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Schematic overview of the initiation phase of acute graft-versus-host disease. During the toxic conditioning regimen with total-body irradiation and/or chemotherapy, the destruction of intestinal epithelial cells leads to the loss of the epithelial barrier function. The subsequent translocation of luminal bacteria as well as the release of endogenous danger molecules such as adenosine triphosphate (ATP) and uric acid result in the production of pro-inflammatory cytokines. Activated host and/or donor antigen-presenting cells then prime allo-reactive donor T cells, which perpetuate acute GVHD. TLR, toll-like receptor; APC, antigen-presenting cell; DAMP, danger-associated molecular pattern; TNF, tumor necrocis factor; IL, interleukin; NOD2, nucleotide-binding oligomerization domain; NLRP3, NACHT, LRR, and PYD domains-containing protein 3.
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential for certain aggressive hematopoietic malignancies. Its success is limited by acute graft-versus-host disease (GVHD), a life-threatening complication that occurs when allo-reactive donor T cells attack recipient organs. There is growing evide...
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Citations
... Donor and recipient genotypes contribute to the severity of GvHD. Research shows the role of receptors in GvHD to prevent the disease and to preserve the donor response to stem cell transplantation [5]. ...
... Also note that 60% of WT were found to have at least one SNP [10], as illustrated in Table 5. The NOD2 gene has an allele mutation (3020insC) that signifies an increased risk of cancer, i.e., 25-35% higher than people without it [5]. NOD2/CARD15 connects to chromosome 16q12, which also can be a marker for a poorer prognosis in laryngeal carcinoma. ...
... NOD2/CARD15 connects to chromosome 16q12, which also can be a marker for a poorer prognosis in laryngeal carcinoma. A person with leukemia may have a coexisting second cancer, particularly in the larynx, head, and neck [5]. ...
Hematopoietic stem-cell transplantation (HSCT) has emerged as a groundbreaking therapeutic option for acute myeloid leukemia (AML) and specific subtypes of acute lymphoblastic leukemia (ALL). The prognostic significance of the NOD2/CARD15 gene has been explored alongside various factors, encompassing diverse patient cohorts and gene variants. Siblings and unrelated donors used for stem cell transplantation exhibit significant associations between their genetic variations and graft-versus-host disease incidence. The transplantation of stem cells for leukemia patients involves numerous considerations, including patient survival, relapse rates, disease stage, donor and recipient ages, and compatibility. This study delved into research on the NOD2/CARD15 gene and its mutations to assess its suitability as a screening tool. A comprehensive literature search encompassing PubMed, ScienceDirect, and Google Scholar articles yielded 4,840 articles. After removing duplicates and applying inclusion and exclusion criteria, we narrowed the search results to 876 articles. Subsequent screening of abstracts and titles resulted in the selection of 230 relevant articles. Further exclusion of 198 articles unrelated to the research question led to the scrutinizing of 32 full-text articles, which were assessed against inclusion and exclusion criteria. Emphasis was placed on articles that specifically investigated the role of NOD2/CARD15 as a predictive factor for HSCT outcomes, ultimately resulting in the inclusion of 19 articles in this study. Single nucleotide polymorphisms (SNPs) such as NOD2 and CARD15 have demonstrated their potential as reliable genetic markers for predicting post-transplantation relapse and disease outcomes. Patients positive for these genetic markers have exhibited reduced overall survival and event-free survival and increased transplant-related mortality. Interventions with interferon-gamma and muramyl tripeptide phosphatidylethanolamine have been considered to mitigate the inflammatory effects of these SNPs, thus enhancing the influence of natural killer cells on abnormal cells and potentially extending patient survival. NOD2/CARD15 typing may aid in identifying patients at higher risk for relapse and improving their clinical outcomes after allogeneic stem cell transplant, particularly in ALL patients. However, no remarkable change was observed in AML patients. Additionally, this study underscores the pivotal roles of adaptive and innate immune responses and their interplay in stem cell transplant immunology.
