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Fischer, J.C.* ; Lin, C.C.* ; Heidegger, S.* ; Wintges, A.* ; Schlapschy, M.* ; Beudert, M.* ; Combs, S.E. ; Bassermann, F.* ; Skerra, A.* ; Haas, T.* ; Poeck, H.*

Regeneration after radiation- and immune-mediated tissue injury is not enhanced by type III interferon signaling.

Int. J. Radiat. Oncol. Biol. Phys. 103, 970-976 (2019)

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Purpose: Type I interferon (IFN-I) and interleukin (IL)-22 modulate regeneration of the thymus and intestinal epithelial cells (IECs) after cytotoxic stress such as irradiation. Radiation-induced damage to thymic tissues and IECs is a crucial aspect during the pathogenesis of inadequate immune reconstitution and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative total body irradiation (TBI), respectively. IL-22 and IFN-I reduce the severity of acute GVHD after allo-HSCT with myeloablative TBI. However, the role of biologically related type III interferon (IFN-III), also known as interferon lambda (IFN-lambda) or IL-28, in this context is unclear. We therefore studied the role of the IFN-III pathway in thymic regeneration and GVHD after TBI and allo-HSCT.Methods and Materials: Cohoused wild-type (WT) and IFN-III receptor-deficient (IL-28 receptor alpha subunit-deficient/IL-28Ra(-/-)) mice were analyzed in models of TBI-induced thymus damage and a model of GVHD after allo-HSCT with myeloablative TBI. PASylated IFN-III (PASylated IL-28A, XL-protein GmbH) was generated to prolong the plasma half-life of IFN-III. Pharmacologic activity and the effects of PASylated IL-28A on radiation-induced thymus damage and the course of GVHD after allo-HSCT with myeloablative TBI were tested.Results: The course and severity of GVHD after myeloablative TBI and allo-HSCT in IL-28Ra(-/-) mice was comparable to those in WT mice. Activation of the IFN-III pathway by PASylated IL-28A did not significantly modulate GVHD after allo-HSCT with TBI. Furthermore, IL28Ra(-/-) mice and WT mice showed similar thymus regeneration after radiation, which could also not be significantly modulated by IFN-III receptor engagement using PASylated IL-28A.Conclusions: We analyzed the role of IFN-III signaling during radiation-mediated acute tissue injury. Despite molecular and biologic homologies with IFN-I and IL-22, IFN-III signaling did not improve thymus regeneration after radiation or the course of GVHD after myeloablative TBI and allo-HSCT. (C) 2018 Elsevier Inc. All rights reserved.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Graft-versus-host Disease ; Il-28 ; Pasylation ; Type Iii Ifn ; Allogeneic Hematopoietic Stem Cell Transplantation ; Conditioning Therapy ; Thymus Regeneration ; Total Body Irradiation; Versus-host-disease; Lambda; Cells; Microbiota; Induction

ISSN (print) / ISBN 0360-3016

e-ISSN 0360-3016

Journal International Journal of Radiation Oncology, Biology, Physics

Quellenangaben Volume: 103, Issue: 4, Pages: 970-976

Publisher Elsevier

Publishing Place Ste 800, 230 Park Ave, New York, Ny 10169 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Radiation Medicine (IRM)