Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

Abstract

Key Points• Donor treatment with agonistic DR3 antibody induces selective expansion of Tregs and reduced activation of conventional T cells.• T cells from DR3 antibodytreated donors result in reduced acute GVHD and preserved GVT effects. numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from aDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4 1 T cells were maintained, resulting in improved survival. Conventional T cells derived from aDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNg, IL-1b, and TNFa) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from aDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of aDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg-based therapies. (Blood. 2015; 126(4):546-557)

Donor Cell Composition and Reactivity Predict Risk of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

“…Additionally, the flow cytometry panel could be expanded to include more cellular markers to identify frequencies of other cellular populations that might play important roles in this context, such as regulatory T-cells, myeloid-derived suppressor cells (MDSCs), and mucosal-associated-invariant T-cells (MAITs). Recent studies suggest that these may play critical roles in GVHD development after HSCT and therefore warrant more extensive studies [65–69]. …”

T cells expressing chimeric antigen receptor promote immune tolerance

“…For intranuclear factors, we used the anti-mouse/rat FoxP3 Staining Set (eBioscience) and for staining dead cells we use Cisplatin (Sigma-Aldrich). Analysis was performed on Cytof, and data were analyzed through Cytobank as previously described (47).…”

“…The cells were then washed in PBS (ThermoFisher). Phosphorylation of STAT5 was detected as described previously (47). Briefly, the cells were pulsed with 0, 100, 1,000, and 2,000 IU/ml recombinant IL-2 (rIL-2, Teceleukin, Hoffmann-La Roche) for 15 minutes before fixation with 4% paraformaldehyde (Sigma-Aldrich).…”

Steroids Versus Steroids Plus Additional Agent in Frontline Treatment of Acute Graft-versus-Host Disease: A Systematic Review and Meta-Analysis of Randomized Trials

“…Sensitive and specific early predictive or prognostic biomarkers of severe aGvHD or of steroid refractoriness could help identify high-risk patients that may benefit from early intervention, perhaps using alternative strategies beyond generic immunosuppression. Future progress in treatment of aGvHD may depend on targeting specific inflammatory mediators 20–23 , alternative immunomodulating approaches 24,25 , and more attention to non-immune-related pathways 26–28 rather than escalating generic immunosuppression.…”