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

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.

Download Full-text

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

10.21203/rs.3.rs-89163/v2 ◽

2021 ◽

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.

Download Full-text

Sustained Remission After Haploidentical Bone Marrow Transplantation in a Child With Refractory Systemic Juvenile Idiopathic Arthritis

10.21203/rs.3.rs-89163/v1 ◽

2020 ◽

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 ◽

Host Disease ◽

Graft Versus Host ◽

Alternative Donor

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 since the age of 15 months with a severe disease course. 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. Therefore, allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team carefully assessed risks and benefits of a transplant procedure with an alternative donor. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated. 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.

Download Full-text

Oral Squamous Cell Carcinomas in Patient with Graft Versus-Host Disease Following Allogenic Bone Marrow Transplantation: A Case Report during Mutant COVID-19 Pandemic

Journal of Dentistry Open Access ◽

10.31487/j.jdoa.2021.01.01 ◽

2021 ◽

pp. 1-6

Author(s):

Khaled Saleh Ben Salah ◽

Abdulfattah A Elturki ◽

Yuossef Swaisi ◽

Fatma M. Emaetig ◽

...

Keyword(s):

Bone Marrow ◽

Case Report ◽

Aplastic Anaemia ◽

Squamous Cell ◽

Graft Versus Host Disease ◽

Haematopoietic Stem Cell ◽

Hematopoietic Stem ◽

Host Disease ◽

Allogenic Bone ◽

Graft Versus Host

Aplastic anaemia is a severe haematological disorder characterized by an inadequate number of hematopoietic stem cells, resulting in pancytopenia, formed by a hypocellular bone marrow. Disorders of this nature are widely treated with haematopoietic stem cell transplantation (HSCT). A potential chronic complication following (HSCT) is the growth of secondary malignancies. Notably, patients suffering from chronic graft versus host disease (cGvHD) secondary to HSCT have been shown to be more susceptible to oral squamous cell carcinoma (OSCC). Here, we present a rare case of a 30-year-old Libyan woman treated with HSCT for aplastic anaemia, with subsequent complications of cGvHD and OSCC after few months of HSCT. These carcinomatous lesions were detected in the buccal gingiva and retromolar pad area at the age of 31. The present case report emphasizes the connection between oral cGvHD and OSCC, and the potential appearance of OSCC after HSCT at any time of patient life. Thus, closer follow-up is mandatory for all patients treated with HSCT who developed cGvHD, and efficient cGvHD prevention and therapeutic approaches are needed.

Download Full-text

Alterations of Bone Marrow Microenvironment in Acute Graft-Versus-Host Disease

Blood ◽

10.1182/blood-2019-126322 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5009-5009

Author(s):

Yan Lin ◽

Quan Gu ◽

Hui Cheng ◽

Zhaofeng Zheng ◽

Sun Guohuan ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Graft Versus Host Disease ◽

Ppar Gamma ◽

Bone Marrow Microenvironment ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

Severe acute graft-versus-host disease (aGVHD) indicates a poor prognosis after allogeneic hematopoietic stem cell transplantation. In our previous study, we found that hematopoiesis was progressively suppressed during aGVHD, while the hematopoietic regenerative potential of donor-derived hematopoietic stem cells remains intact. It prompts us to investigate whether bone marrow niche is a major target of GVHD. We addressed this issue by studying the critical components in bone marrow microenvironment, including mesenchymal stem cell (MSC), osteoblasts and adipocytes in haplo-MHC-matched murine bone marrow transplantation model. By comparing confocal images of femurs from control and aGVHD SCF-GFP mice or Col2.3-GFP mice, we found that both MSCs and osteoblasts were significantly reduced during aGVHD development. In addition, anti-perilipin staining showed that adipocytes were also decreased in aGVHD mice. We found a defect in the differentiation potential of MSCs from aGVHD niche by in vitro culture of both murine and human bone marrow niche cells. qRT-PCR showed decreased gene expressions of PPAR-gamma, Adipoq, Runx1 and Col2a1, suggesting the potential of MSCs differentiation into adipocytes and osteoblasts was blocked. These data provide new insights into the pathogenesis of aGVHD and may improve the clinical management of aGVHD. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Hematopoietic Dysfunction during Graft-Versus-Host Disease: A Self-Destructive Process?

