TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Abstract

Graft-versus-host disease (GVHD) is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 (TLR4), which is a major receptor for bacterial lipopolysaccharides (LPS), in the development of acute GVHD, we used a TLR4-knockout (TLR4 2/2 ) mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4 2/2 mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type (TLR4 1/1 ) mice. In addition, histopathological analyses revealed that in TLR4 2/2 RBALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4 1/1 , TLR4 2/2 mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4 2/2 mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 (Th1) development was obviously attenuated compared with TLR4 1/1 mice dendritic cells, and the levels of interferon-c (IFN-c) and IL-10, Th2-cell specific cytokines, were significantly higher in the serum of TLR4 2/2 RBALB/c than in TLR4 1/1 RBALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.

The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease

“…In line with this, the Toll-like receptors for these molecules have been linked to GVHD development. Clinical and experimental evidence suggests that TLR4 mutations (receptor for lipopolysaccharide) provide a lower risk for acute GVHD, although this receptor may also be important to prevent bacteremia, 73,74 providing protection against disease. In addition, host mutations in the intracellular peptidoglycan receptor nucleotide-binding oligomerization domain-containing 2 (NOD2/CARD15) have been associated with acute GVHD and worse survival after HCT.…”

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

“…For example, Toll-like receptor (TLR) pathways are triggered through receptors on the plasma membrane (TLR2, TLR4) and in endosomes (TLR3, TLR7/8, TLR9). Deleting TLR or NOD-like receptor (NLR) pathways or blocking their activity with small molecule inhibitors significantly reduces acute GVHD (49–52). Similar mechanisms appear to be in place for chronic GVHD.…”

Role of Toll‐like receptor 4 signaling in cutaneous chronic graft‐versus‐host disease

“…Therefore, TLR may play an essential role in target organ damage in cGVHD. Some TLR4 ligands, such as LPS and heparin sulfate, promote acute GVHD , and TLR4 is an established contributor to this disease, whereas TLR4 inactivation by monoclonal antibody or knockout in mice protects mice after HSCT from acute GVHD . Our study shows for the first time that the expression of TLR4 and its related genes is increased in patients with cutaneous cGVHD, indicating that TLR4 may also play an important role in chronic GVHD.…”