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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 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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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.

Mentions: Graft-versus-host disease studies have led to a decrease of early mortality in related-allogeneic HSCTs, but late long-term morbidity and mortality caused by chronic GVHD remains a major challenge (291). The pathogenesis of chronic GVHD is complex and poorly understood, but is likely to involve dysfunction of tolerance determining mechanisms similar to classic autoimmune diseases. Figure 5 summarizes some of the knowledge of the pathophysiology of chronic GVHD. Briefly, negative selection in the thymus is impaired because of thymic epithelial cell (TEC) damage after allogeneic reaction. In addition, the cross talk between alloreactive T-cells and B-cells enhances B-cell activating factor (BAFF) release and production of alloantibodies, which, together with cytokines and chemokines produced by T-cells and B-cells, activates macrophages and induces proliferation and activation of fibroblast and collagen production, resulting in tissue fibrosis. Very few studies showed a direct impact of PAMPs or DAMPs in chronic GVHD. It has been shown that LPS enhances peribronchiolar fibrosis in synergy with TH17 production and leads to chronic pulmonary GVHD (292). However, a clear indirect effect is the altered T- and B-cell homeostasis. Patients with chronic GVHD showed inverted ratio of CD4:CD8 (293). CD4+ regulatory T-cell frequency was dramatically decreased in these patients comparing to patients without active chronic GVHD. This reduction in Tregs:Tcon ratio was explained as following: (i) Tregs acquire a predominately effector memory phenotype (294), (ii) under lymphopenia-induced expansion, CD4+ Tregs proliferate more than conventional T-cells, which increases Treg susceptibility to Fas-mediated apoptosis (295), and (iii) progressive loss of Aire expression by TEC, which is crucial for naive Treg generation (294). In chronic GVHD, critical breakdown in peripheral B-cell tolerance was shown. Among patients with cGVHD, BAFF reaches a persistently high level (296). Chronic exposure to BAFF results in elevated basal expression of the proximal signaling components B-cell linker protein (BLNK) and Syk, which may contribute to increased responsiveness of BCR stimulation (297). Murine models of cGVHD also provided insights showing that unrestrained T follicular helper cells and germinal center B-cells are abnormally increased and strongly correlate with the development of cGVHD (298). Together, chronic GVHD is likely caused by a lack of central tolerance involving thymus dysfunction, disequilibrium of T-reg/Tcon balance, and alloantibodies generated by alloreactive B-cells.


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

Ramadan A, Paczesny S - Front Immunol (2015)

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

License
Show All Figures
getmorefigures.php?uid=PMC4309199&req=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.
Mentions: Graft-versus-host disease studies have led to a decrease of early mortality in related-allogeneic HSCTs, but late long-term morbidity and mortality caused by chronic GVHD remains a major challenge (291). The pathogenesis of chronic GVHD is complex and poorly understood, but is likely to involve dysfunction of tolerance determining mechanisms similar to classic autoimmune diseases. Figure 5 summarizes some of the knowledge of the pathophysiology of chronic GVHD. Briefly, negative selection in the thymus is impaired because of thymic epithelial cell (TEC) damage after allogeneic reaction. In addition, the cross talk between alloreactive T-cells and B-cells enhances B-cell activating factor (BAFF) release and production of alloantibodies, which, together with cytokines and chemokines produced by T-cells and B-cells, activates macrophages and induces proliferation and activation of fibroblast and collagen production, resulting in tissue fibrosis. Very few studies showed a direct impact of PAMPs or DAMPs in chronic GVHD. It has been shown that LPS enhances peribronchiolar fibrosis in synergy with TH17 production and leads to chronic pulmonary GVHD (292). However, a clear indirect effect is the altered T- and B-cell homeostasis. Patients with chronic GVHD showed inverted ratio of CD4:CD8 (293). CD4+ regulatory T-cell frequency was dramatically decreased in these patients comparing to patients without active chronic GVHD. This reduction in Tregs:Tcon ratio was explained as following: (i) Tregs acquire a predominately effector memory phenotype (294), (ii) under lymphopenia-induced expansion, CD4+ Tregs proliferate more than conventional T-cells, which increases Treg susceptibility to Fas-mediated apoptosis (295), and (iii) progressive loss of Aire expression by TEC, which is crucial for naive Treg generation (294). In chronic GVHD, critical breakdown in peripheral B-cell tolerance was shown. Among patients with cGVHD, BAFF reaches a persistently high level (296). Chronic exposure to BAFF results in elevated basal expression of the proximal signaling components B-cell linker protein (BLNK) and Syk, which may contribute to increased responsiveness of BCR stimulation (297). Murine models of cGVHD also provided insights showing that unrestrained T follicular helper cells and germinal center B-cells are abnormally increased and strongly correlate with the development of cGVHD (298). Together, chronic GVHD is likely caused by a lack of central tolerance involving thymus dysfunction, disequilibrium of T-reg/Tcon balance, and alloantibodies generated by alloreactive B-cells.

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