scholarly journals Microbiome-intestine cross talk during acute graft-versus-host disease

Blood ◽  
2020 ◽  
Vol 136 (4) ◽  
pp. 401-409
Author(s):  
Hind Rafei ◽  
Robert R. Jenq
Keyword(s):  
Immune System ◽  
Graft Versus Host Disease ◽  
Hematologic Malignancies ◽  
Host Immune System ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Microbiome Research ◽  
Inflammatory State ◽  
Intestinal Gvhd

Abstract Allogeneic hematopoietic stem cell transplantation (allo-SCT) offers cure for a variety of conditions, in particular, but not limited to, hematologic malignancies. However, it can be associated with life-threatening complications, including graft-versus-host disease (GVHD) and infections, which are factors limiting its widespread use. Technical advances in the field of microbiome research have allowed for a better understanding of the microbial flora of the human intestine, as well as dissection of their interactions with the host immune system in allo-SCT and posttransplant complications. There is growing evidence that the commensal microbiome is frequently dysregulated following allo-SCT and that this dysbiosis can predispose to adverse clinical outcomes, especially including acute intestinal GVHD and reduced overall survival. In this review, we discuss the interactions between the microbiome and the components of the immune system that play a major role in the pathways leading to the inflammatory state of acute intestinal GVHD. We also discuss the microbiome-centered strategies that have been devised or are actively being investigated to improve the outcomes of allo-SCT patients in regard to acute intestinal GVHD.

Clinical molecular imaging in intestinal graft-versus-host disease: mapping of disease activity, prediction, and monitoring of treatment efficiency by positron emission tomography

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2909-2918 ◽  
Author(s):  
Matthias Stelljes ◽  
Sven Hermann ◽  
Jörn Albring ◽  
Gabriele Köhler ◽  
Markus Löffler ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Graft Versus Host Disease ◽  
Fdg Pet ◽  
Emission Tomography ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Fdg Uptake ◽  
Positron Emission ◽  
Intestinal Gvhd

Gastrointestinal graft-versus-host disease (GVHD) is a common and potentially life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Noninvasive tests for assessment of GVHD activity are desirable but lacking. In the present study, we were able to visualize intestinal GVHD-associated inflammation in an allogeneic murine transplantation model by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in vivo. A predominant localization of intestinal GVHD to the colon was verified by histology and fluorescence reflectance imaging of enhanced green fluorescent protein (EGFP)–expressing donor cells. Colonic infiltration by EGFP+ donor lymphocytes matched increased FDG uptake in PET examinations. These preclinical data were prospectively translated into 30 patients with suspected intestinal GVHD beyond 20 days after transplantation. A total of 14 of 17 patients with a diagnostic histology showed significant FDG uptake of the gut, again predominantly in the colon. No increased FDG uptake was detected in 13 patients without histologic evidence of intestinal GVHD. Our findings indicate that FDG-PET is a sensitive and specific noninvasive imaging technique to assess intestinal GVHD, map its localization, and predict and monitor treatment responsiveness. Novel targeted tracers for PET may provide new insights into the pathophysiology of GVHD and bear the potential to further improve GVHD diagnosis.

scholarly journals The Role of Myeloid-Derived Suppressor Cells (MDSCs) in Graft-versus-Host Disease (GVHD)

2021 ◽  
Vol 10 (10) ◽  
pp. 2050
Author(s):  
Christos Demosthenous ◽  
Ioanna Sakellari ◽  
Vassiliki Douka ◽  
Penelope Georgia Papayanni ◽  
Achilles Anagnostopoulos ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Suppressor Cells ◽  
Hematologic Malignancies ◽  
In Vivo Studies ◽  
Myeloid Derived Suppressor Cells ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Published Evidence

Background: Myeloid-derived suppressor cells (MDSCs) are implicated in the complex interplay involving graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) in hematologic malignancies. Methods: A review of literature through PubMed was undertaken to summarize the published evidence on the pathophysiology and clinical implications of MDSCs in allo-HCT. Literature sources published in English since 1978 were searched, using the terms Natural Suppressor (NS) cells, MDSCs, GVHD, and allo-HCT. Results: In vivo studies demonstrated that MDSCs derived from mobilization protocols could strongly suppress allo-responses mediated by T cells and enhance T-Reg activity, thus inhibiting GVHD toxicity. However, the influence of MDSCs on the GVL effect is not fully defined. Conclusions: The induction or maintenance of MDSC suppressive function would be advantageous in suppressing inflammation associated with GVHD. Pathways involved in MDSC metabolism and the inflammasome signaling are a promising field of study to elucidate the function of MDSCs in the pathogenesis of GVHD and translate these findings to a clinical setting.

