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| 3. |
- Lundin, Karin E., et al.
(författare)
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Eleven percent intact PGM3 in a severely immunodeficient patient with a novel splice-site mutation, a case report
- 2018
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Ingår i: BMC Pediatrics. - : Springer. - 1471-2431 .- 1471-2431. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: A novel immunodeficiency, frequently accompanied by high serum-IgE, and caused by mutations in the PGM3 gene was described in 2014. To date there are no unique phenotype characteristics for PGM3 deficiency. PGM3 encodes a carbohydrate-modifying enzyme, phosphoglucomutase 3. Null-mutations are quite likely lethal, and to date only missense mutations or small deletions have been reported. Such mutations frequently cause a combination of reduced enzyme activity and protein instability, complicating determination of the enzyme level needed for survival. Here we present the first patient with a homozygous splice-modifying mutation in the PGM3 gene. An A > G substitution at position c.871 +3 (transcript NM_001199917) is causing a deletion of exon 7 in the majority of PGM3 transcripts. In addition, this case further increases the clinical phenotypes of immunodeficiency caused by PGM3 mutations. Case presentation: We describe the symptoms of a 3-year-old girl who was severely growth retarded, had vascular malformations, extensive eczema, multiple food-allergies, and was prone to infections. Unlike the majority of reported PGM3 deficient patients she lacked skeletal dysplasia and had normal neurocognitive development. In addition to the high serum-IgE, she displayed altered T cell numbers with reduced naive CD4(+) and CD8(+) T-cells, increased number of activated effector memory CD8(+) T cells and aberrant T-cell functions. The patient was homozygous for a new hypomorphic, splice-modifying mutation in the PGM3 gene, causing severely reduced mRNA levels. In the patient's cells, we observed 5% intact mRNA and approximately 11% of the protein levels seen in healthy controls. Treatment with allogeneic hematopoietic stem cell therapy was planned, but unfortunately the clinical condition deteriorated with multi-organ failure, which led to her death at 3 years of age. Conclusions: There is still no specific phenotype identified that distinguishes immunodeficiency caused by PGM3 mutations from other forms of immunodeficiency. The patient described here yields new information on the phenotypic variability among these patients. In addition, since all the synthesized protein is wild-type, it is possible for the first time to estimate the enzyme activity in vivo. The results suggest that1/10 of the normal PGM3 level is sufficient for survival but that it is insufficient for accurate carbohydrate processing.
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- Remberger, Mats, et al.
(författare)
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Improved survival after allogeneic hematopoietic stem cell transplantation in recent years : A single-center study
- 2011
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 17:11, s. 1688-1697
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.
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- Ringdén, Olle, et al.
(författare)
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Transplantation of Autologous and Allogeneic Bone Marrow With Liver From A Cadaveric Donor for Primary Liver Cancer1
- 2000
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 69:10, s. 2043-2048
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundIn histocompatibility mismatched experimental animals, a combination of T-cell-depleted autologous and allogeneic marrow may induce mixed chimerism and tolerance. Patients with large primary liver tumors have a poor outcome. We investigated whether it were possible to induce mixed chimerism and obtain an antitumor effect in a patient with a large primary liver cancer after combined liver and bone marrow transplantation (BMT).MethodsA 46-year-old female with a primary non resectable liver cancer received a liver transplant from a cadaveric donor. Subsequently, she was conditioned with 4×2 Gy of total lymphoid irradiation, 120 mg/kg cyclophosphamide, and 7.5 Gy total body irradiation. Twelve days after liver transplantation, she received T-cell-depleted autologous : cadaveric 5/6 antigen HLA-mismatched marrow in a proportion of CD34+ cells of 0.5 : 3.0×106/kg. Chimerism status was determined with polymerase chain reaction amplification of variable number tandem repeats from DNA obtained from CD3+, CD19+, and CD45+ magnetic-bead-separated cells.ResultsThe early posttransplant period was uneventful; liver function was normal and the hematopoietic engraftment of donor and recipient origin was prompt. [alpha]-fetoprotein levels dropped from 440 to 35 µg/l. One month after marrow transplantation, donor T-cells decreased markedly. Monoclonal antibody OKT-3 and 105/kg donor T-cells were given. One month later, the patient developed diarrhea and abdominal pain. A colonoscopy showed moderate gastrointestinal acute graft-versus-host disease and a Cryptosporidium infection. Three months after BMT, she became a complete donor chimera. Chimera cells showed little, if any, reactivity in mixed lymphocyte cultures to recipient and donor cells, but reacted to third party. Five months after BMT, she developed progressive Aspergillus fumigatus pneumonia and died. No tumor was found at the autopsy.ConclusionWe obtained mixed donor-recipient hematopoietic chimerism without severe acute graft-versus-host-disease, after combined T-cell depleted autologous and allogeneic BMT and a transplantation of a liver from an HLA-mismatched cadaveric donor. Additional donor T-cells enhanced donor bone marrow engraftment, but rejected the autograft. On the basis of this first attempt, further clinical studies are warranted.
