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.

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.

Complete Resolution of Extensive Chronic Graft-Versus-Host Disease with Ibrutinib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5474-5474
Author(s):  
Audrey Scholoff ◽  
Gloria Obi ◽  
Kelty R. Baker ◽  
George Carrum ◽  
Rammurti T Kamble
Keyword(s):  
Graft Versus Host Disease ◽  
Complete Resolution ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Oral Ulcers

Abstract We herein document a complete response of extensive chronic graft-versus-host disease (cGvHD) to a Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib. A 41 years old female with primary refractory MCL underwent mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation in December 2011 (conditioning with CY/TBI and alemtuzumab, graft=6.6x 106/kg CD-34+ cells, tacrolimus alone for GVHD prevention). Following engraftment on day 11, she developed grade III acute GvHD involving the skin and gut on day 17 of transplantation that persisted beyond 100 days post-transplant. Her cGvHD was treated with steroids, but remained active and extensive. Despite persistent cGvHD and 100% donor chimerism she relapsed in July 2012. Treatment with radiation and bendamustine with rituximab failed. By December 2013, the patient had extensive cGvHD manifesting as scleromatous skin thickening, oral ulcers and sclerosis of the buccal mucosa, ocular dryness and diarrhea, and was started on ibrutinib1 560 mg once daily for relapsed MCL. After 8 weeks of therapy, cGvHD had begun to improve. Oral steroids were reduced and ultimately stopped after 26 weeks of ibrutinib; after 30 weeks treatment all cGvHD manifestations resolved completely. A complete remission for MCL was documented at 8 weeks of ibrutinib initiation. Currently she continues to be on 560 mg daily ibrutinib without cGvHD exacerbation or MCL relapse for 22 weeks and 52 weeks, respectively. Chronic graft versus host disease (cGvHD) is mediated donor T cells. The role of B cells in the pathogenesis of cGvHD is increasingly recognized. Two murine studies have explored the role of ibrutinib in cGVHD-like syndromes, one in which there is T cell driven sclerodermatous cGvHD and a second in which there is Ab driven multiorgan system cGvHD that includes bronchiolitis obliterans (BO). Administration of ibrutinib decreased the incidence and severity of sclerodermatous, and improved pre-existing lesions and also improved pulmonary fibrosis and reduced BO. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Our report provides the evidence that BTK inhibition led to complete resolution of cGvHD and supports exploration of its role in future clinical trials. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Adriana Gutiérrez-Hoya ◽  
Rubén López-Santiago ◽  
Jorge Vela-Ojeda ◽  
Laura Montiel-Cervantes ◽  
Octavio Rodríguez-Cortés ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Treg Cells ◽  
Protective Role ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tc17 Cells

CD8+ T cells that secrete proinflammatory cytokines play a central role in exacerbation of inflammation; however, a new subpopulation of CD8 regulatory T cells has recently been characterized. This study analyzes the prominent role of these different subpopulations in the development of graft-versus-host disease (GVHD). Samples from 8 healthy donors mobilized with Filgrastim® (G-CSF) and 18 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated by flow cytometry. Mobilization induced an increase in Tc1 (p<0.01), Th1 (p<0.001), Tc17 (p<0.05), and CD8+IL-10+ cells (p<0.05), showing that G-CSF induces both pro- and anti-inflammatory profiles. Donor-patient correlation revealed a trend (p=0.06) toward the development of GVHD in patients who receive a high percentage of Tc1 cells. Patients with acute GVHD (aGVHD), either active or controlled, and patients without GVHD were evaluated; patients with active aGVHD had a higher percentage of Tc1 (p<0.01) and Tc17 (p<0.05) cells, as opposed to patients without GVHD in whom a higher percentage of CD8 Treg cells (p<0.01) was found. These findings indicate that the increase in Tc1 and Tc17 cells is associated with GVHD development, while regulatory CD8 T cells might have a protective role in this disease. These tests can be used to monitor and control GVHD.

