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

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 1865-1872 ◽  
Author(s):  
Olaf Penack ◽  
Ernst Holler ◽  
Marcel R. M. van den Brink
Keyword(s):  
Immune Responses ◽  
Graft Versus Host Disease ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Adaptive Immune ◽  
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.

Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease

Blood ◽  
2021 ◽  
Author(s):  
Yun Zhang ◽  
Lichong Shen ◽  
Katja Dreissigacker ◽  
Honglin Zhu ◽  
Thuong Trinh-Minh ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Graft Versus Host Disease ◽  
Molecular Mechanisms ◽  
Nuclear Accumulation ◽  
Clinical Use ◽  
Canonical Wnt Signaling ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Canonical Wnt

Chronic graft-versus-host disease (cGvHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGvHD remain poorly understood and targeted therapies are not well established for clinical use. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGvHD (sclGvHD). WNT signaling was activated in human sclGvHD with increased nuclear accumulation of the transcription factor β-catenin and WNT-biased gene expression signature in lesional skin. Treatment with highly selective tankryase inhibitor G007-LK, CK1α agonist pyrvinium or LRP6 inhibitor salinomycin, abrogated the activation of WNT signaling and protected against experimental cGvHD, without significant impact on graft-versus-leukemia effect (GvL). Treatment with G007-LK, pyrvinium or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d)→BALB/c (H-2d) and in the LP/J (H-2b)→C57BL/6 (H-2b) model of sclGvHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect, inflammation-dependent effects in sclGvHD. Our findings may have direct translational potential, as pyrvinium is in clinical use and tankyrase inhibitors are in clinical trials for other implications.

scholarly journals The Role of Intestinal Microbiota in Acute Graft-versus-Host Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Yuanyuan Chen ◽  
Ye Zhao ◽  
Qiao Cheng ◽  
Depei Wu ◽  
Haiyan Liu
Keyword(s):  
Immune Responses ◽  
Intestinal Microbiota ◽  
Graft Versus Host Disease ◽  
Inflammatory Diseases ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Host Immune Responses ◽  
Acute Graft

The mammalian intestinal microbiota is a complex ecosystem that plays an important role in host immune responses. Recent studies have demonstrated that alterations in intestinal microbiota composition are linked to multiple inflammatory diseases in humans, including acute graft-versus-host disease (aGVHD). aGVHD is one of the major obstacles in allogeneic hematopoietic stem cell transplantation (allo-HSCT), characterized by tissue damage in the gastrointestinal (GI) tract, liver, lung, and skin. Here, we review the current understanding of the role of intestinal microbiota in the control of immune responses during aGVHD. Additionally, the possibility of using probiotic strains for potential treatment or prevention of aGVHD will be discussed.

Chapter 4: Pathogenesis of TBE with a focus on molecular mechanisms

2020 ◽  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Reverse Genetics ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Knock Out ◽  
Adaptive Immune ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

In this chapter we describe the pathogenesis of tick-borne encephalitis virus (TBEV). To cause infection, TBEV needs to cross three different barriers; the physical, the innate and adaptive and the blood-brain barrier. The trigger of innate immune and adaptive immune responses, by TBEV is necessary to clear the infection. TBEV employs strategies to evade the innate immune response. Tools to study TBEV pathogenicity such as mouse knock-out models and reverse genetics are also discussed.

scholarly journals Clinical Significance of Long Noncoding RNA-DC Expression in Acute Graft Versus Host Disease (AGVHD) Development