... Each type of TLR can respond to pathogen-associated molecular patterns (PAMPs) or damage associated molecular pattern molecules (DAMPs) released by tissue injury caused by the conditioning regimen pre allo-HCT. Release of reactive oxygen species and DAMPs such as high mobility group box 1 (HMGB1) further amplify inflammatory cytokine production via TLR signaling thereby positioning ECs as both a target and contributor of the "cytokine storm" that perpetuates GVHD (40)(41)(42). TLR stimulation signals through mitogen-activated protein kinases (MAPKs), promoting the release of pro-inflammatory cytokines and increasing expression of E/P-selectin and integrins ICAM-1 and VCAM-1 on ECs (35, 43, 44). In mouse models of acute GVHD, allogeneic recipients showed upregulation of VCAM-1, ICAM-1 in the GI tract compared to syngeneic recipients with concomitant increase in T cell infiltration in GVHD target organs of skin, liver and GI tract (45). ...
To date, the only curative treatment for high-risk or refractory hematologic malignancies non-responsive to standard chemotherapy is allogeneic hematopoietic transplantation (allo-HCT). Acute graft-versus-host disease (GVHD) is a donor T cell-mediated immunological disorder that is frequently fatal and the leading cause of non-relapse mortality (NRM) in patients post allo-HCT. The pathogenesis of acute GVHD involves recognition of minor and/or major HLA mismatched host antigens by donor T cells followed by expansion, migration and finally end-organ damage due to combination of inflammatory cytokine secretion and direct cytotoxic effects. The endothelium is a thin layer of endothelial cells (EC) that line the innermost portion of the blood vessels and a key regulator in vascular homeostasis and inflammatory responses. Endothelial cells are activated by a wide range of inflammatory mediators including bacterial products, contents released from dying/apoptotic cells and cytokines and respond by secreting cytokines/chemokines that facilitate the recruitment of innate and adaptive immune cells to the site of inflammation. Endothelial cells can also be damaged prior to transplant as well as by alloreactive donor T cells. Prolonged EC activation results in dysfunction that plays a role in multiple post-transplant complications including but not limited to veno-occlusive disease (VOD), transplant associated thrombotic microangiopathy (TA-TMA), and idiopathic pneumonia syndrome. In this mini review, we summarize the biology of endothelial cells, factors regulating EC activation and the role of ECs in inflammation and GVHD pathogenesis.
... U etiopatogenezi GvHD-a ključnu ulogu imaju davaočevi T limfociti u sadejstvu sa drugim imunokompetentnim efektorskim ćelijama i proinflamacijskim medijatorima. Nastanku ove komplikacije svakako može doprineti deficit funkcije imunskog sistema primaoca, najviše hipofunkcija B limfocita, što dovodi do neefikasnosti u eliminisanju donor-specifičnih antigena.Prema mišljenju nekih postoji i deficit funkcije timusa -što potrvdjuje učestalija pojava GvHD kod starijih primalaca (55)(56)(57). Kako se antigeni sistema ABO ne eksprimiraju samo na krvnim ćelijama već i na drugim tkivima i organima, izohemaglutinini davaoca takođe se mogu vezati za te ćelije domaćina. Pojedini autori smatraju da upravo ABO inkompatibilne transplantacije mo-gu biti jedan od faktora nastanka bolesti kalem protiv domaćina (47,(57)(58)(59). ...
