Immunopathology and biology-based treatment of steroid-refractory graft-versus-host disease

Abstract

Acute graft-versus-host disease (GVHD) is one of the major life-threating complications after allogeneic cell transplantation (allo-HCT). Although steroids remain first-line treatment, roughly one half of patients will develop steroid refractory GVHD (SR-GVHD) which portends an extremely poor prognosis. Many agents, which have shown encouraging response rates in early phase I/II trials for prevention and treatment, have been unsuccessful in demonstrating a survival advantage when applied in the setting of SR-GVHD. The discovery of novel treatments has been further complicated by the absence of clinically informative animal models that address what may reflect a distinct pathophysiology. Nonetheless, the combined knowledge of established bone marrow transplantation (BMT) models and recent human trials in SR-GVHD patients are beginning to illuminate novel mechanisms for inhibiting T cell signaling and promoting tissue tolerance that provide an increased understanding of the underlying biology of SR-GVHD. Here we discuss recent findings of newly appreciated cellular and molecular mechanisms and provide novel translational opportunities for advancing the effectiveness of treatment in SR-GVHD.

IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice

“…1a ). High serum concentration of Reg3α, ST2 and sTNFR has been associated with SR-Gut-aGVHD in patients 27 . The 4-DEX-treated recipients also showed marked increase in serum Reg3γ, ST2, and sTNFR as compared with non-GVHD or 1-DEX-treated GVHD recipients (Fig.…”

“…Interestingly, although positive response with administration of IL-22 was 100% in low-risk Gut-aGVHD patients, it was <50% in high-risk patients 56 . Patients with SR-Gut-aGVHD belongs to high-risk 27 . Consistent with pathogenic role of neutrophils 43 , 44 , we observed that anti-IL-22 treatment markedly reduced neutrophil infiltration in the colon tissues of Gut-aGVHD induced by Tc22 cells.…”

“…Corticosteroids are used for initial treatment of aGVHD 26 . Some patients develop steroid-resistant or refractory (SR) Gut-aGVHD, and the pathogenesis of SR-Gut-aGVHD remains enigmatic 27 , 28 . Steroid-treatment effectively suppresses Th1/Tc1 but not Th17 29 , and IL-17A + CD4 + T cells infiltrate the intestinal tissues of patients with SR-Gut-aGVHD 30 .…”

“…Steroid-treatment effectively suppresses Th1/Tc1 but not Th17 29 , and IL-17A + CD4 + T cells infiltrate the intestinal tissues of patients with SR-Gut-aGVHD 30 . However, targeting steroid-resistant T cells with ATG or anti-CD25 in patients with SR-Gut-aGVHD has not been effective 27 . A recent study with murine models indicated that T cells were dispensable for SR-GVHD pathogenesis 31 .…”

Safety and Efficacy of Fecal Microbiota Transplantation for Grade IV Steroid Refractory GI-GvHD Patients: Interim Results From FMT2017002 Trial

“…Conventionally, glucocorticoids are used as the first-line therapy for GI-GvHD. Unfortunately, almost half of the patients do not respond well to glucocorticoids (3)(4)(5). The survival of patients with GI-GvHD treated with standard steroid regimen ranges between 5% and 30% (4-8).…”