Cytokines in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 357

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FIGURE 16.2
Cytokine production after HSCT. Following conditioning-induced tissue damage, NK and NKT cells are activated through activating receptor ligands (e.g., NKG2D) and
inhibitory receptors (e.g., killer inhibitory receptors (KIR)) and TCR ligation (in the case of NKT cells), resulting in rapid IFN- γ release and the licensing of recipient APC
(i.e., by upregulation of CD40 and CD80/86). Transplanted donor T cells are activated following interaction with these host APCs and undergo expansion and Th1/Tc1
differentiation. Of note, Th17/Tc17 differentiation can also occur, in response to IL-6 and TGF- β , as can the development of regulatory T cells (under the influence of TGF-
β alone) and these cells act to dampen disease. IFN- γ production by donor T cells augments gut damage via (i) promoting Th1 and Tc1 differentiation and subsequent
cytolysis against target tissue (e.g., via perforin/granzyme), (ii) direct cytopathic effects of the cytokine itself on the GIT, and (iii) priming monocytes/macrophages such
that they secrete quantities of TNF and lymphotoxin following signaling by TLR ligands that are themselves directly cytopathic to the GIT. In contrast to these pathogenic
effects, IFN- γ secretion by donor T cells is critical in the lung parenchyma to induce PDL1 expression, which subsequently inhibits donor T-cell survival and infiltration
within this organ, preventing the development of idiopathic pneumonia syndrome (IPS). In contrast, IL-17 is pathogenic at this site, in addition to the skin. IFN- γ also
promotes GVL effects via (i) the enhancement of CTL expansion and function (e.g., perforin/granzyme-dependent killing) and (ii) acting on leukemia cells directly (e.g.,
to upregulate MHC expression and death receptors), rendering them more susceptible to T-cell-mediated cytolysis. Regulatory T cells are also involved in decreasing
donor T-cell alloreactivity and inflammation via both IL-10-dependent and -independent mechanisms. (This figure has been modified from the original version, which was
originally published in Robb R J and Hill G R. 2012; Blood 119: 5351-8.) (Artwork by Madeleine Flynn, Queensland Institute of Medical Research.)
of proteins than either of the other IFN subtypes, but contribute to antiviral
responses and induce activation of many of the same genes as the type I
and II IFN molecules. This subtype is poorly understood at this time and
has not been studied in GVHD or GVL responses. Both type I interferons
and IFN-γ play critical roles in GVHD and GVL.
IFN- γ
IFN-γ is a pleiotropic cytokine that is produced in large amounts by Th1 and
Tc1 cells early after HSCT and is the archetypal “Th1” cytokine generated