Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

Abstract

With the increasing use of mismatched, unrelated, and granulocyte colony-stimulating factor–mobilized peripheral blood stem cell donor grafts and successful treatment of older recipients, chronic graft-versus-host disease (cGVHD) has emerged as the major cause of nonrelapse mortality and morbidity. cGVHD is characterized by lichenoid changes and fibrosis that affects a multitude of tissues, compromising organ function. Beyond steroids, effective treatment options are limited. Thus, new strategies to both prevent and treat disease are urgently required. Over the last 5 years, our understanding of cGVHD pathogenesis and basic biology, born out of a combination of mouse models and correlative clinical studies, has radically improved. We now understand that cGVHD is initiated by naive T cells, differentiating predominantly within highly inflammatory T-helper 17/T-cytotoxic 17 and T-follicular helper paradigms with consequent thymic damage and impaired donor antigen presentation in the periphery. This leads to aberrant T- and B-cell activation and differentiation, which cooperate to generate antibody-secreting cells that cause the deposition of antibodies to polymorphic recipient antigens (ie, alloantibody) or nonpolymorphic antigens common to both recipient and donor (ie, autoantibody). It is now clear that alloantibody can, in concert with colony-stimulating factor 1 (CSF-1)-dependent donor macrophages, induce a transforming growth factor β–high environment locally within target tissue that results in scleroderma and bronchiolitis obliterans, diagnostic features of cGVHD. These findings have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition. This new understanding of cGVHD finally gives hope that effective therapies are imminent for this devastating transplant complication.

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

“…[36][37][38][39] Furthermore, changes in levels of tissue factors associated with fibrosis suggest a decreased propensity for tissue fibrosis and restoration of normal organ function. 40,41 These findings, together with the demonstration of clinical response across multiple organs, support the hypothesis that ibrutinib is affecting cGVHD at a pathogenic level and not just treating symptoms of cGVHD.…”

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

“…29,65 In spleens, frequency of total granulocytes was significantly reduced after B-I09 administration in the B10.D2 to BALB/c model (data not shown), in agreement with previous reports indicating that XBP-1 is critically involved in the differentiation and recruitment of granulocyte subsets into tissues leading to inflammatory fibrosis, 11,68,69 and that these subsets are involved in cGVHD. 70,71 Current leading therapies for cGVHD directly target B cells or T cells, 31,60 whereas the current study and previous literature suggest that inhibition of the IRE-1a/ XBP-1 pathway via B-I09 could directly impact other cell subsets involved in cGVHD development in addition to B cells and T cells, 65 such as dendritic cells, 10 granulocytes, 11 and even nonhematopoietic cells. 67 The ultimate goal of the HCT field is to cure cancers such as leukemia without producing deleterious GVHD.…”

“…28,60 In our study, recipients of XBP-1 KO donor grafts or recipients treated with an IRE-1a/XBP-1 pathway inhibitor B-I09 displayed reduced chronic CD8…”

Treating chronic GVHD-induced fibrosis?

“…Fibrosis may lead to severe life-threatening chronic respiratory deficiency if it involves the peribronchiolar pulmonary lobules. [2][3][4] Once fixed (and nonevolutive), fibrosis is poorly amenable to any therapeutic measure.…”

“…5 In some models, the chronic inflammatory state is maintained by T-helper 17 cells. [2][3][4] In this issue of Blood, Yamakawa et al designed an elegant set of experiments showing that targeting HSP47, a collagenspecific molecular chaperone that plays a critical role in collagen synthesis in myofibroblasts, leads to an impressive reduction in collagen deposition without inducing systemic immunosuppression (see figure). They first showed using immunofluorescent staining an accumulation of myofibroblasts in the dermis of animals after allogeneic transplantation.…”