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

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

Int J Radiat Oncol Biol Phys. 2018 Nov 29;:

Authors: Fischer JC, Lin CC, Heidegger S, Wintges A, Schlapschy M, Beudert M, Combs SE, Bassermann F, Skerra A, Haas T, Poeck H

Abstract
PURPOSE: Type I interferon (IFN-I) and IL-22 modulate regeneration of the thymus and intestinal epithelial cells (IECs) after cytotoxic stress like 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 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- λ) 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.
MATERIALS AND METHODS: Co-housed wild-type (WT) and IFN-III receptor-deficient (IL-28 receptor-alpha-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) was generated to prolong plasma half-life of IFN-III. Pharmacological activity and effects of PASylated IL-28A on radiation-induced thymus damage and the course of GVHD after allo-HSCT with myeloablative TBI were tested.
RESULTS: Course and severity of GVHD after myeloablative TBI and allo-HSCT in IL-28 receptor-alpha-deficient mice was comparable to 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 biological 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.

PMID: 30503785 [PubMed - as supplied by publisher]

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