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Fulminant gastrointestinal graft-versus-host disease concomitant with cytomegalovirus infection:Case report and literature review

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World Journal of Gastroenterology 2013年第4期19卷 597-603页

作者： Hidetaka Okubo Naoyoshi Nagata Naomi Uemura Department of Gastroenterology and Hepatology National Center for Global Health and MedicineTokyo 162-8655Japan Department of Gastroenterology and Hepatology Kohnodai HospitalIchikawa 272-0827ChibaJapan

Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-CMV disease,the mucosal findings and the clinical course showed marked improvements during long-term clinical observation.The endoscopic findings were remarkable,with diffuse sloughing mucosa in the stomach and highly active inflammation and deep discrete ulcers throughout the colon.Changes in the CMV quantitative polymerase chain reaction results were correlated with the endoscopic mucosal findings and were useful for assessing the efficacy of the treatment.Although a definite diagnosis of GI-GVHD is generally made by endoscopy with biopsy,the gross appearance of this disease can vary depending on the endoscopy.In this paper,we also conduct a literature review of patients with GI-GVHD.

关键词： Acute gastrointestinal graft-versus-host disease Allogenic stem-cell transplantation Cytomegalovirus gastrointestinal disease Cytomegaloviruspolymerase chain reaction Endoscopy

Effect and mechanism of acute graft versus host disease on early diffuse murine lung injury following allogeneic stem cell transplantation

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Science China(Life Sciences) 2009年第11期52卷 1016-1022页

作者： NING Juan, LIU Qi Fa, LUO Xiao Dan, FAN Zhi Ping & Zhang Yu Department of Hematology, Southern Hospital, Southern Medical University, Guang Zhou 510515, China Department of Hematology Southern Hospital Southern Medical University Guang Zhou China

To explore the effect and pathogenssis of acute graft-versus-host disease (aGVHD) on early diffuse lung injury in allogeneic hematopoietic stem cell transplantation (allo-HSCT), we established an aGVHD model of C57BL/6→BALB/c mice. Chest computed tomography (CT) scans, histopathology and the levels of cytokines including tumor necrosis factor α (TNFα) and Interferon (IFNγ) in lungs were dynamically detected in recipient mice after transplantation. The incidence of aGVHD was respectively 0%, 0% and 100% in simple irradiation group (A), syngeneic transplant group(B) and allogeneic transplant group (C). Chest CT scans of recipient mice were normal in 3 groups on days +3 and +7 after transplantation. CT showed that two of ten mice had bilateral lung diffuse infiltrate on day +12 (on the brink of death) in group A and 6 of 10 mice had bilateral lung diffuse infiltrate on day +14 (3 d after aGVHD occurring) in group C, and were normal on days +12 and +14 in group B after transplantation. Histopathology of lungs in the 3 groups was similar, consisting of minor interstitial pneumonitis on day +3. Group A showed edema, hyperplasia of epithelial cells and widened alveolar interval on day +7, and epithelial cell necrosis, lymphocyte infiltration, hemorrhage, protein leakage, and local consolidation on day +12. The histopathology of group B showed slight edema of epithelial cells on +7 day, which were slighter than that on day +3, and virtually normal on day +14. The histopathology in group C was characterized by the significant expansion and congestion of capillaries, and lymphocyte infiltration on day +7, the acute pneumonitis was present involving tissue edema, lymphocyte and macrophage infiltration, protein leakage and perivascular inflammation on day +14. In group A, the levels of TNFα were lower on day +7 than on day +3. In group B, the levels of TNFα attained a peak on day +3, which decreased on days +7 and +14. In group C, the levels of TNFα were highest on day +7 and there was a significant difference between those

关键词： lung injury acute graft-versus-host disease allogeneic hematopoietic stem cell transplantation

Immune Regulatory Cell Biology and Clinical Applications to Prevent or Treat Acute graft-versus-host Disease

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Engineering 2019年第1期5卷 98-105页

作者： Bruce R. Blazar Masonic Cancer Center & Division of Blood and Marrow Transplantation Department of Pediatrics University of Minnesota Minneapolis MN 55455 USA

The most common approaches to prevent and treat graft-versus-host disease (GVHD) are intended to deplete or suppress the T cells capable of mediating or supporting alloresponses;however, this renders the recipients functionally T cell deficient and hence highly susceptible to infections and tumor recurrence. Depletion is often accomplished through the use of broadly reactive antibodies, while functional impairment is typically achieved by pharmacological agents that require long-term administration (usually six months or more), have significant side effects, and may not result in tolerance (i.e., nonresponsiveness) of donor T cells to conditioning regimen-resistant host alloantigen-bearing cells. As our knowledge of immune system homeostasis has increased, cell populations with immune regulatory function have been identified and characterized. Although such cell populations are typically present in low frequencies, methods to isolate and expand these cells have permitted their supplementation to the donor graft or infusion late post-transplant in order to stifle GVHD. This review discusses the biology and preclinical proof of concept of GVHD models, along with GVHD outcomes that focus exclusively on immune regulatory cell therapies that have progressed to clinical testing.