MiR-146a Regulates the TRAF6/TNF-Axis in Donor T Cells during Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 843-843
Author(s):  
Natalie Stickel ◽  
Gabriele Prinz ◽  
Dietmar Pfeifer ◽  
Annette Schmitt-Graeff ◽  
Marie Follo ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Negative Regulator ◽  
Snp Analysis ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Introduction: Acute graft-versus-host disease (GvHD) arises from the attack of recipient tissues by donor allogeneic T cells and represents one of the major limitations of allogeneic hematopoietic cell transplantation (allo-HCT). In spite of many clinical trials, the standard immunosuppressive regimens for prevention of acute GvHD have improved little in the last two decades. Hence, a better understanding of the biology of acute GvHD may improve therapeutic options. MicroRNA-146a (miR-146a) was found to be increased in the sera of patients with GvHD. Therefore, we aimed to decipher the role of miR-146a in allogeneic donor T cells during GvHD by functional studies and in patients undergoing allo-HCT by single nucleotide polymorphism (SNP) analysis. Methods: We used two different murine major MHC mismatch models for acute GvHD. Recipient mice were conditioned with irradiation before transplantation of bone marrow and either wildtype or miR-146a deficient T cells from allogeneic donor mice. Furthermore, genomic DNA from 289 patients that underwent allo-HCT and their respective hematopoietic stem cell donors was isolated in order to determine their miR-146a rs2910164genotype. Results: We observed miR-146a upregulation in T cells of mice developing acute GvHD compared to untreated mice in a major MHC and a minor histocompatibility antigen mismatch model. Transfer of miR-146a deficient T cells caused increased GvHD severity, elevated TNF serum levels and reduced survival. Conversely, the phytochemical induction of miR-146a or its overexpression in donor T cells using a specific miR-146a mimic reduced GvHD severity. TNF receptor-associated factor 6 (TRAF6), a verified target of miR-146a, was upregulated in miR-146a-/- T cells following alloantigen stimulation. Higher TRAF6 levels translated into increased NF-κB activity and TNF production in miR-146a-/- T cells, while other pro-inflammatory cytokine levels were unaffected. The detrimental effect of miR-146a deficiency in T cells could be antagonized by TNF blockade in vivo. Moreover, in contrast to WT T cells, over expression of miR-146a in Tnf deficient T cells had no effect on their alloreactivity. In the human system, the minor genotype of the SNP rs2910164, which causes reduced miR-146a expression, was more frequent in patients developing acute GvHD grade III/IV compared to all other allo-HCT recipients (n=289). Conclusions: Taken together we show that miR-146a functions as a negative regulator of the TRAF6/TNF-axis in allogeneic donor T cells during GvHD, leading to reduced TNF transcription. Given our observation on the predictive role of the SNP leading to decreased miR-146a expression in acute GvHD in patients and the possibility to exogenously enhance miR-146a expression, we provide a novel and targeted molecular approach to mitigate GvHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Extracorporeal photopheresis: cellular therapy for the treatment of acute and chronic graft-versus-host disease

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 639-644 ◽  
Author(s):  
Jennifer Schneiderman
Keyword(s):  
Graft Versus Host Disease ◽  
Large Scale ◽  
Cellular Therapy ◽  
Uv Light ◽  
Immunosuppressive Agents ◽  
White Blood Cells ◽  
Extracorporeal Photopheresis ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for many disease states. Despite significant improvements in strategies used to prevent and treat acute and chronic graft-versus-host disease (a/cGVHD), they continue to negatively affect outcomes of HSCT significantly. Standard, first-line treatment consists of corticosteroids; beyond this, there is little consistency in therapeutic regimens. Current options include the addition of various immunosuppressive agents, the use of which puts patients at even higher risks for infection and other morbidities. Extracorporeal photopheresis (ECP) is a widely used cellular therapy currently approved by the US Food and Drug Administration for use in patients with cutaneous T-cell lymphoma; it involves the removal of peripherally circulating white blood cells, addition of a light sensitizer, exposure to UV light, and return of the cells to the patient. This results in a series of events ultimately culminating in transition from an inflammatory state to that of tolerance, without global immunosuppression or known long-term adverse effects. Large-scale, prospective studies of the use of ECP in patients with a/cGVHD are necessary in order to develop the optimal treatment regimens.

