TH17 predominant T-cell responses in radiation-induced bowel disease are modulated by treatment with adipose-derived mesenchymal stromal cells.

Abstract

Radiation proctitis is an insidious disease associated with substantial morbidity and mortality. It may develop following the treatment of several cancers by radiotherapy when normal colorectal tissues are present in the irradiation field. There is no unified approach for the assessment and treatment of this disease, partly due to insufficient knowledge about the mechanism involved in the development of radiation proctitis. However, unresolved inflammation is hypothesized to have an important role in late side effects. This study aimed to analyse the involvement of specific immunity in colorectal damage developing after localized irradiation, and evaluate the benefit of immunomodulatory mesenchymal stromal cells isolated from adipose tissue (Ad-MSCs) for reduction of late side effects. Our experimental model of colorectal irradiation induced severe colonic mucosal damage and fibrosis that was associated with T-cell infiltration. Immune cell activation was investigated; adoptive transfer of T cells in nude rats showed stronger colonization by T cells isolated from irradiated rats. The predominant role of T cells in late radiation-induced damage and regeneration processes was highlighted by in vivo depletion experiments. Treatments using Ad-MSCs reduced T-cell infiltration in the colon and reduced established colonic damage as measured by histological score, functional circular muscle contractibility, and collagen deposition. Here, we have demonstrated for the first time the predominance of the TH17 population compared to TH1 and TH2 in radiation-induced bowel disease, and that this is reduced after Ad-MSC treatment. Additionally, we demonstrated in vitro that IL17 acts directly on colonic smooth muscle cells to induce expression of pro-inflammatory genes that could participate in the development of radiation-induced injury. Our data demonstrate that the TH17 population is specifically induced during development of radiation-induced side effects in the colon. Moreover, Ad-MSC treatment modulates the TH17 population and reduces the extracellular matrix remodelling process induced following irradiation.