Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies.

Published on Dec 17, 2020in Frontiers in Immunology5.085
· DOI :10.3389/FIMMU.2020.607030
Sina Naserian10
Estimated H-index: 10
(French Institute of Health and Medical Research),
Mathieu Leclerc6
Estimated H-index: 6
(French Institute of Health and Medical Research)
+ 1 AuthorsGeorges Uzan35
Estimated H-index: 35
(French Institute of Health and Medical Research)
Source
Abstract
Graft versus host disease (GVHD) is one of the main causes of mortality and the reason for up to 50 % of morbidity after hematopoietic stem cell transplantations (HSCT) which is the treatment of choice for many blood malignancies. Thanks to years of research and exploration, we have acquired a profound understanding of the pathophysiology and immunopathology of these disorders. This led to the proposition and development of many therapeutic approaches during the last decades, some of them with very promising results. In this review, we have focused on the recent GVHD treatments from classical chemical and pharmacological prophylaxis to more innovative treatments including gene therapy and cell therapy, most commonly based on the application of a variety of immunomodulatory cells. Furthermore, we have discussed the advantages and potentials of cell-free therapy as a newly emerging approach to treat GVHD. Among them, we have particularly focused on the implication of the TNF-TNFR2 axis as a new immune checkpoint signaling pathway controlling different aspects of many immunoregulatory cells.
References202
Newest
#1Natasha Kekre (Ottawa Hospital)H-Index: 17
#2Haesook T. Kim (Harvard University)H-Index: 74
Last. Corey Cutler (Harvard University)H-Index: 92
view all 18 authors...
The α4s7 integrin is upregulated on naive and memory T cell subsets in patients who subsequently develop gastrointestinal (GI) acute GVHD. Natalizumab (Tysabri®, Biogen Inc.) acts against the α4 subunit that mediates homing of lymphocytes to the GI tract. We initiated a phase II study of natalizumab with corticosteroids for initial treatment of acute GI GVHD. In total, 300 mg IV of natalizumab was given, with steroids initiated up to 3 days prior. Twenty-one subjects were treated, median age was...
2 CitationsSource
#1Ghada Beldi (French Institute of Health and Medical Research)H-Index: 2
#2Maryam Khosravi (University of Paris)H-Index: 1
Last. Sina Naserian (French Institute of Health and Medical Research)H-Index: 10
view all 7 authors...
BACKGROUND In addition to their multilineage potential, mesenchymal stem cells (MSCs) have a broad range of functions from tissue regeneration to immunomodulation. MSCs have the ability to modulate the immune response and change the progression of different inflammatory and autoimmune disorders. However, there are still many challenges to overcome before their widespread clinical administration including the mechanisms behind their immunoregulatory function. MSCs inhibit effector T cells and oth...
12 CitationsSource
#1Sina Naserian (French Institute of Health and Medical Research)H-Index: 10
#2Mohamed Essameldin Abdelgawad (Helwan University)H-Index: 7
Last. Georges Uzan (French Institute of Health and Medical Research)H-Index: 35
view all 8 authors...
BACKGROUND Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites. Since EPCs from patients with vascular disorders are impaired and inefficient, allogenic sources from adult or cord blood are considered as good alternatives. However, due to the reaction of immune system against allogenic cells which usually lead to their elimination, we focused on the exa...
15 CitationsSource
#1Jaeyoon Ryu (Catholic University of Korea)H-Index: 3
#2Joo-Yeon Jhun (Catholic University of Korea)H-Index: 17
Last. Mi-La Cho (Catholic University of Korea)H-Index: 56
view all 10 authors...
Fibrosis is the formation of excess connective tissue in an organ or tissue during a reparative or reactive process. Graft-versus-host disease (GvHD) is a medical complication of allogeneic tissue transplantation with transplanted donor T cell-mediated inflammatory response; it is characterized by a severe immune response with fibrosis in the final stage of the inflammatory process. T helper 17 cells play a critical role in the pathogenesis of GvHD. Fingolimod (FTY720), an analogue of sphingosin...
2 CitationsSource
#1Yaqun Hong (Fujian Medical University)H-Index: 2
#2Bo Wan ('KCL': King's College London)H-Index: 2
Last. Xiaofan Li (Fujian Medical University)H-Index: 6
view all 3 authors...
Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy, but graft-vs-host disease (GVHD) has limited the survival quality and overall survival of hematopoietic stem cell transplantation. Understanding of the immune cells' reaction in pathophysiology of GVHD has improved, but a review on the role of macrophages in GVHD is still absent. Studies have observed that macrophage infiltration is associated with GVHD occurrence and development. In this revie...
6 CitationsSource
#1Birgit Sawitzki (Charité)H-Index: 42
#2Paul N. Harden (University of Oxford)H-Index: 20
Last. Edward K. Geissler (Fraunhofer Society)H-Index: 3
view all 61 authors...
Summary Background Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. Methods The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 ...
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#1Guido Moll (Charité)H-Index: 22
#2Norman Drzeniek (Charité)H-Index: 2
Last. Petra Reinke (Charité)H-Index: 72
view all 6 authors...
Integrating adaptive and innate immune compatibility testing into the guidelines for cell, tissue and organ transplantation is paramount for safe and effective therapies. There is an urgent clinical need for new guidelines on hemocompatibility testing of intravascular (IV) cellular therapeutics, in particular mesenchymal stromal cells (MSCs). IV-MSCs account for half of all registered MSC-trials and are now in growing demand as potential treatment for coronavirus-induced disease (COVID-19). No a...
52 CitationsSource
#1Richard Proust (French Institute of Health and Medical Research)H-Index: 6
#2Anne-Charlotte Ponsen (French Institute of Health and Medical Research)H-Index: 3
Last. J. Peltzer (French Institute of Health and Medical Research)H-Index: 3
view all 15 authors...
BACKGROUND: Cardiovascular diseases are the main cause of morbidity and mortality worldwide. Restoring blood supply to ischemic tissues is an essential goal for the successful treatment of these diseases. Growth factor or gene therapy efficacy remains controversial, but stem cell transplantation is emerging as an interesting approach to stimulate angiogenesis. Among the different stem cell populations, cord blood-endothelial progenitor cells (CB-EPCs) and more particularly cord blood-endothelial...
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#1Neema Negi (National University of Ireland, Galway)H-Index: 1
#2Matthew D. Griffin (National University of Ireland, Galway)H-Index: 65
The immunomodulatory potential of mesenchymal stromal cells (MSCs) and regulatory T cells (T-reg) is well recognized by translational scientists in the field of regenerative medicine and cellular therapies. A wide range of preclinical studies as well as a limited number of human clinical trials of MSC therapies have not only shown promising safety and efficacy profiles but have also revealed changes in T-reg frequency and function. However, the mechanisms underlying this potentially important ob...
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#1Robert ZeiserH-Index: 64
#2von Bubnoff NH-Index: 1
Last. Gérard SociéH-Index: 123
view all 14 authors...
BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice da...
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Acute graft-versus-host disease (aGVHD) remains a significant and severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to the occurrence of aGVHD, allo-HSCT significantly increases the mortality rate compared with autologous hematopoietic stem cell transplantation (auto-HSCT). In this study, auto-HSCT and allo-HSCT aGVHD mouse models were built to detect the difference in CD4+ lymphocyte in different tissues based on ribonucleic acid sequencing (RNA-Seq) ana...
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