Acute graft- vs. host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding protein-1 (XBP-1s).
Inflammasome activity within recipient tissue directly impacts murine GVHD severity. NLRP3-deficient mice are partially protected from acute GVHD, while transfer of allogeneic NLRP3-deficient donor T cells to normal hosts has no protective effect. This suggests that inflammasome activity in antigen present cells, and/or DCs, contribute to acute GVHD. Furthermore, microRNA-155 is known to regulate DC inflammasome activity. MicroRNA-155 deficient murine DCs exhibit impaired IL-1β production from the inflammasome, and such recipient mice also develop significantly less severe acute GVHD.
In other studies, GVHD but not no GVHD transplant control mice were shown to induce inflammasome activation in myeloid-derived suppressor cells within the first 5 days post-transplant resulting in a loss of their suppressor function. Inflammasome activation has been linked to the expression of the purinergic receptors P2x7R and P2Y2, that can sense ATP from damage-associated molecular patterns produced during GVHD, while neutralizing ATP or purinergic receptor triggering reduces GVHD.
Similarly in patients, high ATP levels have been documented in the peritoneal fluid of patients with severe GVHD. Altogether, this evidence strongly supports the pathogenic role of the inflammasome in acute GVHD biology. However, translating this concept to clinical transplantation remains a challenge. Administering IL-1 receptor antagonist failed to prevent acute GVHD in some, but not all murine models, and in patients treated in the early post- or peri-HCT period, respectively.
While the inflammasome and IL-1β are biologically relevant to GVHD pathogenesis, the best strategy to target IL-1β and control donor T cells remains uncertain. Given the fundamental contributions of the inflammasome to acute GVHD and XBP-1s as a regulator of inflammasome activation, targeting ER stress via XBP-1s inactivation could represent a novel strategy to prevent acute GVHD.
In support of this possibility is work in autoimmune syndromes showing that blocking ER stress with tauroursodeoxycholic acid ameliorates experimental autoimmune encephalomyelitis and reduces Th17 differentiation. In a donor B cell dependent chronic GVHD model, suppressing XBP-1s in donor B cells reduces murine chronic GVHD. While these findings in murine chronic GVHD are important, translational questions regarding how the ER stress response influences human acute GVHD pathogenesis were not addressed.
The present work is distinct from observations in murine chronic GVHD, as we demonstrate that siRNA knock down or a small molecule inhibitor of XBP-1s can ameliorate DC-allostimulation of human T cells, and using a human skin xenograft model we show that pharmacologic inhibition of XBP-1s can reduce donor alloreactivity in vivo. Mechanistically, we also demonstrate how blocking the ER stress response of DCs impacts responding donor T cell activation and differentiation. Herein, we provide human data that support XBP-1s+ DCs are relevant biologic targets to prevent acute GVHD, without loss of Treg function or anti-tumor activity by CTLs and NK cells.