scholarly journals Newly Found Peacekeeper: Potential of CD8+ Tregs for Graft-Versus-Host Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Weihao Wang ◽  
Tao Hong ◽  
Xiaoqi Wang ◽  
Rui Wang ◽  
Yuxuan Du ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cellular Therapy ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cytokine Levels ◽  
Underlying Mechanisms ◽  
Clinical Advances

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most effective and potentially curative treatment for a variety of hematologic malignancies. However, graft-versus-host disease (GVHD) is a major obstacle that limits wide application of allo-HSCT, despite the development of prophylactic strategies. Owing to experimental and clinical advances in the field, GVHD is characterized by disruption of the balance between effector and regulatory immune cells, resulting in higher inflammatory cytokine levels. A reduction in regulatory T cells (Tregs) has been associated with limiting recalibration of inflammatory overaction and maintaining immune tolerance. Moreover, accumulating evidence suggests that immunoregulation may be useful for preventing GVHD. As opposed to CD4+ Tregs, the CD8+ Tregs population, which constitutes an important proportion of all Tregs, efficiently attenuates GVHD while sparing graft-versus-leukemic (GVL) effects. CD8+ Tregs may provide another form of cellular therapy for preventing GVHD and preserving GVL effects, and understanding the underlying mechanisms that different from those of CD4+ Tregs is significant. In this review, we summarize preclinical experiments that have demonstrated the role of CD8+ Tregs during GVHD and attempted to obtain optimized CD8+ Tregs. Notably, although optimized CD8+ Tregs have obvious advantages, more exploration is needed to determine how to apply them in the clinic.

Oral chronic graft-versus-host disease symptom experience and cytokine correlates in survivors after transplantation for hematologic malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 19510-19510
Author(s):  
J. M. Fall-Dickson ◽  
E. S. Ramsay ◽  
M. Imanguli ◽  
J. Guadagnini ◽  
J. Odom ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Hematologic Malignancies ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Oral Pain ◽  
Oral Dryness ◽  
Clinically Significant

19510 Background: Oral chronic graft-versus-host-disease (cGVHD) is a frequent, clinically significant sequela of hematopoietic stem cell transplant (HSCT). No optimal treatment exists; molecular pathogenesis remains unclear. This descriptive study assessed stomatitis, oral pain, and dry mouth severity, and correlations with proinflammatory cytokine levels in stimulated submandibular saliva samples from cGVHD patients. Methods: Subjects were enrolled in the NCI sponsored cGVHD natural history protocol. Stomatitis severity was assessed with the Oral Mucositis Rating Scale (OMRS) (0–103); oral pain and dryness were self-reported via VAS (0–10). Saliva samples were collected on ice, stored at -80°C, centrifuged at 4000xg for 10 minutes at 4°C, and supernatant retained. Salivary TNFa, IL1a, and IL6 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) (R & D Systems, Minneapolis, MN). Results: Adult male and female subjects (N = 42) with cGVHD after HSCT primarily for hematologic malignancies were prescribed systemic (n = 34) and/or topical (n = 4) immunosuppressive agents, and opioids (n = 19). All subjects had mild to moderate stomatitis (OMRS mean = 18.38; range = 2.0 to 46) with erythema (n = 40), lichenoid (n = 32), and ulceration (n = 25). Mild to severe oral dryness (43%) (mean = 2.56; range 0 to 10) was more clinically significant than oral pain (8%) (mean = .13). Salivary cytokine concentrations were: TNFa (n = 32; mean = .31 pg/mL; range 0 to 2.8); IL1a (n = 29; mean = 85.23 pg/mL; range = 13 to 250), and IL6 (n = 29; mean = 2.48 pg/mL; range 0.100 to 10.00). Significant associations by Pearson Product Moment correlation were: TNFa and erythema (r = .34; p < .05); IL1a and oral dryness (r = .40; p < .05); IL6 and OMRS (r = .49; p < .01), erythema (r = .63; p < .001), and ulceration (r = .38; p < .05). Conclusions: Paucity of oral pain may be related to appropriate management. Moderate to strong correlations between salivary TNFa and IL6 and oral cGVHD severity, and IL1a and oral dryness suggest utility as correlates of disease severity and symptom, and monitors of therapeutic response to investigational agents. No significant financial relationships to disclose.

