TNFAIP8 Deficiency Exacerbates Acute Graft Versus Host Disease in a Murine Model of Allogeneic Hematopoietic Cell Transplantation

Abstract

Background. Gastrointestinal acute graft-versus-host disease (GVHD) occurring after allogeneic hematopoietic cell transplant is an allo-reactive T cell and inflammatory cytokine driven organ injury with epithelial apoptosis as 1 of its hallmark findings and is associated with significant mortality. Tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8 or TIPE) acts as a negative mediator of apoptosis via inhibition of caspase-3 activation, promotes cell proliferation and Tipe −/− deficiency is associated with increased inflammation. Methods. To evaluate the role of TIPE in acute GVHD, naive C57BL/6 and Tipe −/− C57BL/6 mice were conditioned with 1000 cGy single dose total body irradiation, followed by transplantation of 10 million bone marrow cells and 20 million splenocytes from either syngeneic C57BL/6 or allogeneic BALB/c donors. Results. Allo TIPE-deficient mice developed exacerbated gut GVHD compared with allo controls and had significantly decreased survival (6 wk overall survival: 85% versus 37%; P < 0.05), higher clinical GVHD scores, more profound weight loss, increased serum proinflammatory cytokines (interleukin-17A, TNF, interleukin-6, and interferon-γ). T-cell infiltration into the ileum was increased; epithelial proliferation was decreased along with significantly higher levels of chemokines KC and monokine induced by gamma interferon. Using bone marrow chimeric experiments, TIPE was found to have a role in both hematopoietic and nonhematopoietic cells. Conclusions. Absence of TIPE results in excessive inflammation and tissue injury after allo-HCT, supporting that TIPE confers immune homeostasis and has tissue-protective function during the development of gut GVHD and may be a potential future target to prevent or treat this complication after allogeneic HCT.

Current research status of TNFAIP8 in tumours and other inflammatory conditions (Review)

“…TNFAIP8 deficiency induced the downregulation of Ki-67 in non-haematopoietic and haematopoietic cells, increased epithelial cell apoptosis, destroyed the epithelial barrier integrity and increased symbiotic bacterial transmission, resulting in enhanced leukocyte infiltration and inflammatory responses, increased levels of proinflammatory cytokines such as IL-17A, TNF and interferon γ, and increased expression of chemokine (C-X-C motif) ligand 1, which contributes to exacerbating GVHD. This finding suggests that TNFAIP8 plays an important role in maintaining intestinal homeostasis and preventing complications associated with allograft transplantation (80). Controlled overexpression of TNFAIP8 might be an innovative therapeutic for GVHD progression.…”

“…Allogeneic stem cell transplantation (aSCT) causes chronic graft-versus-host disease (cGVHD), and TNFAIP8 is a candidate molecular target of cGVHD and aSCT (79). In a previous study, allogeneic haematopoietic cell transplantation caused acute GVHD in the gastrointestinal tract, and TNFAIP8-knockout mice exhibited significantly exacerbated GVHD, weight loss and increased mortality rates (80). TNFAIP8 deficiency induced the downregulation of Ki-67 in non-haematopoietic and haematopoietic cells, increased epithelial cell apoptosis, destroyed the epithelial barrier integrity and increased symbiotic bacterial transmission, resulting in enhanced leukocyte infiltration and inflammatory responses, increased levels of proinflammatory cytokines such as IL-17A, TNF and interferon γ, and increased expression of chemokine (C-X-C motif) ligand 1, which contributes to exacerbating GVHD.…”

TNFAIP8: Inflammation, Immunity and Human Diseases

“…Recently, the role of TNFAIP8 in acute Graft Versus-Host Disease was investigated in a murine model, and the study revealed that TNFAIP8 deficiency in allogeneic C57BL/6 recipient mice have a lower survival rate compared with allogeneic wild type recipients. TNFAIP8 deficiency increased splenic CD4 + cells levels, serum cytokines (IL-17A, TNF, and IL-6) levels, and active caspase-3 expression in the small intestine, whereas, cell survival factor Ki-67 expression was significantly decreased in epithelial cells of small intestine suggesting that TNFAIP8 might be involved in increased GI tract pathology risk [48]. Moreover, the expression of TNFAIP8 and TIPE2 is associated with diabetic nephropathy in glomeruli from streptozotocin (STZ)-induced diabetic rats, and renal biopsies of diabetic patients in vivo [49].…”