Limits...
Various forms of tissue damage and danger signals following hematopoietic stem-cell transplantation.

Ramadan A, Paczesny S - Front Immunol (2015)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Melvin and Bren Simon Cancer Center, Indiana University , Indianapolis, IN , USA ; Department of Microbiology and Immunology, Indiana University , Indianapolis, IN , USA.

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.

No MeSH data available.


Related in: MedlinePlus

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4309199&req=5

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.

Mentions: The pathogenesis of GVHD can be summarized in three sequential steps: first, the conditioning regimen damages the tissues, causing production of danger signals, which are detailed in this review, and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6. The culmination of these events is what the field refers to as the “cytokine storm,” which activates host antigen-presenting cells (APCs) and the newly infused donor T-cells. The second phase involves proliferation and differentiation of donor T-cells in response to host APCs, which results in rapid intracellular biochemical cascades that induce production of T helper (TH) 1, TH17 (for CD4 T-cells), T cytotoxic (TC) 1, and TC17 cells (for CD8 T-cells) that secrete cytokines such as interferon (IFN)-γ, IL-2, IL-17, and TNF-α. The last step is a complex cascade of cellular mediators and soluble inflammatory molecules that work synergistically to amplify local tissue injury. These mediators further amplify inflammation and target tissue destruction. GVHD is also characterized by an imbalance between the effector T-cells and the regulatory T-cells (Tregs). At all of these steps, the inflammatory cascade and various types of tissue damage lead to the release of biomarkers of GVHD into the blood, the detection of which can be achieved via blood tests. Markers such as elafin (skin-specific), regenerating islet-derived 3-alpha (REG3α, gut-specific), suppressor of tumorigenicity 2 (ST2, a member of the IL-1 receptor family, binding IL-33), and others are detailed in this review. Figure 1 summarizes these events.


Various forms of tissue damage and danger signals following hematopoietic stem-cell transplantation.

Ramadan A, Paczesny S - Front Immunol (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309199&req=5

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.
Mentions: The pathogenesis of GVHD can be summarized in three sequential steps: first, the conditioning regimen damages the tissues, causing production of danger signals, which are detailed in this review, and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6. The culmination of these events is what the field refers to as the “cytokine storm,” which activates host antigen-presenting cells (APCs) and the newly infused donor T-cells. The second phase involves proliferation and differentiation of donor T-cells in response to host APCs, which results in rapid intracellular biochemical cascades that induce production of T helper (TH) 1, TH17 (for CD4 T-cells), T cytotoxic (TC) 1, and TC17 cells (for CD8 T-cells) that secrete cytokines such as interferon (IFN)-γ, IL-2, IL-17, and TNF-α. The last step is a complex cascade of cellular mediators and soluble inflammatory molecules that work synergistically to amplify local tissue injury. These mediators further amplify inflammation and target tissue destruction. GVHD is also characterized by an imbalance between the effector T-cells and the regulatory T-cells (Tregs). At all of these steps, the inflammatory cascade and various types of tissue damage lead to the release of biomarkers of GVHD into the blood, the detection of which can be achieved via blood tests. Markers such as elafin (skin-specific), regenerating islet-derived 3-alpha (REG3α, gut-specific), suppressor of tumorigenicity 2 (ST2, a member of the IL-1 receptor family, binding IL-33), and others are detailed in this review. Figure 1 summarizes these events.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Melvin and Bren Simon Cancer Center, Indiana University , Indianapolis, IN , USA ; Department of Microbiology and Immunology, Indiana University , Indianapolis, IN , USA.

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.

No MeSH data available.


Related in: MedlinePlus