6 Odeljenje medicinskih nauka, Srpska akademija nauke i umetnosti. Sažetak Alogena transplantacija matičnih ćelija hematopoeze (MĆH) se više decenija uspešno primenju-je u lečenju brojnih urođenih i stečenih, malignih i benignih hematoloških, ali i drugih oboljenja. Pored podudarnosti, u sistemu humanih leukocitnih antigena (HLA) između davaoca i primaoca, na ishod transplantacije utiče i vrsta oboljenja, stadijum bolesti, uzrast bolesnika, kondicioni režim i profilaksa post-transplantacijskih komplikacija. Nepodudarnost bolesnika i davaoca u sistemu ABO nije kontraindikacija za izvođenje transplantacije i prisutna je kod oko jedne trećine od ukupnog broja transplantacija. Postoje tri oblika ABO-nepodudarnosti: a) major (npr. primalac O, davalac A) koju odlikuje prisustvo antitela u cirkulaciji primaoca koja su us-merena protiv eritrocitnih antigena davaoca; b) minor (npr. primalac A, davalac O) čija je karakteristika prisustvo antitela u suspenziji MĆH usmerena na eritrocite primaoca; c) bidi-rekcijska ili dvosmerna inkompatibilija (npr. davalac A, primalac B) koja predstavlja kombi-naciju prethodna dva oblika. Uprkos adekvatnim pripremnim procedurama u pretransplantac-ijskom toku, kod svih ABO inkompatibilija između davaoca i primaoca postoji rizik od hemolizne reakcije. U pojedinim slučajevima može doći i do odloženog prihvatanja kalema crvene loze i čiste aplazije crvene loze, naročito ukoliko postoji major ili bidirekcijska ABO-inkompatibilija. Sve veći broj autora ABO-inkompatibiliju navodi kao jedan od uzroka nastanka bolesti kalem protiv domaćina. Nasupot tome, neki autori tvrde da ABO inkomatibilija ne dovodi do neželjenih reakcija nakon transplantacije matičnih ćelija hematopoeze. Ključne reči: alogena transplantacija, matične ćelije hematopoeze, ABO-inkompatibilija Uvod Alogena transplantacija matičnih ćelija hem-atopoeze (MĆH) se više decenija uspešno primenjuje u lečenju brojnih uro-đenih i ste-čenih, malignih i benignih hema-toloških, ali i drugih oboljenja. Usavršavan-jem protokola kondicioniranja i prikupljana matičnih ćelija hematopoeze, transplantacija MĆH postaje utemeljen način lečenja za mnoga hematološka i onkološka oboljenja, bolesti imunog sistema i metabolizma. Pored podudarnosti u sistemu humanih leu-kocitnih antigena (HLA) davaoca i pri-maoca, na ishod alogene transplantacije, utiču i di
... GVHD is the result of immunological attack on recipient organs or tissues by donor allogeneic T cells. The current disease model is that pretreatment conditioning, including chemotherapy and/or whole-body IR, causes loss of epithelial barrier function and tissue damage, leading to translocation of bacterial components and release of endogenous danger signals (337). These signals induce proinflammatory cytokines, activation of antigen-presenting cells, and alloreactive donor T cell differentiation (337,338). ...
... The current disease model is that pretreatment conditioning, including chemotherapy and/or whole-body IR, causes loss of epithelial barrier function and tissue damage, leading to translocation of bacterial components and release of endogenous danger signals (337). These signals induce proinflammatory cytokines, activation of antigen-presenting cells, and alloreactive donor T cell differentiation (337,338). GVHD can manifest in either acute or chronic form, each with distinct clinical presentation, timing from transplant, and pathogenesis. Acute GVHD usually presents earlier than chronic GVHD, although they can occur at the same time, called "overlap syndrome" (339). ...
Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological function of salivary glands, as well as how they are affected by disease and injury will direct the development of therapy to repair and regenerate them. Significant recent advances, particularly in the OMICS field, increase our understanding of how salivary glands develop at the cellular, molecular and genetic levels; the signaling pathways involved, the dynamics of progenitor cell lineages in development, homeostasis and regeneration and the role of the extracellular matrix microenvironment. These provide a template for cell and gene therapies as well as bioengineering approaches to repair or regenerate salivary function.
