UBC Theses and Dissertations
Granzyme B : a novel therapeutic target for radiation dermatitis Pawluk, Megan
Radiation dermatitis (RD) is observed in up to 90% of patients receiving radiation therapy. Symptoms of RD include redness, scaling, and crusted wounds. Severe symptoms can prevent future radiation treatments. Current treatments are not effective and may cause severe side effects. Granzyme B (GzmB) was originally characterized as a serine protease secreted by cytotoxic lymphocytes to promote target cell apoptosis. It is now recognized that GzmB can be secreted by other immune cell and non-immune cell populations. GzmB is elevated in a number of inflammatory skin disorders, such as atopic dermatitis, autoimmune blistering, impaired wound healing and scarring. Previous studies suggest that extracellular GzmB cleaves E-cadherin, filaggrin, and decorin leading to reduced epithelial barrier function and scarring. Based on these findings, I hypothesized that GzmB contributes to increased RD severity and delayed healing through the cleavage of epithelial barrier proteins and/or matrix proteins. GzmB expression and cell source, E-cadherin, filaggrin, and decorin levels were assessed using immunohistochemical analysis of biopsies from RD patients. The role of GzmB was investigated in an established RD murine model, comparing GzmB knockout (GzmB-/-) to wild type (WT) mice. The dorsal skin was exposed to a single 40 gray dose of radiation. RD severity was blindly scored. Tissues were harvested at days 4, 14, and 46 post-radiation exposure. Tissues were examined for GzmB, immune cell infiltrate, scarring, and decorin. Macrophages and mast cells expressed GzmB while E-cadherin, filaggrin, and decorin were reduced in human RD skin compared to healthy skin. GzmB-/- mice exhibited a decrease in RD severity compared to WT mice from day 4 to day 12. CD3+ T-cell levels were reduced and neutrophil infiltration was observed at day 14. GzmB was expressed by resident mast cells in WT mice. GzmB-/- mice exhibited less scar area and more decorin than WT mice at day 46. In summary, GzmB may contribute to RD severity through E-cadherin, filaggrin, and decorin cleavage. The RD murine model suggests that depletion of GzmB attenuates severity of RD and could mitigate scarring. These studies provide a rationale for pursuing GzmB as a novel therapeutic target for the treatment of RD.
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