Cells ◽

10.3390/cells10082051 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2051

Author(s):

Konradin F. Müskens ◽

Caroline A. Lindemans ◽

Mirjam E. Belderbos

Keyword(s):

Bone Marrow ◽

Graft Versus Host Disease ◽

Treatment Options ◽

Major Complication ◽

Cell Number ◽

Suppressive Therapy ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic (stem) cell transplantation (HCT). Clinically, GvHD is associated with severe and long-lasting hematopoietic dysfunction, which may contribute to the high mortality of GvHD after HCT. During GvHD, excessive immune activation damages both hematopoietic stem and progenitor cells and their surrounding bone marrow niche, leading to a reduction in cell number and functionality of both compartments. Hematopoietic dysfunction can be further aggravated by the occurrence—and treatment—of HCT-associated complications. These include immune suppressive therapy, coinciding infections and their treatment, and changes in the microbiome. In this review, we provide a structured overview of GvHD-mediated hematopoietic dysfunction, including the targets in the bone marrow, the mechanisms of action and the effect of GvHD-related complications and their treatment. This information may aid in the identification of treatment options to improve hematopoietic function in patients, during and after GvHD.

Download Full-text

Ex Vivo Gene Therapy: Graft-versus-host Disease (GVHD) in NSG™ (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) Mice Transplanted with CD34+ Human Hematopoietic Stem Cells

Toxicologic Pathology ◽

10.1177/0192623319844484 ◽

2019 ◽

Vol 47 (5) ◽

pp. 656-660 ◽

Cited By ~ 3

Author(s):

Sundeep Chandra ◽

Patrizia Cristofori ◽

Carlos Fonck ◽

Charles A. O’Neill

Keyword(s):

Stem Cells ◽

Gene Therapy ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Graft Versus Host Disease ◽

Ex Vivo ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Human Cd34

A therapeutic option for monogenic disorders is gene therapy with ex vivo-transduced autologous hematopoietic stem cells (HSCs). Safety or efficacy studies of ex vivo-modified HSCs are conducted in humanized mouse models after ablation of the murine bone marrow and transfer of human CD34+ HSCs. Engrafted human CD34+ cells migrate to bone marrow and differentiate into various human hematopoietic lineages. A 12-week study was conducted in NSG™ mice to evaluate engraftment, differentiation, and safety of human CD34+ cells that were transduced ( ex vivo) with a proprietary lentiviral vector encoding a human gene (BMRN-1) or a mock (green fluorescent protein) vector. Several mice intravenously injected with naive CD34+ cells or transduced CD34+ cells had variable lymphohistiocytic inflammatory cell infiltrates and microgranulomas in the liver and lungs consistent with graft-versus-host disease (GVHD). Spleen, bone marrow, stomach, reproductive tract, but not the skin had similar inflammatory changes. Ex vivo viral transduction of CD34+ cells did not impact engraftment or predispose to xenogeneic GVHD.

Download Full-text

Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease

Blood ◽

10.1182/blood-2009-02-206920 ◽

2010 ◽

Vol 115 (16) ◽

pp. 3390-3397 ◽

Cited By ~ 7

Author(s):

Laurent Burnier ◽

François Saller ◽

Linda Kadi ◽

Anne C. Brisset ◽

Rocco Sugamele ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Antigen Presenting Cells ◽

Allogeneic Bone ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Antigen Presenting

Abstract Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6−/− mice received allogeneic non–T cell–depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6−/− recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6−/− recipients' liver. When mice received 0.5 × 106 allogeneic T cells with T cell–depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6−/− than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6−/− T-cell proliferation. We therefore assessed the response of WT or Gas6−/− ECs to tumor necrosis factor-α. Lymphocyte transmigration was less extensive through Gas6−/− than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

Download Full-text

Does Donor Epstein-Barr Virus (EBV) Seropositivity Affect Recipient's Risk of Graft Versus Host Disease (GVHD) in Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT)?