scholarly journals How I treat refractory chronic graft-versus-host disease

Blood ◽  
2019 ◽  
Vol 133 (11) ◽  
pp. 1191-1200 ◽  
Author(s):  
Stefanie Sarantopoulos ◽  
Adela R. Cardones ◽  
Keith M. Sullivan
Keyword(s):  
Graft Versus Host Disease ◽  
Treatment Options ◽  
Hematologic Malignancies ◽  
Initial Therapy ◽  
Clinic Visit ◽  
Prognostic Indicators ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Life Threatening

Abstract Approximately 35% to 50% of patients otherwise cured of hematologic malignancies after allogeneic hematopoietic stem cell transplantation will develop the pleomorphic autoimmune-like syndrome known as chronic graft-versus-host disease (cGVHD). Since in 2005, National Institutes of Health (NIH) consensus panels have proposed definitions and classifications of disease to standardize treatment trials. Recently, the first agent was approved by the US Food and Drug Administration for steroid-refractory cGVHD. Despite these advances, most individuals do not achieve durable resolution of disease activity with initial treatment. Moreover, standardized recommendations on how to best implement existing and novel immunomodulatory agents and taper salvage agents are often lacking. Given the potential life-threatening nature of cGVHD, we employ in our practice patient assessment templates at each clinic visit to elucidate known prognostic indicators and red flags. We find NIH scoring templates practical for ongoing assessments of these complex patient cases and determination of when changes in immunosuppressive therapy are warranted. Patients not eligible or suitable for clinical trials have systemic and organ-directed adjunctive treatments crafted in a multidisciplinary clinic. Herein, we review these treatment options and offer a management and monitoring scaffold for representative patients with cGVHD not responding to initial therapy.

Genetics of Intestinal Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-51-SCI-51
Author(s):  
Marcel R.M. van den Brink
Keyword(s):  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Intestinal Flora ◽  
Microbial Flora ◽  
Intestinal Immunity ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Intestinal Microbial Flora ◽  
Intestinal Gvhd

Abstract SCI-51 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapy with curative potential for a variety of malignant and nonmalignant diseases. Despite standard prophylactic regimens, graft-versus-host disease (GVHD) continues to limit the success of outcomes in allo-HSCT patients. Gastrointestinal (GI) GVHD is the predominant contributor to acute GVHD-related mortality. The pathophysiology of GI GVHD has unique features that are related to the important interactions between the donor allograft (especially donor alloreactive T cells), mucosal adaptive and innate intestinal immunity, intestinal epithelial homeostasis, and the intestinal microbial flora. The pathophysiology of intestinal GVHD has many similarities with inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis (UC). At last count, 99 susceptibility loci/genes for Crohn’s and UC have been published. Multiple genes are involved in IL-23/Th17 signaling, defective processing of intracellular bacteria involving autophagy and innate immunity (including NOD2 and ATG16L1), and defects in barrier function and shared susceptibility with other autoimmune diseases (such as type 1 and 2 DM). Early studies in mice and in patients suggested a link between an individual’s intestinal microbial flora and his/her propensity for GVHD resulting in varying protocols for gut decontamination, which continue at some centers to this date. We will discuss the latest data regarding the role in intestinal GVHD of genetic changes in the before-mentioned pathways and genes in the donor and host, as well as its interactions with the intestinal flora. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Guillaume Morelle ◽  
Martin Castelle ◽  
Graziella Pinto ◽  
Sylvain Breton ◽  
Matthieu Bendavid ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Juvenile Idiopathic Arthritis ◽  
Graft Versus Host Disease ◽  
Immune Thrombocytopenia ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Sustained Remission ◽  
Refractory Disease ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Background Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. Case report A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. Conclusion Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.

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