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| 6. |
- Ryden, Mikael, et al.
(författare)
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Transplanted Bone Marrow-Derived Cells Contribute to Human Adipogenesis
- 2015
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 22:3, s. 408-417
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Tidskriftsartikel (refereegranskat)abstract
- Because human white adipocytes display a high turnover throughout adulthood, a continuous supply of precursor cells is required to maintain adipogenesis. Bone marrow (BM)-derived progenitor cells may contribute to mammalian adipogenesis; however, results in animal models are conflicting. Here we demonstrate in 65 subjects who underwent allogeneic BM or peripheral blood stem cell (PBSC) transplantation that, over the entire lifespan, BM/PBSC-derived progenitor cells contribute similar to 10% to the subcutaneous adipocyte population. While this is independent of gender, age, and different transplantation-related parameters, body fat mass exerts a strong influence, with up to 2.5-fold increased donor cell contribution in obese individuals. Exome and whole-genome sequencing of single adipocytes suggests that BM/PBSC-derived progenitors contribute to adipose tissue via both differentiation and cell fusion. Thus, at least in the setting of transplantation, BM serves as a reservoir for adipocyte progenitors, particularly in obese subjects.
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| 7. |
- Svenberg, Petter, et al.
(författare)
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Improved overall survival for pediatric patients undergoing allogeneic hematopoietic stem cell transplantation - A comparison of the last two decades.
- 2016
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Ingår i: Pediatric Transplantation. - : Wiley. - 1397-3142 .- 1399-3046. ; 20:5, s. 667-74
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Tidskriftsartikel (refereegranskat)abstract
- Pediatric protocols for allogeneic hematopoietic SCT have been altered during the last two decades. To compare the outcomes in children (<18 yr old), who underwent SCT at our center during 1992-2002 (P1) and 2003-2013 (P2). We retrospectively analyzed 188 patients in P1 and 201 patients in P2. The most significant protocol changes during P2 compared with P1 were a decrease in MAC protocols, particularly those containing TBI, an increase in RIC protocols, and altered GvHD prophylaxis. In addition, P2 had more patients with nonmalignant diagnoses (p = 0.002), more mismatched (MM) donors (p = 0.01), and more umbilical CB grafts (p = 0.03). Mesenchymal or DSCs were used for severe acute GvHD during P2. Three-yr OS in P1 was 58%, and in P2, it was 78% (p < 0.001). Improved OS was seen in both malignant disorders (51% vs. 68%; p = 0.05) and nonmalignant disorders (77% vs. 87%; p = 0.04). Multivariate analysis showed that SCT during P2 was associated with reduced mortality (HR = 0.57; p = 0.005), reduced TRM (HR = 0.57; p = 0.03), unchanged relapse rate, similar rate of GF, less chronic GvHD (HR = 0.49; p = 0.01), and more acute GvHD (HR = 1.77, p = 0.007). During recent years, OS has improved at our center, possibly reflecting the introduction of less toxic conditioning regimens and a number of other methodological developments in SCT.
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| 8. |
- Svenberg, Petter, et al.
(författare)
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The importance of graft cell composition in outcome after allogeneic stem cell transplantation in patients with malignant disease
- 2019
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Ingår i: Clinical Transplantation. - : Wiley. - 0902-0063 .- 1399-0012. ; 33:6
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Tidskriftsartikel (refereegranskat)abstract
- Background Graft-versus-host disease (GVHD) and relapse remain majobstacles ftreatment success in allogeneic hematopoietic stem cell transplantation (HSCT). In the present study, we evaluated the immune cell profile of the graft to outcome after HSCT.Study design and method Flow cytometry data of graft cell subsets [CD34+, CD3+, CD19+, CD4+, CD8+, CD3-CD56+CD16+, CD4+CD127lowCD25high] from G-CSF primed peripheral blood stem cell (PBSC) donors was collected retrospectively from 299 patients with hematological malignancies undergoing HSCT between 2006 and 2013. The association to overall survival, transplant-related mortality (TRM), GVHD and probability of relapse was analyzed. Patients outcome from HLA-identical sibling (Sib) (n = 97) and unrelated donors (URD) (n = 202) were analyzed separately as all URD patients received anti-thymocyte globulin (ATG).Results Five-year overall survival was similar in the two cohorts (68% (Sib) vs 65% (URD)). The relapse incidence was significantly lower in the Sib cohort (24% vs 35%, P = 0.04). Multivariate analysis in the URD group revealed an association between a higher CD8+ dose and less relapse (HR, 0.94; 95%CI, 0.90-0.98; P = 0.006) as well as an association between higher CD34+ dose and both higher TRM (HR, 1.09; 95%CI, 1.02-1.20; P = 0.02) and relapse (HR, 1.09; 95%CI, 1.01-1.17; P = 0.025). The Sib analysis showed an association between a higher graft CD19+ dose and more severe acute GVHD (HR, 1,09; 95%CI, 1.03-1.15; P = 0.003) and TRM (HR, 1.09; 95%CI, 1.01-1.17; P = 0.036). In addition, a higher CD4+ graft content was associated to an increased risk for chronic GVHD (HR, 1.02; 95%CI 1.00-1.04; P = 0.06).Conclusion These data indicate an importance of PBSC dongraft composition in patients with a hematological malignancy.
