Upregulation of IFN-Inducible and Damage-Response Pathways in Chronic Graft-versus-Host Disease

Abstract

Although Chronic Graft-versus-Host Disease (CGVHD) is the primary non-relapse complication of allogeneic transplantation, understanding of its pathogenesis is limited. To identify the main operant pathways across the spectrum of CGVHD, we analyzed gene expression in circulating monocytes, chosen as in situ systemic reporter cells. Microarrays identified two interrelated pathways: (1) Interferon-inducible genes and (2) innate receptors for cellular damage. Corroborating these with multiplex RNA quantitation, we found that multiple IFN-inducible genes (affecting lymphocyte trafficking, differentiation and antigen presentation) were concurrently upregulated in CGVHD monocytes compared to normal and nonCGVHD controls. IFN-inducible chemokines were elevated in both lichenoid and sclerotic CGHVD plasma and linked to CXCR3+ lymphocyte trafficking. Furthermore, the IFN-inducible genes CXCL10 and TNFSF13B (BAFF) levels were correlated at both the gene and plasma levels, implicating IFN-induction as a factor in elevated BAFF levels in CGVHD. In the second pathway, DAMP/PAMP receptor genes capable of inducing Type I IFN were upregulated. Type I IFN-inducible MxA was expressed in proportion to CGVHD activity in skin, mucosa and glands, and expression of TLR and RIG-1 receptor genes correlated with upregulation of Type I IFN-inducible genes in monocytes. Finally, in serial analyses following transplant, IFN-inducible and damage-response genes were upregulated in monocytes at CGVHD onset and declined upon therapy and resolution in both lichenoid and sclerotic CGVHD patients. This interlocking analysis of IFN-inducible genes, plasma analytes and tissue immunohistochemistry strongly supports a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD.

Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity

“…However, in clinical alloSCT, in which pharmacologic immunosuppression is given, such a rise in IFN-γ may only infrequently occur, and this may in part contribute to the more global GVL resistance of myeloblastic leukemias. Chronic GVHD (cGVHD) has been associated with a lower risk for AML relapse, and recent data suggest that cGVHD is associated with the action of IFN-γ (37). Perhaps the sustained IFN-γ associated with cGVHD contributes to GVL, along with alloreactive cytolytic T cells.…”

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

“…The IL-33 receptor, ST2/IL1RL1, now recognized as a biomarker for both acute and chronic GVHD, is also released in response to cell damage (83–87). Third, gene expression in circulating monocytes from clinical samples has revealed that multiple interferon (IFN)-inducible genes and receptors for pathogen-associated molecular patterns and damage-associated molecular patterns [known as pattern recognition receptors (PRRs)] become upregulated at the time of onset of chronic GVHD, remaining elevated in patients with active disease (88). These IFN-inducible and PRR genes were comparably upregulated in patients with cutaneous lichenoid infiltrates and in those with extensive sclerotic involvement, providing a common operant mechanism across the spectrum of chronic GVHD manifestations (88).…”

“…Third, gene expression in circulating monocytes from clinical samples has revealed that multiple interferon (IFN)-inducible genes and receptors for pathogen-associated molecular patterns and damage-associated molecular patterns [known as pattern recognition receptors (PRRs)] become upregulated at the time of onset of chronic GVHD, remaining elevated in patients with active disease (88). These IFN-inducible and PRR genes were comparably upregulated in patients with cutaneous lichenoid infiltrates and in those with extensive sclerotic involvement, providing a common operant mechanism across the spectrum of chronic GVHD manifestations (88). Use of a neutralizing Type I IFN receptor (IFNAR) antibody prevented skin and vascular changes in a sclerotic chronic GVHD murine model (B10.D2→BALB/c), and a similar strategy reduced Th1 activation and collagen production in a phase I clinical trial for patients with for systemic sclerosis (89, 90).…”

The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease

“…In one of the studies, CXCL10 and another CXCR3-binding protein, CXCL9, were both increased. However, only CXCL10 had an ROC curve AUC of ≥0.75, and was validated in different groups [41,42,46]. Another CXCR3 ligand involved in the pathogenesis of cGVHD is CXCL11.…”