Although available data indicate an association among pretransplantation conditioning intensity, intestinal barrier loss, and severity of graft-vs-host disease, the multiple effects of irradiation and other types of conditioning have made it difficult to precisely identify the role of intestinal barrier loss in graft-vs-host disease.
In a study reported in Science Translational Medicine, Nalle and colleagues developed graft-vs-host disease models that permitted identification of individual pretransplantation variables. It was found that intestinal damage was required for development of MHC minor-mismatch graft-vs-host disease but not for major-mismatch graft-vs-host disease. Natural killer cells in the transplant recipient were found to prevent minor-mismatch graft-vs-host disease via a perforin-dependent process that limited the expansion of alloreactive T cells and their infiltration into the target organ.
Myeloid differentiation primary response protein 88 (MyD88)-mediated Toll-like receptor 4 signaling on donor cells was required for minor-mismatch graft-vs-host disease. Intestinal damage could be bypassed by parenteral lipopolysaccharide administration, indicating that the influx of bacterial components associated with intestinal barrier loss is a central component in minor-mismatch graft-vs-host disease pathogenesis.
The authors concluded, “In all, the data demonstrate that pretransplant conditioning plays a dual role in promoting minor mismatch [graft-vs-host disease] by both depleting recipient [natural killer] cells and inducing intestinal barrier loss.” ■
Nalle SC, et al: Sci Transl Med 6:243ra87, 2014.