Mette Hazenberg, haematologist at Amsterdam University Medical Center, comments on a recent publication in the Journal of Clinical Investigation.
Corticosteroids impair epithelial regeneration in immune-mediated intestinal damage
Arnhold ea, J Clin Invest. 2024;134(7):e155880; https://doi.org/10.1172/JCI155880
While allogeneic hematopoietic progenitor cell transplantation (HCT) is very effective in curing patients with hematologic diseases, outcomes are significantly reduced by graft versus host disease (GvHD). In particular when steroid-refractory, acute GvHD has a dismal outcome and steroid-refractory GvHD represents an important unmet medical need.
One of the key factors in the initiation and perpetuation of GvHD is tissue damage. Causes of tissue damage are often iatrogenic (radiotherapy, chemotherapy), or transplantation-related, such as opportunistic infections (e.g. CMV reactivation) and damage to the microbiome. Irrespective of the cause, tissue damage leads to the release of damage associated molecules, translocation of bacteria across barriers and the activation of the donor immune system. Historically, attention has been focused on the role of alloreactive lymphocytes and in particular T cells in GvHD pathophysiology. With the more recent interest in the tissue barrier protective roles of the microbiome and in innate immune cells such as myeloid derived suppressor cells (MDSC) that mitigate alloreactivity and innate lymphoid cells (ILC) that are important mediators of tissue homeostasis and repair, the awareness of the role of tissue damage and impaired tissue repair in GvHD pathophysiology is on the rise.
In their paper, Lindemans, Hanash and their groups addressed the unresolved issue of corticosteroid refractory acute GvHD pathophysiology. Corticosteroids act by inhibiting the activation and function of innate and adaptive immune cells. However, expression of the glucocorticoid receptor is not restricted to the immune system. The investigators demonstrated that the glucocorticoid receptor is also expressed on enterocytes, and on epithelial stem and progenitor cells. In a comprehensive series of experiments, making use of mouse models and murine and human ex vivo gastro-intestinal organoids, Lindemans and Hanash show that corticosteroids reduce epithelial proliferation and repair of intestinal epithelial cells.
Radiotherapy induces damage of the epithelial barriers of the gut by activating apoptotic pathways in epithelial cells. Surviving cells then enter into a proliferative phase, where crypts are regenerated and epithelial damage repaired. The investigators demonstrated that corticosteroid treatment initiated <24 hours after irradiation protected epithelial cells through the upregulation of anti-apoptotic genes. However, when started during the regenerative phase, 3-6 days after radiotherapy, corticosteroid therapy actually enhanced epithelial damage and crypt loss. When epithelial damage was induced by alloreactive T cells, or by IFNg, the proinflammatory cytokine released by activated T cells, corticosteroid therapy significantly impaired epithelial repair. Steroids impaired the activity of the transcription factor STAT3. Knowing that the tissue reparative cytokine interleukin (IL)-22 enhances STAT3 activity, the investigators added IL-22 to corticosteroid-treated, irradiated organoids. This rescued epithelial recovery, an observation that was confirmed in a GvHD mouse model.
This manuscript is the product of a long-lasting and successful transatlantic collaboration of physician scientists. The finding that corticosteroids impact directly on epithelial cell proliferation and regeneration and as such perpetuate alloreactive lymphocyte induced damage of the intestine is an important step in the understanding of steroid-refractory GvHD pathophysiology. It provides rationale to the clinical observation that delaying corticosteroid therapy can be detrimental, because it inhibits epithelial repair. Moreover, it adds to the growing understanding that prevention of tissue damage and enhancement of tissue recovery are equally important as suppression of alloreactive immune cells. Classically this is done by reducing the intensity of conditioning regimens, and recently the investigators provided clinical evidence for IL-22 and corticosteroid combination therapy (Ponce ea, Blood 2023; PMID: 36399701). Other approaches that are currently under investigation are aimed at preventing or repairing damage to the microbiome (dietary interventions, fecal microbiome transplantation; see for a recent comprehensive overview of this area Din ea, Molecular Medicine 2025; DOI: 10.1186/s10020-024-01060-x) or directed at the transfer of tissue reparative immune cells such as innate lymphoid cells (Bruce ea, Blood Advances 2021; DOI: 10.1182/bloodadvances.2020001514).