Blood ◽

10.1182/blood.v128.22.5766.5766 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5766-5766

Author(s):

Erden Atilla ◽

Esmanur Kaplan ◽

Pinar Ataca Atilla ◽

Selami Kocak Toprak ◽

Pervin Topcuoglu ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Graft Versus Host Disease ◽

Peripheral Blood ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

Abstract Introduction: EBV seropositivity in general population is 80%. Reactivation of latent infection in pre-transplant seropositive patients causes post-transplant lenfoproliferative disease (PTLD) following Allo-HSCT. The effect of donor EBV positivity on recipient's risk of graft versus host disease is not clear. Our aim is to present EBV seroprevalence and PTLD incidence as well as demonstrating the relation of EBV seropositivity with GVHD. Patients and Methods: A total of 364 allogeneic stem cell transplant recipients and donors were evaluated retrospectively from 2006 to 2015. During Allo-HSCT preparation procedures all recipients and donors were serologically tested. EBV specific IgG (VCA-IgG, EBNAIgG, EA-IgG) and IgM (VCA-IgM) antibodies were determined by Chemiluminescence by ARCHITECT lab analyzers using commercially available kits (Abbott, USA). All patients were followed for reactivation. Results: EBV IgG positivity was detected in 338 of recipients (92.8%) and 283 of donors (77.7%). There was no statistically difference detected between related or unrelated transplants. The mean age was 37 (range 16-67). 217 recipients were male (60%). 295 (81%) patients were transplanted for malign hematological diseases. The majority of patients were grafted from full-matched related donors (258, 71%). The most common source of stem cell was peripheral blood in 299 patients (82%) followed by bone-marrow in 56 patients (15%), bone-marrow plus peripheral blood in 9 patients (3%). 273 (75%) patients received myeloablative conditioning regimen. All patients received prophylactic acyclovir (in related transplants 400mg 3 times daily, in un-related transplants 800mg 3 times daily) starting from conditioning and up to three months posttranplant period. One pretransplant seropositive 26 year-old aplastic anemia patient had PTLD with EBV IgM positivity within 3 months posttransplant. He received 4 cycles of rituximab and prednisolone and achieved complete response. Three patients had EBV IgM positivity in posttransplant 4, 9 and 24th months with symptoms of infectious mononucleosis. The seropositivity resolved without treatment. Acute GVHD developed in 223 patients (61%) whereas chronic GVHD was detected in 285 (78%) of patients. The incidence of acute GVHD was similar when donor was EBV seropositive compared to seronegative (78% vs 22%, p=0.72). Chronic GVHD incidence was similar between donor EBV seropositive group compared to seronegative group (80% vs 20%, P=0.199). Conclusion: EBV seropositivity is common detected in 92.8% of our allo-HSCT recipient cohort. Donor EBV status did not have an effect on developing acute or chronic GVHD. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Wnt/β-catenin signaling mediates the abnormal osteogenic and adipogenic capabilities of bone marrow mesenchymal stem cells from chronic graft-versus-host disease patients

Cell Death and Disease ◽

10.1038/s41419-021-03570-6 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Han-zhou Qi ◽

Yi-ling Ye ◽

Yuan Suo ◽

Hong Qu ◽

Hai-yan Zhang ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Graft Versus Host Disease ◽

Underlying Mechanism ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Ppar Γ ◽

Marrow Mesenchymal Stem Cells

AbstractChronic graft-versus-host disease (cGVHD) is the main cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mesenchymal stem cells (MSCs) in bone marrow (BM) remain unclear in the pathophysiology of cGVHD. In this study, we analyzed BM-MSCs from 66 patients after allo-HSCT, including 33 with active cGVHD and 33 without cGVHD. BM-MSCs showed similar morphology, frequency, phenotype, and proliferation in patients with or without cGVHD. MSCs from the active cGVHD group showed a decreased apoptosis rate (P < 0.01). Osteogenic capacity was increased while adipogenic capacity was decreased in the active cGVHD MSCs compared with no-cGVHD MSCs. The expressions of osteogenic gene RUNX2 and COL1A1 were higher (P < 0.001) while adipogenic gene PPAR-γ and FABP4 were lower (P < 0.001) in the active cGVHD MSCs than no-cGVHD MSCs. These changes were associated with the severity of cGVHD (P < 0.0001; r = 0.534, r = 0.476, r = −0.796, and r = −0.747, respectively in RUNX2, COL1A1, PPAR-γ, and FABP4). The expression of Wnt/β-catenin pathway ligand Wnt3a was increased in cGVHD-MSCs. The dysfunction of cGVHD-MSCs could be reversed by Dickkopf related protein 1(DKK1) to inhibit the binding of Wnt3a. In summary, the differentiation of BM-MSCs was abnormal in active cGVHD, and its underlying mechanism is the upregulated of Wnt3a through Wnt/β-catenin signaling pathway of MSCs.

Download Full-text