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Review
. 2015 Jan 28;6:14.
doi: 10.3389/fimmu.2015.00014. eCollection 2015.

Various Forms of Tissue Damage and Danger Signals Following Hematopoietic Stem-Cell Transplantation

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Free PMC article
Review

Various Forms of Tissue Damage and Danger Signals Following Hematopoietic Stem-Cell Transplantation

Abdulraouf Ramadan et al. Front Immunol. .
Free PMC article

Abstract

Hematopoietic stem-cell transplantation (HSCT) is the most potent curative therapy for many malignant and non-malignant disorders. Unfortunately, a major complication of HSCT is graft-versus-host disease (GVHD), which is mediated by tissue damage resulting from the conditioning regimens before the transplantation and the alloreaction of dual immune components (activated donor T-cells and recipient's antigen-presenting cells). This tissue damage leads to the release of alarmins and the triggering of pathogen-recognition receptors that activate the innate immune system and subsequently the adaptive immune system. Alarmins, which are of endogenous origin, together with the exogenous pathogen-associated molecular patterns (PAMPs) elicit similar responses of danger signals and represent the group of damage-associated molecular patterns (DAMPs). Effector cells of innate and adaptive immunity that are activated by PAMPs or alarmins can secrete other alarmins and amplify the immune responses. These complex interactions and loops between alarmins and PAMPs are particularly potent at inducing and then aggravating the GVHD reaction. In this review, we highlight the role of these tissue damaging molecules and their signaling pathways. Interestingly, some DAMPs and PAMPs are organ specific and GVHD-induced and have been shown to be interesting biomarkers. Some of these molecules may represent potential targets for novel therapeutic approaches.

Keywords: alarmins; biomarkers; damage-associated molecular patterns; danger signals; graft-versus-host disease; innate immunity; pathogen-associated molecular patterns; tissue damage.

Figures

Figure 1
Figure 1
Pathogenesis of acute GVHD. Conditioning by irradiation and/or chemotherapy causes tissue damage. Damaged tissues and cells release DAMPs (HMGB-1), PAMPs (LPS) from gut microbiota as well as inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which contribute to the “cytokine storm.” These are the first danger signals that activate host APCs, which activate and polarized donor T-cells toward pathogenic T-cells (TH1 and TH17 for CD4 and TC1, TC17 for CD8). Activated pathogenic T-cells infiltrate target organs (i.e., GI tract, liver, skin) and amplify local tissue destruction. The presence of regulatory T-cells (Tregs) helps reduce GVHD severity through the inhibition of pathogenic cells activation and/or expansion at early or further phases of GVHD. Some of these DAMPs and PAMPs such as elafin (skin-specific), regenerating islet-derived 3-alpha (REG3α, gut-specific), and suppressor of tumorigenicity 2 (ST2, a member of the IL-1 receptor family, binding IL-33) have been shown to be biomarkers.
Figure 2
Figure 2
Toll-like receptors and IL-1 receptor family signaling pathways. ST2L (IL-33r) and IL-1r signal through the MyD88, IRAK4, and TRAF6 pathway. ST2L and IL-1r share this pathway with most TLRs. Binding of ST2L, IL-1r, and TLRs activates NF-κb, resulting in the release of inflammatory cytokines. Most TLRs signal through MyD88 expect for TLR3, which signals through the TRIF pathway. TLR4 can signal through both MyD88 and TRIF. TLR3, TLR7/TLR8, and TLR9 are expressed in the endosome while other TLRs are expressed on the cell surface. TLR1 and TLR6 recognize their ligand with TLR2 heterodimers.
Figure 3
Figure 3
Pathogen-associated molecular patterns and DAMPs share the same pathogen recognition receptors. TLR4 recognizes LPS from Gram negative bacteria as well as DAMPS [i.e., HMGB-1, heat shock proteins (HSP)70/90, and heparan sulfate]. NOD can recognize peptidoglycan, which is known as TLR2 ligand, and some DAMPs such as ATP, S100 proteins, and uric acid. These signaling pathways all end with activation of NF-κb.
Figure 4
Figure 4
Roles of IL-23 in GI GVHD. Conditioning induces IL-23 production and LPS release from the GI tract. LPS and IL-23 act together to prime APCs to activate alloreactive T-cells. Activated T-cells produce IFN-γ and other inflammatory cytokines, resulting in the elimination of ILC3 and damage of the intestinal stem cells. This leads to more gut injury and GI GVHD (left). In the absence of alloreactive donor T-cells, IL-23 stimulates ILC3 to release IL-22, which protects the intestinal stem-cell compartment and promotes gut recovery from conditioning damage (right).
Figure 5
Figure 5
Pathogenesis of chronic GVHD. The thymic epithelial cells (TECs) are damaged by alloreactive T-cells leading to impaired negative selection. In addition, alloreactive B- and T-cells cross talk leading to sBAFF release and production of alloantibodies by plasma cells. At the same time, cytokines and chemokines produced by B- and T-cells activate macrophages and monocytes. Together, antibodies and TGFβ induce fibroblasts proliferation and activation as well as collagen production, which results in fibrosis in target organs such as the lungs.

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