Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors

Abstract

Acute graft-versus-host disease (GVHD) remains the major obstacle to a more favorable therapeutic outcome of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is characterized by tissue damage in gut, liver, and skin, caused by donor T cells that are critical for antitumor and antimicrobial immunity after HSCT. One obstacle in combating GVHD used to be the lack of understanding the molecular mechanisms that are involved in the initiation phase of this syndrome. Recent research has demonstrated that interactions between microbial-associated molecules (pathogen-associated molecular patterns [PAMPs]) and innate immune receptors (pathogen recognition receptors [PRRs]), such as NOD-like receptors (NLRs) and Toll-like receptors (TLRs), control adaptive immune responses in inflammatory disorders. Polymorphisms of the genes encoding NOD2 and TLR4 are associated with a higher incidence of GVHD in HSC transplant recipients. Interestingly, NOD2 regulates GVHD through its inhibitory effect on antigen-presenting cell (APC) function. These insights identify important mechanisms regarding the induction of GVHD through the interplay of microbial molecules and innate immunity, thus opening a new area for future therapeutic approaches. This review covers current knowledge of the role of PAMPs and PRRs in the control of adaptive immune responses during inflammatory diseases, particularly GVHD.

Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2rγnull H2-Ab1 tm1GruTg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease

“…These regimens stimulate the release of proinflammatory cytokines such as interleukin (IL)-1 and tumour necrosis factor (TNF) and induce damage in the gastrointestinal tract, resulting in exposure to microbial products such as lipopolysaccharide (LPS) [10][11][12][13]. The induced inflammatory response triggers increased expression of major histocompatibility complex (MHC), co-stimulatory molecules, adhesion molecules and chemokines that promote the activation of donor immune cells [6].…”

The Microbiome and Graft Versus Host Disease

“…Further, utilizing cytosine-phosphorothioateguanine oligodeoxynucleotides (CpG ODNs), which mimics bacterial and viral DNA and stimulates TLR9, Blazar et al found that CpG treatment enhanced allo-T cell responses leading to increased GVHD severity and mortality [72]. These TLR9 dependent studies emphasize the importance of TLR signaling for host APC function during GVHD [73]. The analysis of TLR9 gene associated polymorphisms on the clinical outcome of 413 donors showed no association of the TLR9 polymorphisms with incidence or severity of GVHD [70,73].…”

“…These TLR9 dependent studies emphasize the importance of TLR signaling for host APC function during GVHD [73]. The analysis of TLR9 gene associated polymorphisms on the clinical outcome of 413 donors showed no association of the TLR9 polymorphisms with incidence or severity of GVHD [70,73]. However, patients with the T1486C mutation exhibited significantly improved survival due to reduced TRM and relapse rate.…”

'Nodophagy'

“…Their clinical implication may be more farreaching, as the roles of both Nod2 and autophagy continue to expand beyond IBD to include graft-versus-host disease, sepsis and malignancies to name but a few. [9][10][11][12][13] Thus, the strong association of NOD2 gene polymorphisms with CD suggests a crucial role of this receptor in coordinating the innate and adaptive antimicrobial defense in CD pathogenesis.…”