... Fischer et al. (111) also found more severe graft-versus-host disease (GVHD) in mice receiving allogeneic hematopoietic stem cell transplantation than in wild-type mice in clinical models. The main reason explaining this is that during allogeneic hematopoietic stem cell transplantation, damaged or dead epithelial cells release endogenous risk signals and are perceived by pattern recognition receptors on antigen-presenting cells, triggering the release of proinflammatory cytokines and T cells from major donor sources, which attack and destroy host cells and tissues, causing graft-versus-host disease (112). ...
Intrauterine adhesion (IUA) is an endometrial fibrosis disease caused by repeated operations of the uterus and is a common cause of female infertility. In recent years, treatment using mesenchymal stem cells (MSCs) has been proposed by many researchers and is now widely used in clinics because of the low immunogenicity of MSCs. It is believed that allogeneic MSCs can be used to treat IUA because MSCs express only low levels of MHC class I molecules and no MHC class II or co-stimulatory molecules. However, many scholars still believe that the use of allogeneic MSCs to treat IUA may lead to immune rejection. Compared with allogeneic MSCs, autologous MSCs are safer, more ethical, and can better adapt to the body. Here, we review recently published articles on the immunomodulation of allogeneic and autologous MSCs in IUA therapy, with the aim of proving that the use of autologous MSCs can reduce the possibility of immune rejection in the treatment of IUAs.
... Several studies have demonstrated an alteration of cytokines and chemokines in patients with hematological malignancy undergoing HSCT who subsequently develop invasive fungal disease [18,30,31] and IA in particular [18,32,33]. For example, in adult hematology patients with proven/probable invasive fungal disease (IFD), increases of serum cytokine levels of IL-15 and IL-2R as well as chemokines levels of CCL2 and MIP-1α were observed, whereas the level of IL-4 was significantly lowered, compared to those with no evidence of IFD [18]. ...
Invasive pulmonary aspergillosis is a frequent complication in immunocompromised individuals, and it continues to be an important cause of mortality in patients undergoing hematopoietic stem cell transplantation. In addition to antifungal therapy used for mycoses, immune-modulatory molecules such as cytokines and chemokines can modify the host immune response and exhibit a promising form of antimicrobial therapeutics to combat invasive fungal diseases. Cytokine and chemokine profiles may also be applied as biomarkers during fungal infections and clinical research has demonstrated different activation patterns of cytokines in invasive mycoses such as aspergillosis. In this review, we summarize different aspects of cytokines that have been described to date and provide possible future directions in research on invasive pulmonary aspergillosis following hematopoietic stem cell transplantation. These findings suggest that cytokines and chemokines may serve as useful biomarkers to improve diagnosis and monitoring of infection.
... Toll-like receptors (TLRs) are the most important family of receptors in the early to middle stages of infectious immunity, cooperatively recognizing patterns present in microorganisms and augmenting the synthesis of inflammatory mediators [14][15][16][17]. Previous studies [18][19][20][21] have suggested that the TLR -signaling pathway plays important roles in the anti-microbial immunity and GVHD after allogeneic SCT. TLR genes have several functional single-nucleotide polymorphisms (SNPs), which have been shown to be associated with the survival outcomes after allogeneic SCT in our recent reports [22,23]. ...
UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.
... 12-14 GVHD is potentiated when innate immune sensors, mainly in hematopoietic and nonhematopoietic antigen-presenting cells (APCs), are activated in response to pathogen-associated molecular patterns and damage-associated molecular patterns released by pretransplant chemotherapy or irradiation that result in upregulating certain cytokines. 15 Recent work by our laboratory and others has established that 1 such innate sensor, STING, is a potent regulator of GVHD. 16,17 The initial studies that demonstrated the ability of STING to regulate GVHD used murine models of major histocompatibility complex (MHC)-mismatched HSCT and recipients (B6-Goldenticket, B6-STING gt/gt ) expressing a missense mutation in the STING gene. ...
