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Abstract Number: 1502

Hedgehog Signaling in Murine Chronic Sclerodermatous Graft-Versus-Host Disease

Pawel Zerr1, Katrin Palumbo-Zerr1, Alfiya Distler2, Michal Tomcik3, Stefan Vollath2, Louis E. Munoz2, Christian Beyer4, Clara Dees5, Friederike Egberts6, Ilaria Tinazzi7, Francesco Del Galdo8, Oliver Distler9, Georg Schett10, Bernd M. Spriewald11 and Joerg HW Distler2, 1Department of Internal Medicine 3 and Institute for Clinical Immunology, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 2Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 3Institute of Rheumatology, Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague 2, Czech Republic, 4Department of Internal Medicine 3, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 5Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 6Department of Dermatology, Department of Dermatology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany, 7Unit of Rheumatology, Scleroderma Research Program, Leeds Institute of Molecular Medicine, Division of Musculoskeletal Diseases, University of Leeds, Leeds, United Kingdom, 8Musculoskeletal Diseases, Scleroderma Research Program, Leeds Institute of Molecular Medicine, Division of Musculoskeletal Diseases, University of Leeds, Leeds, United Kingdom, 9Department of Rheumatology, Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland, 10Institute for Clinical Immunology, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 11Department of Internal Medicine V, Department of Internal Medicine V, University of Erlangen-Nuremberg, Erlangen, Germany

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Bone marrow and scleroderma

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Sclerodermatous chronic graft-versus-host disease (cGvHD) is a prognosis limiting complication of allogeneic bone marrow transplantation. cGvHD can manifest on virtually every organ system. However, the skin is most commonly affected with progressive skin fibrosis resembling the findings in systemic sclerosis (SSc). The hedgehog pathway plays a critical role in cellular differentiation during embryogenesis, but also for tissue homeostasis in adult. The prominent role of hedgehog signaling in various tumors prompted the development of small molecule inhibitors, some of which have already been successfully tested in clinical trials.  

Methods: Sublethally irradiated recipient mice received miHAg-mismatched bone marrow to induce sclerodermatous cGvHD. Activation of sonic hedgehog (Shh) pathway in cGvHD was analyzed by immunohistochemistry for Shh and its downstream transcription factors Gli-1 and Gli-2 in human and murine skin. Smoothened (Smo) inhibitor LDE223 was used to investigate the efficacy of hedgehog inhibition for prevention and treatment of murine cGvHD. Skin samples were analyzed for dermal thickness, myofibroblast counts and hydroxyproline content. The effect of Shh on cultured fibroblasts was analyzed by quantification of stress fibers formation, real time PCR for Col1a2 and the collagen content in supernatants.

Results: Hedgehog signaling was activated in human and murine cGvHD with increased expression of Shh, Gli-1 and Gli-2. Inhibition of coreceptor Smo with LDE223 was well tolerated without evidence of toxicity. LDE223 effectively reduced cGvHD in both preventive and therapeutic regime without decreasing the desired graft versus leukemia effect. Treatment with LDE223 initiated either before disease onset or after first clinical signs of cGvHD, significantly reduced clinical signs such as weight loss, alopecia and skin ulcers. Moreover, inhibition of Smo effectively ameliorated the histological changes of cGvHD. Preventive as well as therapeutic regime of LDE223 significantly decreased the dermal thickness, the number of myofibroblasts and the hydroxyproline content compared to control mice. Of note, therapeutic regime of LDE223 did not only stop progression, but induced histological regression of cGvHD. While LDE223 did not ameliorate leukocyte infiltration, B- or T cell activation, incubation of human dermal fibroblasts with Shh induced fibroblast activation with increased release of collagen and myofibroblast differentiation, suggesting a direct inhibitory effect on fibroblasts as mechanism of action.

Conclusion: This is the first study on the role of hedgehog signaling in sclerodermatous cGvHD. We demonstrate that hedgehog signaling is activated in cGvHD and stimulates progression of cGvHD by activating resident fibroblasts. Considering the potent therapeutic effects of Smo inhibition in preventive as well as therapeutic settings, good tolerance and lack of interference with the desired GVL and the availability of Smo inhibitors for clinical trials, our findings might have direct translational implications and stimulate clinical trials with Smo inhibitors in cGvHD and other fibrotic diseases such as SSc.


Disclosure:

P. Zerr,
None;

K. Palumbo-Zerr,
None;

A. Distler,
None;

M. Tomcik,
None;

S. Vollath,
None;

L. E. Munoz,
None;

C. Beyer,
None;

C. Dees,
None;

F. Egberts,
None;

I. Tinazzi,
None;

F. Del Galdo,
None;

O. Distler,
None;

G. Schett,
None;

B. M. Spriewald,
None;

J. H. Distler,
None.

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