The road to refractory graft-versus-host disease is paved with good intentions
Daniel North, Ronjon Chakraverty
Daniel North, Ronjon Chakraverty
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Commentary

The road to refractory graft-versus-host disease is paved with good intentions

Abstract

Refractory acute graft-versus-host disease (GVHD) occurs when the immune injury exceeds the capacity of injured tissues to regenerate and repair. While glucocorticoids have been used for decades to treat GVHD, Arnhold, Chang, and colleagues in this issue of the JCI question whether this approach can in fact be counterproductive. Using in vivo experimental models of GVHD and in vitro intestinal organoids, the study authors show that glucocorticoid exposure directly impeded small intestinal epithelial proliferation and survival, thus preventing the resolution of injury. These findings suggest that future treatment approaches for acute GVHD should include measures to reduce immune reactivity as well as interventions to actively promote tissue resilience.

Authors

Daniel North, Ronjon Chakraverty

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Figure 1

Glucocorticoids impair tissue tolerance in intestinal GVHD.

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Glucocorticoids impair tissue tolerance in intestinal GVHD. The relation...
The relationship between tissue homeostasis and acute intestinal GVHD can be modeled in a linear graph as tissue health versus immune reactivity, in which the degree of tolerance is reflected in the steepness of the slope. In the absence of immune injury, tissue health corresponds with homeostasis. Tissues with high tolerance display a shallow slope and are more likely to reach resolution with treatment. Conversely, tissues with low tolerance show a steep slope and are more likely to remain in an unresolved disease state despite treatment. At the onset of acute intestinal GVHD, inhibition of immune reactivity in tissues with high tolerance may permit the resolution of disease, provided baseline tissue tolerance remains intact. However, if glucocorticoid treatment not only reduces immune reactivity but also reduces tissue tolerance, GVHD will remain unresolved. Notably, the promotion of epithelial regeneration by IL-22 can offset glucocorticoid mediation reductions in tissue tolerance, thus facilitating a return to homeostasis and health. Diagram adapted from Wu and Reddy (25).