关键词： graft-versus-host disease (GVHD) Immune regulatory cells Cell therapy

Nanoparticle-encapsulated allogeneic T cells mitigate graft-versus-host disease but retain graft-versus-leukemia activity

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中国药理学通报 2015年第B11期31卷 33-34页

Aim Allogeneic hematopoietic stem cell transplantation （HSCT） has curable potential for hematopoietic malignancies through graft-versus-leukemia （GVL） effects but is often associated with life-threatening graft-versus-host disease （GVHD）. Donor T cells play an important role in the pathological process of GVHD. In this study, to determinate immunoisolation through encapsulating T cells with biomaterials could be a promising approach to atten- uate GVHD. Methods T cells were isolated from spleens of donor C57B1/6 mice by magnetic cell separation and coated by layer-by-layer in chitosan and alginate. BALB/c recipient mice were established by GVHD mode and leukemia mode. Xenogen IVIS imaging system was used for live animal imaging. Donor BMCs and T cell subsets were analyzed by flow cytometry. Results In this study, we successfully encapsulated T cells of mice in multilay- ers of chitosan and alginate. In vitro studies showed that the encapsulation did not change the phenotype of T cells as defined through the following parameters： size, viability, proliferation, antibody binding, cytokine secretion, and cytotoxicity. Mice transplanted with encapsulated allogeneic T cells exhibited less severe acute GVHD and pro- longed survival. The mice showed a lower GVHD score, less liver damage, a smaller CD8/CD4 T cell ratio, and a higher number of donor BM-derived cells following transplantation with encapsulated donor T cells. When this GVHD model was combined with implantation of A20 lymphoma cells, GVL of encapsulated T cells was not com- promised, while GVHD was still suppressed and the mouse survival also prolonged. Conclusion These studies demonstrate that encapsulation of T cells with bio-degradable materials could attenuate the severity of GVHD but re- taine GVL, which presents a novel and potentially safer and effective approach of allogeneic HSCT for future clini- cal application.

关键词： nanoparticle encapsulation T cells graft-versus-host disease graft-versus-leukemia immunoisola- tion

Everyone has a donor:contribution of the Chinese experience to global practice of haploidentical hematopoietic stem cell transplantation

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Frontiers of Medicine 2019年第1期13卷 45-56页

作者： Meng Lv Yingjun Chang Xiaojun Huang Peking University People's Hospital Peking University Institute of HematologyBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044China Peking-Tsinghua Center for Life Sciences Beijing 100044China

Human leukocyte antigen (HLA)-matched donors for hematopoietic stem cell transplantation (HSCT) have long been scarce in China. Haploidentical (haplo) donors are available for the vast majority of patients, but toxicity has limited this approach. Three new approaches for haplo-HSCT originated from Italy, China, and USA in 1990 and have been developed to world-renowned system up to now. The Chinese approach have been greatly improved by implementing new individualized conditioning regimens, donor selection based on non-HLA systems, risk-directed strategies for graft-versus-host disease and relapse, and infection management. Haplo-HSCT has exhibited similar efficacy to HLA-matched HSCT and has gradually become the predominant donor source and the first alternative donor choice for allo-HSCT in China. Registry-based analyses and multicenter studies adhering to international standards facilitated the transformation of the unique Chinese experience into an inspiration for the refinement of global practice.This review will focus on how the new era in which "everyone has a donor" will become a reality in China.

关键词： haploidentical hematopoietic stem cell transplantation conditioning graft-versus-host disease relapse infection donor selection

Mesenchymal stem cells targeting the GVHD

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Science China(Life Sciences) 2009年第7期52卷 603-609页

作者： ZHAO Robert ChunHua Center of Tissue Engineering Peking Union Medical College & Chinese Academy of Medical Sciences

Acute graft-versus-host disease(GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues.About 35%-50% of hematopoietic stem cell transplant(HSCT) recipients will develop acute GVHD.It is associated with considerable morbidity and mortality,particularly in patients who do not respond to primary therapy,which usually consists of glucocorticoids(steroids).Most of the available second-line and third-line treatments for steroid-refractory acute GVHD induce severe immunodeficiency,which is commonly accompanied by lethal infectious complications.Mesenchymal stem cells(MSCs) have been shown to mediate immunomodulatory effects.The recently elucidated immunosuppressive potential of mesenchymal stem cells has set the stage for their clinical testing as cellular immunosuppressants,MSCs have been used in patients with steroid-refractory acute GVHD,and encouraging responses have been obtained in many studies.The utility of MSCs for the treatment of GVHD is becoming clear.

