Immunomodulatory properties in inflammatory diseases of low dose irradiation

Transcription

1 Immunomodulatory properties in inflammatory diseases of low dose irradiation Franz Rödel Department of Radiotherapy and Oncology University of Frankfurt am Main DoReMi Workshop Low dose radiation effects on the immune system: current knowledge and future research needs November 5-7, 2013, Budapest

2 Historic publications Röntgen W. (1895): Discovery of X-rays Sokolow N. (1898): Polyarthritis 100 % response Röntgenstrahlen gegen Gelenkrheumatismus Fortschr. Röntgenstr. 1, p 209 Stenbek O. (1898): Polyarthritis 80 % response Om behandling of kronsik ledgangs-rheumatism med Röntgenstralar. Sv Läk Förh 1, p 117

3 Immune modulatory properties of ionizing radiation (clinical point of view) Low dose Single dose: < 1.0 Gy Total dose: < 12.0 Gy Solely percutaneously High dose Single dose: > 1.0 Gy (1.8-2 Gy) Total dose: > 30.0 Gy Percutaneously and interstitially Therapy of inflammatory and degenerative diseases Anti-inflammatory effects Therapy of malignant diseases Inflammatory effects

4 Clinical observations Low dose Radiotherapy is in clinical use for treatment of benign inflammatory diseases for several decades At present more than patients are treated per year in Germany Improvement of clinical symptoms in average with 3-5 fractions of Gy not exceeding a cumulative dose of 6.0 Gy! If necessary repeated after 6-12 weeks

5 Mechanisms of anti-inflammatory radiotherapy?

6 Anti-inflammatorypropertiesoflowdose irradiation: Endothelium as a target

7 Mechanisms of anti-inflammatory radiotherapy: Modulation of adhesion

8 First experimental setup: adhesion assays Irradiation of the EC Stimulation Addition of PBMC 30 min, 4 o C, shear conditions 30 min, 37 o C Fixation Analysis Streptavidin CY 3

9 Kern et al. RadiotherOncol, 2000; Hildebrandt et al. IntJ Radiat Biol, 2002 Rödel et al. Int J RadiatBiol, 2002; Rödel et al. StrahlentherOnkol, 2004 Adhesion of PBMC to activated endothelial cells following anti-inflammatory radiotherapy adherent PBMC (rel.value) h 12 h 24 h Dose (Gy) Dose (Gy) Dose (Gy) 1.3 TGF-ß 1 expression (rel. values) Time after irradiation (h)

10 Rödel et al. Int J RadiatBiol 2002 Mechanisms of anti-inflammatory X irradiation: Induction of TGF-β 1 in endothelial cells

11 Hildebrandt et al. IntJ Radiat Biol 2002 Rödel et al.int J RadiatBiol 2002 Discontinuous expression of E-selectin in irradiated endothelial cells human EA.hy926 murine miend-1 OD 490nm control 0.3 Gy 1 h 2 h 4 h 5 h Time after stimulation OD 490nm control 1.0 Gy 1 h 2 h 4 h 5 h Time after stimulation E-selectin (% pos cells) hours after stimulation Dose (Gy) ELISA FACS

12 Underlying molecular mechanisms? Who was first?

13 NF-κB: a central transcription factor in inflammation Bacterial/ Viral Infections Mitogens/ Chemicals Enzymes (inos) Acute phase Response genes Ionizing Radiation IκB Degradation Transcription Adhesion molecules Cytokines Surface receptors Cytokines/ Growth factors Anti-apoptotic genes

14 Rödel et al. Int J RadiatBiol 2004 Biphasic induction of NF-κB in EC following antiinflammatoryx-irradiation NF-κB Transcriptional activity rlu x 10 5 Ø Dose (Gy) Ø Dose (Gy) TGF-β 1 (pg/ml) PBS Decoy Control Dose (Gy)

15 Rödel et al. Radiother Oncol 2010 Biphasic induction of X-linked inhibitor of apoptosis protein following low dose X-irradiation Holcik, Nat Rev Mol Cell Biol 2001

16 sirna-mediated attenuation of XIAP increases apoptosis and hampers NF-κB activation Calnexin - 90 kda XIAP - 55 kda Dose (Gy)

17 Functionalimpact of XIAP on TGF-β 1 secretion and adhesion of activated endothelial cells

18 Anti-inflammatorypropertiesoflowdose irradiation: Leukocytes as a target

19 Rödel et al. StrahlentherOnkol 2008 Cell-cell contact dependent expression of CCL20 chemokine in polymorphnuclear cells Dose (Gy)

20 Rödel et al. Front Oncol 2012 Current model of the anti-inflammatory properties of low dose irradiation

21 Thanks to University Frankfurt am Main M. Large, S. Reichert, S. Hehlgans University of Erlangen-Nürnberg Department of Radiotherapy U.Gaipl,B.Frey,L.Keilholz Institute for Clinical Immunology M. Herrmann University of Rostock Department of Radiotherapy G. Hildebrandt, K. Manda University of Freiburg Clinical Immunology R. Voll GSI Helmholtz Center for Heavy Ion Research, Darmstadt C. Fournier supported by

22 Thanks for your Attention!