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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

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).
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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).

Mentions: Gut tissue damage may be the first consequence of transplant conditioning and could be of particular significance for GVHD for two main reasons: the transplant conditioning regimen may deplete and/or alter the microbiota and epithelial barrier damage could allow for increased bacterial translocation, specifically in the gut. It is assumed that these processes lead to an increase in inflammation and exacerbate epithelial insult, as shown in an IBD model (216). Certain commensals such as Bifidobacterium strains may protect the host by improving the intestinal barrier. Bifidobacterium have carbohydrate transporters that can generate short-chain fatty acids, particularly acetate, which promotes defense functions in host epithelial cells in the distal colon (217). Recent GVHD studies have begun to analyze the dynamics of the gut flora during HSCT and how the innate immune receptors that recognize microbes may contribute to GVHD pathogenesis. In an experimental irradiation-independent non-myeloablative HSCT model, a gut microbial shift toward pro-inflammatory bacterial species was seen in mice that develop GVHD (136). It is still unclear whether the microbial changes in the gut are the cause or the result of GVHD, and whether these bacterial populations reflect endogenous microflora or overgrowth of pathogenic organisms due to the elimination of benign microbes. Endotoxin is a constituent of normal bowel flora that has the ability to stimulate the release of inflammatory cytokines that are known to be important mediators of clinical GVHD and most likely permeate the systemic circulation through the intestinal barrier, which is disrupted by the conditioning treatment (218). Also, microbial super antigens may activate B-cells by direct stimulation of MHC class II molecules (219). The early phases of changes in the GI tract have been described in animal models that do not use chemotherapy or radiation to condition the host; therefore, direct comparisons to clinical GVHD after bone marrow transplantation are not possible. The initial proliferative phase results in increased crypt cell mitotic activity, crypt lengthening, and the presence of intraepithelial lymphocytes. In experimental systems, this phase seems to be linked to IFN-γ production (220), which increases MHC class II expression and gut permeability by altering tight junction integrity and may modulate crypt stem-cell turnover (221). The histologic features of the GI tract in clinical GVHD and experimental GVHD after myeloablative conditioning are consistent with the destructive and atrophic phases, characterized by villus blunting, lamina propria inflammation, crypt destruction (with crypt stem-cell loss), and mucosal atrophy (222). Cytotoxic T lymphocytes do not appear to play a dominant role in experimental GVHD of the GI tract (215, 223–225), despite the ability of intraepithelial lymphocytes to induce Fas-mediated apoptosis of host-type tumor cells (226). It is clear, when these findings are considered in aggregate, that cytokines and cellular effectors combine to produce the specific damage to target organs as well as the systemic toxicity of acute GVHD. Furthermore, the absence of GVHD toxicity in other visceral organs, such as the kidney (currently debated), argues against circulating cytokines as the sole cause of tissue-specific damage. The infiltrates seen in GVHD target organs are generally thought to consist of T-cells responding to alloantigens presented by host tissues. LPS leakage through the skin or mucosa may act as an adjuvant to the antigens expressed in these tissues, attracting and activating alloreactive donor T-cells. In BMT models, LPS levels increase progressively during the first 4 weeks post-BMT. These levels lead to aggravated disease severity through TLR4 signaling, which induces inflammatory cytokine production. Deficiency of TLR4 on donor bone marrow cells reduces colonic GVHD severity. Interestingly, this reduction in GVHD severity was accompanied with a decrease of IL-23 levels. On the other hand, mice receiving allogeneic bone marrow from IL-23 knockout mice demonstrated less colonic pathology, and low levels of colonic LPS compared to wild-type controls. Interestingly, IL-17 was not detectable in the colon, while IFN-γ was markedly increased, in association with the LPS/IL-23 feedback loop (227). In consequence, IFN-γ activated macrophages after exposure to LPS release a significant amounts of inflammatory cytokines in GI tract but not in other target organs of GVHD (218). IL-23 could also enhance host IL-22-producing type 3 innate lymphoid cells (ILC3s) and promote gut recovery after conditioning. Alloreaction generated by donor T-cells damages the gut stem-cell compartment and eliminates recipient IL-22 producing ILC3, which are the main source of IL-22 in the gut and are known to protect intestinal stem cells (228). A deficiency in ILC3s leads to severe liver and GI GVHD and increases mortality. Moreover, a recent clinical study showed clear correlation between activation and expansion of intestinal ILC3s and the absence of acute GVHD (229). Figure 4 shows a hypothetical model for the roles of IL-23 in GI GVHD. Thus, reductions in the doses of chemoradiotherapy to condition bone marrow transplant recipients have reduced the incidence of GVHD, as demonstrated in experimental models (230, 231). This reduction is the result of reduced priming of mononuclear cells by lower doses of total body irradiation (TBI) and subsequent reductions in TNF-α production (224). Intestinal and liver tissue damage leads to the release of soluble mediators that correlate positively with GI and liver GVHD pathology. Significant augmentation of liver epithelial marker cytokeratin-18 protein (CK18) (232) has been demonstrated in serum from patients with hepatic and GI GVHD. Interestingly, CK18 levels begin to increase before the clinical manifestation of GVHD in some patients. Also, CK18 levels were correlated with bilirubin (liver function marker) levels. This correlation is specific to hepato-intestinal GVHD (233). RegIIIα levels were also significantly increased in patients with GI GVHD as mentioned above (105, 234). It is well known that Reg proteins act downstream of IL-22, which protects the function of intestinal mucosa, intestinal stem cells, and ILC3s (235, 236).


