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      Treatment of radiculomyelopathy in two patients with placenta-derived decidua stromal cells

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          Abstract

          Mesenchymal stromal cells may reverse acute inflammatory disorders. The placenta is important in feto-maternal tolerance. We have used placenta-derived decidua stromal cells (DSCs) to treat graft-versus-host disease and found an immunomodulatory and anti-inflammatory effect. We here report the use of DSCs in two patients with radiculomyelopathy. The first patient was a 73-year old man treated with parotidectomy and irradiation for lymphoma of the neck. Following a Yersinia infection, he developed a radiculomyelopathy in C3/C4 and could not elevate his arms. The second patient was a 34-year old woman who was admitted 8 months after allogeneic hematopoietic stem cell transplantation due to hemolysis, impaired sensorium below arcus, and difficulty in ambulation. Following intravenous infusion of DSCs (1 × 10 6/kg/infusion), the first patient could elevate his arms to the facial level. He experienced recurrent paralysis after 6 months, and the efficacy of four additional DSC infusions, at subsequent occasions, were limited and transient. The second patient was treated with two doses of DSCs (1 × 10 6/kg/infusion). After cell infusion, she was able to stand on one leg, sensation in the belly normalized, and she was discharged. These two cases suggest that DSCs may be useful in the treatment of neuroinflammatory disorders.

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          Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.

          Adult bone-marrow-derived mesenchymal stem cells are immunosuppressive and prolong the rejection of mismatched skin grafts in animals. We transplanted haploidentical mesenchymal stem cells in a patient with severe treatment-resistant grade IV acute graft-versus-host disease of the gut and liver. Clinical response was striking. The patient is now well after 1 year. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.
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            Decidual stromal cells promote regulatory T cells and suppress alloreactivity in a cell contact-dependent manner.

            Acute graft-versus-host disease (GvHD) is a severe adverse event after stem cell transplantation. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) have been used to treat GvHD, but decidual stromal cells (DSCs) isolated from term fetal membrane have advantages compared with BM-MSCs, including increased allosuppression, unlimited supply, and high expression of integrins. We introduced the use of DSCs in patients with steroid refractory aGvHD. In this study, we investigated factors of importance in the reduction of alloreactivity by DSCs. We found that DSCs need to have cell-cell contact in order to mediate suppression in mixed lymphocyte reactions (MLRs). This contact dependency is consistent with an increased frequency of CD4(+)CD25(high)FOXP3(+) regulatory T cells (Tregs) and an augmented intensity of CD25 expression in CD4(+) T cells. Blocking of the activity of indoleamine-2,3-dioxygenase (IDO), prostaglandin E2, PD-L1, and IFN-γ impaired the antiproliferative ability of the DSCs in MLRs. Neutralization of IDO also reduced the frequency of Tregs. In contrast to BM-MSCs, pretreatment of DSCs with high concentrations of IFN-γ (100 U/mL) reduced their ability to suppress alloreactivity, but stimulation of DSCs with MLR supernatants containing low levels of IFN-γ had no effect on the suppressive capacity in MLR. To conclude, DSCs differ in several aspects from MSCs and need to be close to alloreactive lymphocytes to mediate a suppressive effect and increase the frequency of Tregs. Thus, DSCs may not only use paracrine factors for systemic immunosuppression, but also more specifically target T cells locally in affected tissues.
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              Placenta‐Derived Decidua Stromal Cells for Treatment of Severe Acute Graft‐Versus‐Host Disease

              Abstract Severe acute graft‐versus‐host disease (GVHD) is a life‐threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). The placenta protects the fetus from the mother's immune system. We evaluated placenta‐derived decidua stromal cells (DSCs), which differ from bone marrow mesenchymal stromal cells (BM‐MSCs), as a treatment for severe acute GVHD. DSCs were obtained from term placentas. The DSCs were given to 38 patients with severe acute GVHD; 25 were steroid refractory (SR). DSCs were thawed and infused in buffer supplemented with either 10% AB plasma (group 1, n = 17), or 5% albumin (group 2, n = 21). The viability of cells was higher when thawed in albumin rather than AB plasma (p < .001). Group 1 received a higher cell dose (p < .001), cells of lower passage number (p < .001), and fewer infusions (p = .002) than group 2. The GVHD response (no/partial/complete) was 7/5/5 in group 1 and 0/10/11 in group 2 (p = .01). One‐year survival in the two groups was 47% (95% confidence interval [CI] 23–68) and 76% (95% CI 51–89), respectively (p = .016). For the SR patients, 1‐year survival was 73% (95% CI 37–90) in SR group 2 (n = 11), which was better than 31% (95% CI 11–54) in SR group 1 (n = 13; p = .02), 20% (95% CI 5–42) in BM‐MSC treated (n = 15; p = .0015), and 3% (95% CI 0–14) in historic controls (n = 32; p < .001). DSCs are a promising new treatment for severe acute GVHD. Prospective randomized trials are needed for evaluation of efficacy. (Clinical trial NCT‐02172937.) stem cells translational medicine 2018;7:325–332
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                Author and article information

                Contributors
                behnam.sadeghi@ki.se
                Journal
                Int J Hematol
                Int. J. Hematol
                International Journal of Hematology
                Springer Singapore (Singapore )
                0925-5710
                1865-3774
                18 December 2019
                2020
                : 111
                : 4
                : 591-594
                Affiliations
                [1 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Translational Cell Therapy Research (TCR), Department of Clinical Science, Intervention and Technology, Karolinska Institutet, KFC, NOVUM, Plan 6, , Karolinska University Hospital Huddinge, ; Hälsovägen 7, 141 57 Huddinge, Sweden
                [2 ]Department of Neurology, Queen Sofias Hospital, Stockholm, Sweden
                [3 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Department of Oncology and Pathology, Karolinska Institutet, , Karolinska University Hospital Huddinge, ; Stockholm, Sweden
                [4 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Department of Clinical Immunology, , Karolinska University Hospital Huddinge, ; Stockholm, Sweden
                Author information
                http://orcid.org/0000-0002-8721-0400
                Article
                2804
                10.1007/s12185-019-02804-w
                7102257
                31853810
                341eb927-ecc5-424d-b165-8d3662c25de4
                © Japanese Society of Hematology 2019

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 6 August 2019
                : 10 December 2019
                : 12 December 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002794, Cancerfonden;
                Award ID: CAN2013/671
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;
                Award ID: K2014-64X-05971-34-4
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100006313, Barncancerfonden;
                Award ID: PR2013-0045
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007231, Cancerföreningen i Stockholm;
                Award ID: 111293
                Award Recipient :
                Categories
                Case Report
                Custom metadata
                © Japanese Society of Hematology 2020

                Hematology
                myelopathy,decidua stromal cells,mesenchymal stromal cells,graft-versus-host disease

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