关键词： graft-versus-host disease(GVHD) mesenchymal stem cells(MSCs) treatment

Acute GvHD and the cutaneous ultrastructural changes in mismatched bone marrow transplantation

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Journal of Medical Colleges of PLA(China) 1997年第2期12卷 150-154页

作者：李夏新黄志光罗深秋张肇和陈少杰

Six patients treated with human leukocyte antigen (HLA)-mismatched bone marrow transplantation (BMT) suffered from grade I to IV acute graft-versus-host disease (aGvHD) after engrafting. Up to date, 4 patients with grade I to II GvHD have lived for over 2920, 910, 740 and 680 days, respectively. Two other patients died of grade IV hyperacute GvHD. The results seem to indicate that patients in mismatched BMT have a high incidence of aGvHD within a month. The severity of aGvHD is positively correlated with the degree of HLA mismatching. The higher the degree of mismatch of HLA, the earlier and the more severe the aGvHD occurrs. The cutaneous lesion of the patient with GvHD is severe and of ten complicated by mucositis. Lethal hyperacute GvHD must be considered when a patient shows following signs at beginning: (1) The symptoms appear early (within 2weeks) ;(2) peripheral white blood cell count does not recover (<0. 5×109/L) to normal; and (3) high fever persists. In the epidermal ultrastructure of patients, besides acantholysis, autophagic degeneration of keratinocytes,and satellite cell dyskeratosis, there were scattered necrotic keratinocytes, breaking and thickening of basal membrane and presence of a lot of pigment in the intercellular space. These imply that the ultrastructural damages in the skin of patients with aGvHD after mismatched transplantation are more severe than after matched ones.

关键词： human leukocyte antigen a1logenic bone marrow transplantation acute graft-versus-host disease ultrastructure

Optimization of MSC therapeutic strategies for improved GVHD treatment

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国际感染病学（电子版） 2017年第1期6卷 1-7页

作者： Hanyu Wang Weihong Kuang The First Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou China

Mesenchymal stem cells(MSCs) have a powerful immunosuppressive capacity, and they have been used to treat numerous immune diseases, such as refractory graft-versus-host disease. Nevertheless, there are conflicting clinical data. To our knowledge, MSCs from different donors do not share the same qualities and have different immunosuppressive capacities. Infused MSCs are cleared by the recipient's immune cells or macrophages. Therefore, the MSC therapeutic strategy might be the most important factor that determines treatment success. Repeated infusions would lead to a relatively stable MSC concentration, which would benefit a sustained therapeutic effect. In this review, we focus on the quality of MSCs and the associated therapeutic strategy, as well as other potential variables affecting their utility as a cellular pharmaceutical.

关键词： mesenchymal stem cell graft-versus-host disease systematic review

Advances in haplo-identical stem cell transplantation in adults with high-risk hematological malignancies

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World Journal of Stem Cells 2014年第4期6卷 380-390页

作者： Michael J Ricci Jeffrey A Medin Ronan S Foley Department of Pathology and Molecular Medicine McMaster University University Health Network Toronto Ontario M5G 2M1Canada Juravinski Hospital and Cancer Center 711 Con-cession Street

Allogeneic bone marrow transplant is a life-saving procedure for adults and children that have high-risk or relapsed hematological malignancies. Incremental advances in the procedure, as well as expanded sources of donor hematopoietic cell grafts have significantly improved overall rates of success. Yet, the outcomes for patients for whom suitable donors cannot be found remain a significant limitation. These patients may benefit from a hematopoietic cell transplant wherein a relative donor is fully haplotype mismatched. Previously this procedure was limited by graft rejection, lethal graft-versus-host disease, and increased treatmentrelated toxicity. Recent approaches in haplo-identical transplantation have demonstrated significantly improved outcomes. Based on years of incremental preclinical research into this unique form of bone marrow transplant, a range of approaches have now been studied in patients in relatively large phase Ⅱ trials that will be summarized in this review.

关键词： Peripheral blood progenitors Stem cell transplantation graft-versus-host disease Haplo-identical donor Hematological malignancies