2020 ◽  
Vol 13 (9) ◽  
Author(s):  
Leila Jafari ◽  
Abbas Hajifathali ◽  
Mohammad Hossein Mohammadi ◽  
Hamid Ghaedi ◽  
Mehdi Allahbakhshian Farsiani ◽  
...  
Keyword(s):  
Immune Responses ◽  
T Cell Activation ◽  
Graft Versus Host Disease ◽  
Noncoding Rna ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Background: Acute graft versus host disease (aGVHD) is a common complication following allogeneic hematopoietic stem cell transplantation (AHSCT) caused by cellular and inflammatory factors, including those arising from monocytes and dendritic cells as integral parts of the immune system. Long non-coding RNAs (lncRNA) have recently emerged as potential regulators of the immune responses and it is supported that their dysregulation can develop various immune disorders. As an intergenic lncRNA, the lnc-DC was shown to regulate the human monocytes differentiation and antigen presenting cells (APCs) activation during immune responses. It is also shown that lnc-DC knockdown reduces T-cell activation and cytokine release. Objectives: The aim of this study was to assess whether the lnc-DC plays a role in patients with aGVHD by measuring its expression levels compared to non-aGVHD patients on specific time intervals following transplantation. Methods: Participants included 38 patients who underwent primary allogeneic bone marrow transplantation. Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Hypaque gradient from the blood samples collected at days 0, 7, 14, 28, and final day of transplantation. The qRT-PCR was used to quantify the lnc-DC levels. Results: Findings revealed a significant increase in the lnc-DC levels on day 28 and the final day after transplantation in patients with aGVHD compared to non-GVHD patients (CI = 95%, P < 0.03 on day 28 and P < 0.01 on the final day). Furthermore, the receiver operating characteristic (ROC) curve analysis showed an acceptable total area under the curve for the lnc-DC gene expression data, suggesting a fair diagnostic value for lnc-DC. Conclusions: Taken together, data of the present study supported a strong correlation between lncRNA-DC expression and aGVHD occurrence. As a result, lnc-DC may be considered as a new molecular marker for the aGVHD prognosis.

Chapter 4: Pathogenesis of TBE with a focus on molecular mechanisms

2019 ◽  
Author(s):  
Andrea Kröger ◽  
Anna K. Överby
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Reverse Genetics ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Knock Out ◽  
Adaptive Immune ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

• In this chapter we describe the pathogenesis of tick-borne encephalitis virus (TBEV). • To cause infection, TBEV needs to cross three different barriers; the physical, the innate and adaptive, and the blood-brain barrier. • The trigger of innate immune and adaptive immune responses, by TBEV is necessary to clear the infection. • TBEV employs strategies to evade the innate immune response. • Tools to study TBEV pathogenicity such as mouse knock-out models and reverse genetics are also discussed.

Chapter 4: Pathogenesis of TBE with a focus on molecular mechanisms

2021 ◽  
Author(s):  
Andrea Kröger ◽  
Anna K Överby
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Reverse Genetics ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Knock Out ◽  
Adaptive Immune ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

In this chapter we describe the pathogenesis of tick-borne encephalitis virus (TBEV). To cause infection, TBEV needs to cross three different barriers; the physical, the innate and adaptive and the blood-brain barrier. The trigger of innate immune and adaptive immune responses, by TBEV is necessary to clear the infection. TBEV employs strategies to evade the innate immune response. Tools to study TBEV pathogenicity such as mouse knock-out models and reverse genetics are also discussed.

scholarly journals Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 613
Author(s):  
Nidhi Sharma ◽  
Qiuhong Zhao ◽  
Bin Ni ◽  
Patrick Elder ◽  
Marcin Puto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Tacrolimus Concentration ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact ◽  
Risk Of Relapse ◽  
Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

scholarly journals Mast Cell Involvement in Fibrosis in Chronic Graft-Versus-Host Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2385
Author(s):  
Ethan Strattan ◽  
Gerhard Carl Hildebrandt
Keyword(s):  
Wound Healing ◽  
Mast Cell ◽  
Mast Cells ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Fibrotic Disease ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Allogeneic hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host disease (GVHD), classified as either acute or chronic GVHD. While the pathology of acute GVHD is better understood, factors driving GVHD at the cellular and molecular level are less clear. Mast cells are an arm of the immune system that are known for atopic disease. However, studies have demonstrated that they can play important roles in tissue homeostasis and wound healing, and mast cell dysregulation can lead to fibrotic disease. Interestingly, in chronic GVHD, aberrant wound healing mechanisms lead to pathological fibrosis, but the cellular etiology driving this is not well-understood, although some studies have implicated mast cells. Given this novel role, we here review the literature for studies of mast cell involvement in the context of chronic GVHD. While there are few publications on this topic, the papers excellently characterized a niche for mast cells in chronic GVHD. These findings may be extended to other fibrosing diseases in order to better target mast cells or their mediators for treatment of fibrotic disease.

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