Stimulator of Interferon Genes (STING) is an innate immune sensor of cytoplasmic dsDNA originating from microorganisms and host cells. STING plays an important role in the regulation of murine graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be similarly activated during other transplantation modalities. In this review we discuss STING in allo-HSCT, and its prospective involvement in autologous HSCT (auto-HSCT) and solid organ transplantation (SOT), highlighting its unique role in nonhematopoietic, hematopoietic, and malignant cell types.
... It has been demonstrated that bacterial components and endogenous danger molecules, such as HMGB1, that bind to PRRs on myeloid cells can promote production of proinflammatory cytokines that enhance alloreactive T-cell responses against host tissue. 72 Clearly, there is emerging evidence of a role for trained innate immunity in graft tolerance or rejection following solid organ transplantation. Although trained innate immune cells may mediate their effect locally in the graft, the induction of these cells may take place in the periphery. ...
While significant progress has been made to improve short-term survival of transplant patients, long-term acceptance of allografts in solid organ and hematopoietic stem cell (HSC) transplantation is still a significant challenge. Current therapeutics for preventing or treating allograft rejection rely on potent immunosuppressive drugs that primarily target T cells of the adaptive immune response. Promising advances in transplant immunology have highlighted the importance of innate immune responses in allograft acceptance and rejection. Recent studies have demonstrated that innate immune cells are capable of mediating memory-like responses during inflammation, a term known as trained innate immunity. In this process, innate immune cells, such as macrophages and monocytes, undergo metabolic and epigenetic changes in response to a primary stimulus with a pathogen or their products that result in faster and more robust responses to a secondary stimulus. There is also some evidence to suggest that innate immune cells or their progenitors may be more anti-inflammatory after initial stimulation with appropriate agents, such as helminth products. While this phenomenon has primarily been studied in the context of infection, there is emerging evidence to suggest that it could play a vital role in transplantation rejection and tolerance. Mechanisms of training innate immune cells and their progenitors in the bone marrow are therefore attractive targets for mediating long-term solid organ and HSC transplant tolerance. In this review we highlight the potential role of proinflammatory and anti-inflammatory mechanisms of trained innate immunity in solid organ and HSC transplantation.Supplemental Visual Abstract; http://links.lww.com/TP/C137.
... to be a driver of aGVHD, by stimulating innate pattern-recognition receptors, such as Toll-and Nod-like receptors, of host-and/or donor-derived antigen-presenting cells that produce proinflammatory cytokines, as well as by priming donor T cells. 3,4 Furthermore, as shown by some clinical studies, dysbiosis (imbalance of the gut microbiota) increases aGVHD-related mortality. 5,6 Therefore, therapeutic strategies that target the gut microbiota could constitute promising treatment options for the management of aGVHD. ...
Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, management of aGVHD is important for successful transplantation. Mucosal damage and alteration of the gut microbiota after allo-HSCT are key factors in the development of aGVHD. We conducted a prospective study to evaluate the ability of prebiotics, which can alleviate mucosal damage and manipulate the gut microbiota, to mitigate posttransplantation complications, including aGVHD. Resistant starch (RS) and a commercially available prebiotics mixture, GFO, were administered to allo-HSCT recipients from pretransplantation conditioning to day 28 after allo-HSCT. Prebiotic intake mitigated mucosal injury and reduced the incidence of all aGVHD grades combined and of aGVHD grades 2 to 4. The cumulative incidence of skin aGVHD was markedly decreased by prebiotics intake. Furthermore, the gut microbial diversity was well maintained and butyrate-producing bacterial population were preserved by prebiotics intake. In addition, the posttransplantation fecal butyrate concentration was maintained or increased more frequently in the prebiotics group. These observations indicate that prebiotic intake may be an effective strategy for preventing aGVHD in allo-HSCT, thereby improving treatment outcomes and the clinical utility of stem cell transplantation approaches. This study was registered on the University Hospital Medical Information Network (UMIN) clinical trials registry (https://www.umin.ac.jp/ctr/index.htm) as #UMIN000027563.
