Pathophysiology of GvHD and Other HSCT-Related Major Complications

Ghimire, Sakhila; Weber, Daniela; Mavin, Emily; Wang, Xiao Nong; Dickinson, Anne M.; Holler, Ernst

doi:10.3389/fimmu.2017.00079

Cited by 185 publications

(179 citation statements)

References 129 publications

(154 reference statements)

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“…H ematopoietic stem cell transplantation (HSCT) has been used for decades to treat a wide range of hematological malignancies, such as acute myeloid leukemia (AML) (1). Although its efficacy has evolved in the last years, the procedure is still associated with substantial transplant-related morbidity, mainly underlying disease relapse, graft-versus-host disease (GvHD), and infections (2). To improve transplantation outcomes, the impact of donor graft T cell subsets on the clinical outcome after HSCT has been studied.…”

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confidence: 99%

Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution

Arruda

Gaballa

Uhlin

2019

The Journal of Immunology

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Although the impact of donor graft composition on clinical outcomes after hematopoietic stem cell transplantation (HSCT) has been studied, little is known about the role of intragraft gd TCR repertoire on clinical outcomes following HSCT. Using a highthroughput sequencing platform, we sought to analyze the TCR g-chain (TRG) repertoire of gd T cells within donor stem cell grafts and address its potential impact on clinical response in the corresponding patients. A total of 20 peripheral blood stem cell grafts were analyzed, and donors were classified as CMV +/2 . The respective acute myeloid leukemia recipients were followed for disease relapse and acute graft-versus-host disease (aGvHD) development post-HSCT. In all samples, TRG repertoire showed a reduced diversity and displayed overrepresented clones. This was more prominent in grafts from CMV + donors, which presented a more private repertoire, lower diversity, skewed distribution, and reduced usage of the V9-JP pairing. Grafts given to nonrelapse patients presented a more public repertoire and increased presence of long sequence clonotypes. Variable-joining gene segment usage was not associated with aGvHD development, but a higher usage of V2-JP1 pairing and lower usage of V4-J2/V5-J2/V8-JP2 were observed in grafts given to nonrelapse patients. Our work identified five private overrepresented and one public CDR3 sequence (CATWDGPYYKKLF) associated with CMV infection, in addition to 12 highly frequent public sequences present exclusively in grafts given to nonrelapse patients. Our findings show that, despite CMV infection reshaping the TRG repertoire, TRG composition is not associated with aGvHD development, and several public sequences are associated with clinical remission.

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confidence: 99%

Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution

Arruda

Gaballa

Uhlin

2019

The Journal of Immunology

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“…The development of GVHD after the injection of histoincompatible BM is associated with the development of autoimmune disease, that is, with the presence of the autoreactive clone of T-effector cells, which are differentiated from donor hematopoietic stem cells in the recipients' body [2]. Experimental models of GVHD showed that donor effector T-cells attack various tissues of the recipient's body, including the thymus, destroying its architectonics, which leads to thymic involution and lymphopenia [30,31].…”

Section: Determination Of the Number Of Foxp3 Gene Transcripts In сD4mentioning

confidence: 99%

“…A serious disadvantage of transplantation of histoincompatible bone marrow (BM) in clinic is the development of acute or chronic form of the «graft-versus-host» disease (GVHD) in a recipient [1,2]. At present, a variety of approaches to recipient support or bone marrow (BM) treatment to remove T-lymphocytes that are responsible for the GVHD are used to prevent or minimize the development of this pathology.…”

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confidence: 99%

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Immunoregulatory effect of mouse fetal neural cells on the graft-versus-host disease

Goltsev¹,

Babenko²,

Gaevskaya³

et al. 2019

JCOT

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The problem of the treatment of acute and chronic graft-versus-host disease (GVHD), when histoincompatible bone marrow (BM) is used, remains unsolved. An important role in controlling the development of GVHD is played by Treg immunity.The purpose of the study is to evaluate the immunoregulatory effect of native and cryopreserved murine fetal neural cells (FNCs) relative to Treg immunity of mice with GVHD.Materials and methods. Acute GVHD was induced by the injection of histoincompatible BM to lethally irradiated mice. On the 14th day after GVHD induction and transplantation of native or cryopreserved FNCs in animals of all experimental groups, the spleen index, the content of T-regulatory (FOXP3+) cells and the number of foxp3 gene transcripts in the СD4+splenocytes were determined.Results. The recipients of the histoincompatible BM had a decrease in the content of T-reg cells and the level of foxp3 gene expression in the splenocyte population relative to the syngeneic control. Injection of native or cryopreserved FNCs to animals with GVHD caused an increase in the number of T-reg cells. Cryopreserved FNCs are more than native ones enhancing both the relative number of T-reg cells and the level of foxp3 gene expression in the splenocytes, which was characterized by a higher recipients’ survival up to the 16th day of observation.Conclusion. The transplantation of fetal neural cells to recipients with GVHD stimulates the Treg immunity, which is a key to the development of immune conflict. This confirms the possibility of using fetal neural cells as a therapeutic immuno-regulatory agent.

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“…Damage to the gastrointestinal (GI) mucosa in patients undergoing HSCT is a serious but still poorly understood complication. Toxicity of HSCT conditioning regimens and graft-versus-host disease (GvHD) result in a 5-fold increase of the risk of significant GI complications compared with other cancer survivors [1,2]. Chemotherapy and total body irradiation (TBI) can damage GI mucosa and cause diffuse inflammation of GI tract.…”

Section: Introductionmentioning

confidence: 99%

Gastrointestinal peptides in children before and after hematopoietic stem cell transplantation

et al. 2020

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Background: Gastrointestinal tract function and it's integrity are controlled by a number of peptides whose secretion is influenced by severe inflammation. In stomach the main regulatory peptide is ghrelin. For upper small intestine cholecystokinin and lower small intestine glucagon-like peptide-1 are secreted, while fibroblast growth factor-21 is secreted by several organs, including the liver, pancreas, and adipose tissue [12]. Hematopoietic stem cell transplantation causes serious mucosal damage, which can reflect on this peptides. Methods: The aim of the study was to determine fasting plasma concentrations of ghrelin, cholecystokinin, glucagon-like peptide-1, and fibroblast growth factor-21, and their gene expressions, before and 6 months after hematopoietic stem cell transplantation.27 children were studied, control group included 26 healthy children. Results: Acute graft versus host disease was diagnosed in 11 patients (41%, n = 27). Median pre-transplantation concentrations of gastrointestinal peptides, as well as their gene expressions, were significantly lower in studied group compared with the control group. Only median of fibroblast growth factor-21 concentration was nearsignificantly higher before stem cell transplantation than in the control group. The post-hematopoietic transplant results revealed significantly higher concentrations of the studied peptides (except fibroblast growth factor-21) and respective gene expressions as compare to pre transplant results. Median glucagone like peptide-1 concentrations were significantly decreased in patients with features of acute graft versus host disease. Moreover, negative correlation between glucagone like peptide-1 concentrations and acute graft versus host disease severity was found. Conclusions: Increased concentrations and gene expressions of gastrointestinal tract regulation peptides can be caused by stimulation of regeneration in the severe injured organ. Measurement of these parameters may be a useful method of assessment of severity of gastrointestinal tract complications of hematopoietic stem cell transplantation.

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Pathophysiology of GvHD and Other HSCT-Related Major Complications

Cited by 185 publications

References 129 publications

Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution

Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution

Immunoregulatory effect of mouse fetal neural cells on the graft-versus-host disease

Gastrointestinal peptides in children before and after hematopoietic stem cell transplantation

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