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 Acute and Chronic Graft-Versus-Host-Disease – A Focus on Pediatric Patients

JBMTCT ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 140
Author(s):  
Antonio Vaz de Macedo ◽  
Júlia Lopes Garcia ◽  
Roseane Vasconcelos Gouveia ◽  
Rita de Cássia Barbosa Tavares
Keyword(s):  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Cellular Therapy ◽  
Task Force ◽  
Pediatric Population ◽  
Contributory Factor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Blood And Marrow Transplantation

Graft-versus-host disease (GVHD), either in its acute or chronic form, is the main contributory factor for morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent advancements in the classification of this disease, with better applicability and reproducibility of standardized criteria, coupled with improvements in the management of steroid-refractory or resistant cases, have led to promising results. In 2020, the Brazilian Group for Pediatric Bone Marrow Transplantation of the Brazilian Society for Blood and Marrow Transplantation and Cellular Therapy (SBTMO) convened a task force to provide updated, evidence-based guidance for the diagnosis, classification, staging, prophylaxis, and treatment of GVHD, with a focus on the pediatric population, the results of which are presented here.  

scholarly journals Diagnostic and Prognostic Role of Fecal Calprotectin As a Biomarker for Gastrointestinal Graft Versus Host Disease: A Systematic Review of Literature

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5725-5725
Author(s):  
Abdul Rafae ◽  
Mustafa Nadeem Malik ◽  
Ali Younas Khan ◽  
Anum Qureshi ◽  
Muhammad Abu Zar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Graft Versus Host Disease ◽  
Fecal Calprotectin ◽  
Cochrane Library ◽  
Prognostic Role ◽  
Hematopoietic Stem ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: Graft versus host disease (GVHD) is the most significant complication after allogeneic hematopoietic stem cell transplantation (HSCT) and a leading cause of morbidity and mortality. The incidence of acute gastrointestinal graft versus host disease (GI-GVHD) in HSCT patients is reported between 40% to 50%. Fecal calprotectin (FC) has an established role as a diagnostic modality and a biomarker of disease activity in patients with inflammatory bowel disease (IBD). It has been suggested that FC may also play an important role in diagnosing and assessing the severity of GVHD and in determining resistance and response to corticosteroid treatment. Methods: To study the diagnostic and prognostic role of FC in GVHD patients, we performed a systematic review, 19 articles published after 2004 were selected from following four databases (PubMed, Embase, Cochrane Library and Web of Science). Numeric data were summarized using means, medians, and ranges. Categorical data were summarized using absolute values and percentages. Results: A total of 494 patients were included. Two hundred fifty two patients (51%) developed acute GVHD. Hundred seventy nine patients (71%) had GI-GVHD and 73 patients (29%) had non GI-GVHD. In one of the cohorts (n=21), median FC (mFC) levels were 198.9 mg/kg [range(r) =58.4-500] in patients with GVHD versus 32.2 mg/kg (r=15.6-89) in patients without GVHD (p=0.0005). In a similar cohort (n=23), mFC levels were 504 mg/kg in patients with GVHD and 107.4 mg/kg in patients without GVHD (p=<0.001). Five cohorts compared mFC level in GI-GVHD vs. non GI-GVHD patients and the results were as follows: 318 mg/kg (r=36-596) vs. 38 mg/kg (r=35.5-56), p=0.003 (61 patients); 595 mg/kg vs. 51.7 mg/kg, p=<0.001 (64 patients); 396.6 mg/kg (r=142.1-500) vs. 115.2 mg/kg (r=58.4-292.3), p=0.02 (14 patients); 500 mg/kg vs. 95 mg/kg , p=0.0229; 56 mg/kg vs. 121 mg/kg, p=0.67 (31 patients). In another cohort (n=40), mFC level was 193.9 mg/kg in patients with GI-GVHD as compared to mFC level of 53.1 mg/kg in patients with CMV colitis (p=0.017). In another cohort (n=14), mFC level was 134.9 mg/kg (r=58.4-292.3) in patients with grade I-II GVHD as compared to mFC level of 396.6 mg/kg (95.2-500) in patients with grade III-IV GVHD (p=0.029). In another cohort (n=54) with GI-GVHD, corticosteroids responsive patients had mFC level of 64 mg/kg (range 17-360) at onset and 49 mg/kg (range 12-238) at 1 week of treatment while corticosteroid resistant patients had mFC level of 488 mg/kg (range 65-835) at onset and 542 mg/kg (range 121-1080) at 1 week of treatment (p=0.028 at onset and p=0.038 at one week). In another cohort (n=7), mean FC level was 24 mg/kg (r=16-31) in steroid responsive patients as compared to mean FC level of 449 mg/kg (r=116-1111) in steroid resistant patients (p=0.032). Conclusions: Our analysis demonstrates that FC levels are higher in patients with GI-GVHD. Furthermore, a linear correlation is present between FC levels and severity of GVHD. FC levels are higher in patients with steroid-resistant GVHD and can be useful to determine treatment response. Data on FC levels in these patients seem promising and future randomized prospective trials are needed. Disclosures No relevant conflicts of interest to declare.

