Graft-versus-host disease: establishing IL-33 as an important costimulatory molecule

Abstract

Approximately half of patients with hematologic malignancy who are treated with allogeneic hematopoietic stem cell transplantation (alloHCT) experience graft-versus-host disease (GVHD), which has high mortality rates despite immunosuppressive therapy. IL-12 is known to drive donor T cells toward an inflammatory Th1 lineage in GVHD, but other mechanisms also promote pathological Th1 alloimmune responses. In this issue of the JCI , Dwyer et al. report on their use of transgenic mice and alloHCT models of GVHD to demonstrate that IL-33 acts directly on donor T cells to increase Tbet expression independently of IL-12. Notably, IL-33 amplified T cell receptor–signaling pathways and inhibited production of regulatory molecules. These findings firmly establish IL-33 as an important costimulatory molecule for Th1 cells during GVHD and provide a target for reducing GVHD, especially in the gastrointestinal (GI) tract, where damage drives mortality.

Graft-Versus-Host Disease: Can Biomarkers Assist in Differential Diagnosis, Prognosis, and Therapeutic Strategy?

“…Both circulating ST2 and/or IL-33 have been suggested to be elevated in certain pathological conditions, including myocardial infarction, asthma, urticaria, heart failure, and, most recently, in resistant aGVHD [ 5 , 20 , 31 , 32 , 33 , 34 , 35 ]. Conversely, high levels of serum sST2 are a marker of poor prognosis in cardiovascular disease.…”

“…Despite the fact that IL-33/ST2 signaling has been well documented as a crucial mechanism in the onset and severity of aGVHD, particularly manifested in the GI tract of both murine models and stage IV human patients, the collected data seem to reveal a paradoxical role of IL-33 in the development of the disease [ 20 , 33 , 34 , 37 ]. It seems likely that IL-33 exerts different immune responses depending on the disease model, cell type, and inflammatory milieu [ 36 ].…”

“…The paradox of IL-33 is revealed when IL-33 is administered to murine models prior to alloHCT. It appears that early administration of IL-33 before transplantation has a “protective” effect, since it results in the prevention of macrophage activation and a decrease in the number of effector T cells that damage GVHD target tissues [ 33 , 34 ].…”

“…To summarize, the mechanism regulating aGVHD through IL-33/ST2 signaling is complex and remains to be fully elucidated. According to a well-established recent model, a simplified sequence of events may be as follows: The conditioning regimen performed in alloHCT causes damage to the GI epithelium and underlying fibroblastic reticular cells inducing them to produce IL-33 [ 33 , 34 ]. IL-33 then activates donor Th1 cells by binding to mST2; subsequently, Th1 cells differentiate and expand, promoting GVHD and further epithelial damage [ 34 ].…”

“…According to a well-established recent model, a simplified sequence of events may be as follows: The conditioning regimen performed in alloHCT causes damage to the GI epithelium and underlying fibroblastic reticular cells inducing them to produce IL-33 [ 33 , 34 ]. IL-33 then activates donor Th1 cells by binding to mST2; subsequently, Th1 cells differentiate and expand, promoting GVHD and further epithelial damage [ 34 ]. The sST2 serum concentration is suggested to be a predictor of GVHD severity and steroid-resistant aGVHD, and it most likely reflects the activation of and damage to the GI mesenchyme.…”