Reduced p38 mitogen-activated protein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice

Abstract

The gastrointestinal tract is a major target of graft-versus-host disease (GVHD), which constitutes a life-threatening complication of bone marrow transplantation. GVHD is mainly caused by the activation of donor-derived lymphocytes, in which cytokine cascades play essential roles. Since p38 MAPK (p38) has been identified as a regulator of cytokine reactions and proposed as a molecular target for anti-inflammatory therapy, we investigated the contribution of p38 to the severity of murine intestinal GVHD. Unexpectedly, p38a +/-donor graft induced more acute GVHD-related mortality and more severe gut injury. The survival of p38a +/-donor-derived intestinal intraepithelial lymphocytes (IEL) was prolonged in vitro and in vivo, and TNF-a expression in the p38a +/-donor-derived IEL was also increased compared with wild-type cells. In contrast, the p38a +/-grafted mice resulted in decreased expansion of donor lymphocytes in mesenteric lymph nodes, and the up-regulation of IL-12p40 and IL-18 was diminished. These findings suggest that p38 has dichotomous effects for inflammatory response in vivo; not only regulates inflammatory cytokine expression and lymphocyte expansion, but also has distinct regulatory functions for IEL in intestinal GVHD. In conclusion, the inhibition of p38 may not be a suitable antiinflammatory strategy for GVHD due to the associated intestinal injury.

TRAIL‐induced cell death cooperates with IFN‐γ activation in the graft‐versus‐tumor effect against colon tumors

“…We modified the mouse model for allogeneic BMT and DLI with a full mismatch for major histocompatibility complex class I and II (B6 [H‐2b] or BALB/c [H‐2d] into BDF1 [H‐2b/d]) to study the GVT effect against solid tumors. Our preliminary experiments demonstrated that BMT and DLI combined with 1,200 rad irradiation caused 100% mortality from GVHD within 30 days 28. On the other hand, the allogeneic DLI mice survived for at least 2 months under conditions of 950 rad.…”

“…Our preliminary experiments demonstrated that BMT and DLI combined with 1,200 rad irradiation caused 100% mortality from GVHD within 30 days. 28 On the other hand, the allogeneic DLI mice survived for at least 2 months under conditions of 950 rad. Since systemic GVHD could be enhanced in proportion to the irradiation dose, 29 it was assumed GVHD would not be lethal with 950 rad irradiation.…”

Kinase Inhibition as Treatment for Acute and Chronic Graft-Versus-Host Disease

“…Acute GvHD: Although p38 MAPK inhibition seems promising in cGvHD, the treatment is questionable since reduced p38α MAPK levels (heterozygous p38α-KO) in donor grafts were found to accelerate acute intestinal GvHD in mice ( 197 ). Surprisingly, and contrary to the previously described cGvHD study, loss of donor p38 reinforced GvHD severity and reduced the survival of the mice.…”

“…Although p38α loss prolonged the survival of donor-derived intestinal intraepithelial lymphocytes in vitro and in vivo , donor lymphocyte expansion was decreased in the mesenteric lymph nodes upon p38α deficiency. Although the role of p38α-loss in the recipient compartment was not investigated, the study revealed a dichotomous effect of p38α in regulating inflammatory responses, cytokine expression, lymphocyte proliferation and intestinal GvHD after allo-HCT ( 197 ). Taken together with the before-mentioned study, the role of p38 MAPK in GvHD is still unclear and needs more detailed investigation, also comparing effects in chronic and acute GvHD as these could always be different ( 17 , 197 ).…”

“…Although the role of p38α-loss in the recipient compartment was not investigated, the study revealed a dichotomous effect of p38α in regulating inflammatory responses, cytokine expression, lymphocyte proliferation and intestinal GvHD after allo-HCT ( 197 ). Taken together with the before-mentioned study, the role of p38 MAPK in GvHD is still unclear and needs more detailed investigation, also comparing effects in chronic and acute GvHD as these could always be different ( 17 , 197 ). Differences could be due to the models as the study on cGvHD applied an inhibitor, whereas the aGvHD study investigated the role of p38 MAPK using a genetic approach with p38-deficient donor cells.…”