scholarly journals Fecal Microbiota Transplantation As a Therapeutic Option for Graft-Versus-Host-Disease: A Systematic Review and Future Directions

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4869-4869
Author(s):  
Hafiz muhammad Aslam ◽  
Sindhusha Veeraballi ◽  
Shahrukh K. Hashmi
Keyword(s):  
Graft Versus Host Disease ◽  
Clinical Studies ◽  
Case Reports ◽  
Therapeutic Option ◽  
Systemic Review ◽  
Fecal Matter ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: In recent years, there has been an expanding focus on interplay between intestinal microbiotal diversity and outcome of acute graft versus host disease(GVHD) in hematopoietic stem cell transplantation (HCT) recipients. One of the compelling intervention to maintain healthy gut microbiota for better outcome of GVHD in HCT recipients is Fecal microbial transplantation(FMT). Several non randomized small clinical studies and case reports on the efficacy and safety of FMT were reported so far. However, the ultimate role of FMT as a therapeutic option to treat GVHD is yet to be determined due to lack of randomised, large scale, statistically significant studies. Here in, we report a systemic review of literature available so far in an effort to establish a definite role of FMT. Methodology: A systemic literature search was conducted using various electronic databases. The case reports, case series and clinical studies related to FMT were used as a therapeutic or preventative modality specifically for GVHD are included. Results: Upon pooling of data, 87 patients from 6 studies and 5 case reports were included in the study in which complete remission(CR) occured in 43.7% and partial remission(PR) occured in 20.7% patients which is equivalent to 64.4% overall response rate in treating GVHD. Furthermore, out of all the species in fecal matter, clostridium was found to be the most valuable species in decreasing the rates of GVHD re-occurrence. Only a limited number of patients had treatment-related mortality (TRM) from GVHD while few showed mild GI-related (abdominal pain/distention, nausea, regurgitation) and non-GI adverse reactions including infections, anemia, thrombocytopenia, paroxysmal, and atrial fibrillation. We emphasize that the most of the patients did not have any major complications after FMT. Conclusion: We conclude that the FMT is a safe and effective strategy for the management of GVHD based on our study. The establishment of gut diversity along with the patient's intrinsic factors like fucosyltransferase 2 (FUT2) secretor status and baseline gut microbial diversity play a major role in the success of FMT. Given the restricted size and absence of randomized data, one cannot portray FMT as a standard of care yet, however, the low or absent toxicity along with improvement in survival justifies this modality to be tested in a randomized fashion. We strongly encourage the transplant community to enroll patients in innovative trials utilizing FMT, as this may be a one of the safest strategies for both prevention and treatment of GVHD Disclosures No relevant conflicts of interest to declare.

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