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| 9. |
- Uhlin, Michael, et al.
(författare)
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Mesenchymal Stem Cells Inhibit Thymic Reconstitution After Allogeneic Cord Blood Transplantation
- 2012
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Ingår i: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 21:9, s. 1409-1417
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Tidskriftsartikel (refereegranskat)abstract
- Cord blood (CB) as a source of stem cells has been a successful addition to the field of allogeneic stem cell transplantation (ASCT). The increased human leukocyte antigen (HLA) permissiveness of CB grafts has made it possible for more patients to undergo treatment. The drawback is that patients suffer from a longer period of compromised immunity. We analyzed T-cell receptor excision circles (TRECs), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels after cord blood transplantation (CBT) in 50 patients transplanted at our center. These immunological parameters were compared retrospectively with clinical factors and complications. We found that TREC levels after CBT were lower in adults, patients with myeloablative conditioning, and in patients with a lower nucleated cell dose in the graft. In addition mesenchymal stem cells (MSC) as co-infusion at the time of CBT had a negative effect on TREC reconstitution. This was found to be associated with decreased overall survival for this patient category. Reduced IgM and IgG levels post-CBT were associated with a major ABO mismatch, and infusion of MSCs. Our results highlight the importance of close monitoring of the immune reconstitution after CBT. In addition it shows a potentially new suppressive effect of MSCs on the immune system.
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| 10. |
- Uzunel, Mehmet
(författare)
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The methodology and significance of minimal residual disease detection after allogeneic stem cell transplantation
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allogeneic stem cell transplantation (SCT) is the choice of therapy for leukemia patients who respond poorly to conventional chemotherapy. Despite high remission rates after SCT, relapse of the underlying disease remains one of the most frequent causes of treatment failure. Graftversus-host disease (GVHD), a major complication after SCT, is caused by the activation of alloreactive donor T-cells. Although being life threatening in its severe forms, GVHD has a protective effect called the graft-versus-leukemia effect (GVL). In order to use the GVL effect of donor T-cells, donor lymphocyte infusions (DLI) is now used as a treatment for relapse after SCT. Response to DLI is usually better when the tumor load is low. Therefore, sensitive methods to detect residual leukemic cells are needed in order to identify patients who are at the highest risk of relapse and to start immunotherapeutic interventions when the tumor load is still low. Minimal residual disease (MRD) refers to the presence of leukemic cells below the detection limit of standard morphological analysis. The most sensitive and widely used techniques for MRD detection are based on the PCR technology. The aim of this thesis is to evaluate the clinical significance of MRD detection in leukemia patients receiving SCT. In patients with acute myeloid leukemia (AML), we evaluated the significance of mixed chimerism (MC) analysis, the detection of recipient-derived hematopoietic cells after SCT. MC analysis was performed in the leukemia-affected cell lineage to increase the specificity and sensitivity of the method. MC was detected in 14 of 30 patients. Ten of these 14 patients relapsed as compared to 2 of 16 with donor chimerism (p<0.01). MC was detected a median time of 66 (range 23-332) days before hernatological relapse. Using immunoglobulin and T-cell receptor gene rearrangements as clonal markers, we analyzed MRD levels before and after SCT in patients with acute lymphoblastic leukemia (ALL). MRD detection before SCT was associated with increased risk of relapse. However, GVHD was shown to protect against relapse in patients with high levels of MRD. MRD detection after SCT was also associated with a high risk of relapse. Relapse occurred in 8 of 9 MRD positive patients as compared to 6 of 23 MRD negative patients (p<0.01). MRD was detected a median of 5.5 (range 0.5-30) months before relapse. In recent years, nonmyeloablative SCT (NST) has been studied as a safer approach for patients who are not eligible for the toxic conditioning regimens given before SCT. We studied the kinetics of MRD and MC in chronic myeloid leukemia (CML) patients receiving NST and compared the results to those obtained from CML patients receiving a conventional SCT (CST). A competitive PCR approach was performed for quantitative MRD analysis of BCR-ABL transcripts. In the early posttransplant period, higher incidence and levels of MC and MRD were found in NST patients as compared to CST patients. However, molecular remissions were subsequently achieved in most NST patients. Wilms tumor gene (WTI) has been reported as a "panleukemic" MRD marker in many studies. We wanted to evaluate WTI as a MRD marker by comparing the kinetics of WTI levels with that of BCR- ABL using realtime quantitative PCR. We found a background expression of WTI healthy controls. In addition, WTI analysis was not sensitive enough to predict relapse. In conclusion, MRD analysis in leukemia patients provides the possibility to identify patients at high risk of relapse after SCT. Adoptive immunotherapy based on MRD results may prevent relapse and improve outcome for patients with poor prognosis.
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