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

Ramadan A, Paczesny S - Front Immunol (2015)

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

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

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).
Mentions: Gut tissue damage may be the first consequence of transplant conditioning and could be of particular significance for GVHD for two main reasons: the transplant conditioning regimen may deplete and/or alter the microbiota and epithelial barrier damage could allow for increased bacterial translocation, specifically in the gut. It is assumed that these processes lead to an increase in inflammation and exacerbate epithelial insult, as shown in an IBD model (216). Certain commensals such as Bifidobacterium strains may protect the host by improving the intestinal barrier. Bifidobacterium have carbohydrate transporters that can generate short-chain fatty acids, particularly acetate, which promotes defense functions in host epithelial cells in the distal colon (217). Recent GVHD studies have begun to analyze the dynamics of the gut flora during HSCT and how the innate immune receptors that recognize microbes may contribute to GVHD pathogenesis. In an experimental irradiation-independent non-myeloablative HSCT model, a gut microbial shift toward pro-inflammatory bacterial species was seen in mice that develop GVHD (136). It is still unclear whether the microbial changes in the gut are the cause or the result of GVHD, and whether these bacterial populations reflect endogenous microflora or overgrowth of pathogenic organisms due to the elimination of benign microbes. Endotoxin is a constituent of normal bowel flora that has the ability to stimulate the release of inflammatory cytokines that are known to be important mediators of clinical GVHD and most likely permeate the systemic circulation through the intestinal barrier, which is disrupted by the conditioning treatment (218). Also, microbial super antigens may activate B-cells by direct stimulation of MHC class II molecules (219). The early phases of changes in the GI tract have been described in animal models that do not use chemotherapy or radiation to condition the host; therefore, direct comparisons to clinical GVHD after bone marrow transplantation are not possible. The initial proliferative phase results in increased crypt cell mitotic activity, crypt lengthening, and the presence of intraepithelial lymphocytes. In experimental systems, this phase seems to be linked to IFN-γ production (220), which increases MHC class II expression and gut permeability by altering tight junction integrity and may modulate crypt stem-cell turnover (221). The histologic features of the GI tract in clinical GVHD and experimental GVHD after myeloablative conditioning are consistent with the destructive and atrophic phases, characterized by villus blunting, lamina propria inflammation, crypt destruction (with crypt stem-cell loss), and mucosal atrophy (222). Cytotoxic T lymphocytes do not appear to play a dominant role in experimental GVHD of the GI tract (215, 223–225), despite the ability of intraepithelial lymphocytes to induce Fas-mediated apoptosis of host-type tumor cells (226). It is clear, when these findings are considered in aggregate, that cytokines and cellular effectors combine to produce the specific damage to target organs as well as the systemic toxicity of acute GVHD. Furthermore, the absence of GVHD toxicity in other visceral organs, such as the kidney (currently debated), argues against circulating cytokines as the sole cause of tissue-specific damage. The infiltrates seen in GVHD target organs are generally thought to consist of T-cells responding to alloantigens presented by host tissues. LPS leakage through the skin or mucosa may act as an adjuvant to the antigens expressed in these tissues, attracting and activating alloreactive donor T-cells. In BMT models, LPS levels increase progressively during the first 4 weeks post-BMT. These levels lead to aggravated disease severity through TLR4 signaling, which induces inflammatory cytokine production. Deficiency of TLR4 on donor bone marrow cells reduces colonic GVHD severity. Interestingly, this reduction in GVHD severity was accompanied with a decrease of IL-23 levels. On the other hand, mice receiving allogeneic bone marrow from IL-23 knockout mice demonstrated less colonic pathology, and low levels of colonic LPS compared to wild-type controls. Interestingly, IL-17 was not detectable in the colon, while IFN-γ was markedly increased, in association with the LPS/IL-23 feedback loop (227). In consequence, IFN-γ activated macrophages after exposure to LPS release a significant amounts of inflammatory cytokines in GI tract but not in other target organs of GVHD (218). IL-23 could also enhance host IL-22-producing type 3 innate lymphoid cells (ILC3s) and promote gut recovery after conditioning. Alloreaction generated by donor T-cells damages the gut stem-cell compartment and eliminates recipient IL-22 producing ILC3, which are the main source of IL-22 in the gut and are known to protect intestinal stem cells (228). A deficiency in ILC3s leads to severe liver and GI GVHD and increases mortality. Moreover, a recent clinical study showed clear correlation between activation and expansion of intestinal ILC3s and the absence of acute GVHD (229). Figure 4 shows a hypothetical model for the roles of IL-23 in GI GVHD. Thus, reductions in the doses of chemoradiotherapy to condition bone marrow transplant recipients have reduced the incidence of GVHD, as demonstrated in experimental models (230, 231). This reduction is the result of reduced priming of mononuclear cells by lower doses of total body irradiation (TBI) and subsequent reductions in TNF-α production (224). Intestinal and liver tissue damage leads to the release of soluble mediators that correlate positively with GI and liver GVHD pathology. Significant augmentation of liver epithelial marker cytokeratin-18 protein (CK18) (232) has been demonstrated in serum from patients with hepatic and GI GVHD. Interestingly, CK18 levels begin to increase before the clinical manifestation of GVHD in some patients. Also, CK18 levels were correlated with bilirubin (liver function marker) levels. This correlation is specific to hepato-intestinal GVHD (233). RegIIIα levels were also significantly increased in patients with GI GVHD as mentioned above (105, 234). It is well known that Reg proteins act downstream of IL-22, which protects the function of intestinal mucosa, intestinal stem cells, and ILC3s (235, 236).

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