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- Hammarström, Lennart, et al.
(författare)
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Transfer of IgA deficiency to a bone-marrow-grafted patient with aplastic anaemia
- 1985
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Ingår i: The Lancet. - 1474-547X. ; 325:8432, s. 778-781
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Tidskriftsartikel (refereegranskat)abstract
- IgA deficiency developed in a 2-year-old boy with aplastic anaemia who received a bone-marrow graft from his HLA-identical, 6-year-old, IgA-deficient sister. Southern blot analysis revealed the presence of alpha-genes in both children, thus suggesting a defect of lymphocyte stem-cell differentiation as a cause of IgA deficiency. Tissue typing showed homozygosity of HLA A1, B8, DR3, the haplotype associated with IgA deficiency in healthy people. Despite normal serum levels of IgG subclasses in both donor and recipient, both children showed a relative lack of specific IgG2 anticarbohydrate antibodies. This suggests that their IgA deficiency is part of a more fundamental aberration of immunoglobulin class and subclass distribution.
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- Moll, Guido, et al.
(författare)
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Cryopreserved or fresh mesenchymal stromal cells : Only a matter of taste or key to unleash the full clinical potential of MSC therapy?
- 2016
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Ingår i: Advances in Experimental Medicine and Biology. - Cham : Springer International Publishing. - 2214-8019 .- 0065-2598. ; 951, s. 77-98
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Bokkapitel (refereegranskat)abstract
- Mesenchymal stromal cells (MSCs) harbor great therapeutic potential for numerous diseases. From early clinical trials, success and failure analysis, bench-to-bedside and back-to-bench approaches, there has been a great gain in knowledge, still leaving a number of questions to be answered regarding optimal manufacturing and quality of MSCs for clinical application. For treatment of many acute indications, cryobanking may remain a prerequisite, but great uncertainty exists considering the therapeutic value of freshly thawed (thawed) and continuously cultured (fresh) MSCs. The field has seen an explosion of new literature lately, outlining the relevance of the topic. MSCs appear to have compromised immunomodulatory activity directly after thawing for clinical application. This may provide a possible explanation for failure of early clinical trials. It is not clear if and how quickly MSCs recover their full therapeutic activity, and if the “cryo stun effect” is relevant for clinical success. Here, we will share our latest insights into the relevance of these observations for clinical practice that will be discussed in the context of the published literature. We argue that the differences of fresh and thawed MSCs are limited but significant. A key issue in evaluating potency differences is the time point of analysis after thawing. To date, prospective double-blinded randomized clinical studies to evaluate potency of both products are lacking, although recent progress was made with preclinical assessment. We suggest refocusing therapeutic MSC development on potency and safety assays with close resemblance of the clinical reality.
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| 4. |
- Moll, Guido, et al.
(författare)
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Different Procoagulant Activity of Therapeutic Mesenchymal Stromal Cells Derived from Bone Marrow and Placental Decidua
- 2015
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Ingår i: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 28:S2, s. 50-51
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Tidskriftsartikel (refereegranskat)abstract
- While therapeutic mesenchymal stromal/stem cells (MSCs) have usually been obtained from bone marrow, perinatal tissues have emerged as promising new sources of cells for stromal cell therapy. In this study, we present a first safety follow-up on our clinical experience with placenta-derived decidual stromal cells (DSCs), used as supportive immunomodulatory and regenerative therapy for patients with severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). We found that DSCs are smaller, almost half the volume of MSCs, which may favor microvascular passage. DSCs also show different hemocompatibility, with increased triggering of the clotting cascade after exposure to human blood and plasma in vitro. After infusion of DSCs in HSCT patients, we observed a weak activation of the fibrinolytic system, but the other blood activation markers remained stable, excluding major adverse events. Expression profiling identified differential levels of key factors implicated in regulation of hemostasis, such as a lack of prostacyclin synthase and increased tissue factor expression in DSCs, suggesting that these cells have intrinsic blood-activating properties. The stronger triggering of the clotting cascade by DSCs could be antagonized by optimizing the cell graft reconstitution before infusion, for example, by use of low-dose heparin anticoagulant in the cell infusion buffer. We conclude that DSCs are smaller and have stronger hemostatic properties than MSCs, thus triggering stronger activation of the clotting system, which can be antagonized by optimizing the cell graft preparation before infusion. Our results highlight the importance of hemocompatibility safety testing for every novel cell therapy product before clinical use, when applied using systemic delivery.
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- Olsson, Richard F., et al.
(författare)
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Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency : The Karolinska Experience
- 2016
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 100:6, s. 1356-1362
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Tidskriftsartikel (refereegranskat)abstract
- Background. Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. Methods. We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m(2)) and fludarabine (30 mg/m(2)) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/ kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. Results. A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. Conclusions. Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.
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