origine dai tubuli renali portò alla definizione di una singola entità denominata Adenocarcinoma renale, distinto nelle seguenti forme (classificazione di Mainz): 
a cellule chiare (70%)

a cellule cromofile (15%)

a cellule cromofobe (5%)

carcinoma dei dotti collettori (2%)
Renal Cell Carcinoma  RCC belongs to a small group of cancers where immunemediated mechanisms play important roles in limiting tumor
growth.  Patients with active, disseminated disease are typically
characterized by predominant Th2- or T regulatory-type immunity  RCC lesions contain tumor-infiltrating lymphocytes reported to be “functionally inappropriate”, dysfunctional or pro-apoptotic
Tatsumi, T., Kierstead, L.S., Ranieri, E., Gesualdo, et al, J Exp Med, 2003
Renal Cell Carcinoma (RCC) In RCC spontaneous tumor regression can be observed, although in rare cases, in metastatic disease. This suggests that RCC expresses tumor antigens specifically recognized by T cells
Immune mechanisms play a role in limiting tumor growth
Finke J., L.S. Kierstead, E. Ranieri, W.J. Storkus, Humana Press, 2000
Mechanisms of tumor evasion
Mapara MY et al J Clin Oncol, 2004
Mediators of Immune Defense Dendritic Cell
innate
adaptive Antibodies B
T-Lymphocytes CTL
Macrophages NK cells Treg
Th
Tumor
NK
Cytokines
Study Design  DC specific T cell immune Response
 Identification of immunogenic RCC cell lines  Immunotherapy  Molecular pathogenesis and drugs  Biomarkers identification  Diagnosis/monitoring of disease
Dendritic cells and immune responses
DENDRITIC CELL BIOLOGY DCs are the most potent antigenpresenting cells that play a central role in immunity
coordinating
human
They comprise different subsets at different stage of maturation They have potential advantages as cellular adjuvants for immunotherapy strategies
Antigen cross-presentation and T cell immune response TAAs
Tumor Antigens
Immune attack against the tumor
Tumor cells
Dendritic cell
CD4
CD4
Activated/Mature DC
DC migration
CD8
Lymphocyte migration
CD8
Lymph node
NA T0 +
DC
NA T0
T21 +
T21 DC LYS
NA
T21
DC
+L
YS
TU
CL YS +A +D b II CL YS +A bI NA NA T21 T21 +T U +T U+ NA Ab T21 II +T U+ Ab I
+D
NA
DC
L LYS YS T0 +A +D bI CL YS +A b II NA T0 NA +T T0 U +T U+ NA Ab T0 I +T U+ Ab II
T0 +
T21
NA
NA
NA
NA
Spot numbers/100.000 T cells
RCC : from where we started….  RCC Cell Lines Characterization to obtain the most immunogenic RCC line: 60 RCC lines: 10% (5-6 RCC lines).
IFNg Elispot Assay
350
300
250
200
150
100
50
0
ELTHEM cell line
A
B (A) Real Time-PCR of tumor markers (OFA, CE, hTERT, Ruas) and interleukin-6 (B) Microsatellite instability (MSI) and loss of heterozygosity (LOH) (C) Immunocytochemistry (CAM 5.2, the mitochondrial markers, the vimentin, cytokeratin AE1/AE3, cytokeratin 19, EGF-R, the EMA, CD10 and Ki 67)
C
ELTHEM cell line A
(A) Mixed Lymphocytes Tumor cell Cultures Cytotoxicity test of CD8+ T lymphocytes against autologous ELTHEM clone (60% lysis, E / T = 60:1).
B
(B) ELISPOT test for IFNg release. The block of the response of class I test shows the 91% specificity.
ELTHEM proteomic profile A
B
MW 150 KDa
C
10
3
10 pH
(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 autologous dendritic cells as natural cellular adjuvants Peripheral Blood
Cytokines Dendritic Cell
Re-infusion
RCC Antigen Patent
: Linea cellulare di carcinoma renale e suo uso". Brevetto Industriale N. MI2005 A002018 (21.10.05).
Inventors: E. Ranieri, L. Gesualdo, W. Herr, M. Battaglia.
International Patent : PCT/EP2006/06763, 20.10.06
DC MONITORING DC phenotyping In RCC tissue and lymph nodes
RCC PATIENT
Immunity induction cancer, infective disease
DC subsets analysis by IHC
Tolerogenicity DC Phenotyp...
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