Fig. 1.
Fig. 1. The immunopathophysiology of GVHD. / Schematic representation of central role of GI tract damage during GVHD. In phase 1, the conditioning regimen (irradiation, chemotherapy, or both) leads to the damage and activation of host tissues, especially the intestinal mucosa. This allows the translocation of LPS from the intestinal lumen to the circulation, stimulating the secretion of the inflammatory cytokines TNF-α and IL-1 from host tissues, particularly macrophages. These cytokines increase the expression of MHC antigens and adhesion molecules on host tissues, enhancing the recognition of MHC and minor histocompatibility antigens by mature donor T cells. Donor T-cell activation in phase 2 is characterized by the proliferation of Th1 T cells in the presence of IL-12 and the secretion of IL-2 and IFN-γ. IL-2 and IFN-γ induce further T-cell expansion and CTL and NK cell responses, and they activate mononuclear phagocytes. The CTL and NK effectors damage tissue by perforin/granzyme, FasL, and TNF-α. In phase 3, effector functions of activated mononuclear phagocytes are triggered by the secondary signal provided by LPS and other immuno-stimulatory molecules that leak through the intestinal mucosa damaged during phases 1 and 2. This damage results in the amplification of local tissue injury, and it further promotes an inflammatory response. Damage to the GI tract in this phase, principally by inflammatory cytokines, amplifies LPS release and leads to the “cytokine storm” characteristic of severe acute GVHD. Double lines show the points at which KGF and IL-11 both interrupt this process, whereas single lines reflect interruption by IL-11 only. IL-11, but not KGF, promotes type 2 donor T-cell differentiation and inhibits IFN-γ secretion. Neither IL-11 nor KGF impairs CTL or NK function, thereby preserving GVL effects. The reduction in GI tract damage by these “cytokine shields” prevents systemic LPS translocation and reduces inflammatory cytokine production, culminating in reduced GI tract damage and subsequent death from GVHD.

The immunopathophysiology of GVHD.

Schematic representation of central role of GI tract damage during GVHD. In phase 1, the conditioning regimen (irradiation, chemotherapy, or both) leads to the damage and activation of host tissues, especially the intestinal mucosa. This allows the translocation of LPS from the intestinal lumen to the circulation, stimulating the secretion of the inflammatory cytokines TNF-α and IL-1 from host tissues, particularly macrophages. These cytokines increase the expression of MHC antigens and adhesion molecules on host tissues, enhancing the recognition of MHC and minor histocompatibility antigens by mature donor T cells. Donor T-cell activation in phase 2 is characterized by the proliferation of Th1 T cells in the presence of IL-12 and the secretion of IL-2 and IFN-γ. IL-2 and IFN-γ induce further T-cell expansion and CTL and NK cell responses, and they activate mononuclear phagocytes. The CTL and NK effectors damage tissue by perforin/granzyme, FasL, and TNF-α. In phase 3, effector functions of activated mononuclear phagocytes are triggered by the secondary signal provided by LPS and other immuno-stimulatory molecules that leak through the intestinal mucosa damaged during phases 1 and 2. This damage results in the amplification of local tissue injury, and it further promotes an inflammatory response. Damage to the GI tract in this phase, principally by inflammatory cytokines, amplifies LPS release and leads to the “cytokine storm” characteristic of severe acute GVHD. Double lines show the points at which KGF and IL-11 both interrupt this process, whereas single lines reflect interruption by IL-11 only. IL-11, but not KGF, promotes type 2 donor T-cell differentiation and inhibits IFN-γ secretion. Neither IL-11 nor KGF impairs CTL or NK function, thereby preserving GVL effects. The reduction in GI tract damage by these “cytokine shields” prevents systemic LPS translocation and reduces inflammatory cytokine production, culminating in reduced GI tract damage and subsequent death from GVHD.

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