Lymphocyte functions triggered by antigen recognition and co-stimulation signals are associated with a rapid and intense cell division, and hence with metabolism adaptation. The nucleotide cytidine ...5' triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids. CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 with CTPS2); the respective roles of these two enzymes are not known. CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes. Here we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells had decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. CTPS1 may therefore represent a therapeutic target of immunosuppressive drugs that could specifically dampen lymphocyte activation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary of Key Recommendations
Diagnosis
It is recommended that the diagnosis of veno‐occlusive disease (sinusoidal obstruction syndrome) VOD (SOS) be based primarily on established clinical criteria ...(modified Seattle or Baltimore criteria) (1A).
Ultrasound imaging may be helpful in the exclusion of other disorders in patients with suspected VOD (SOS) (1C).
It is recommended that liver biopsy be reserved for patients in whom the diagnosis of VOD (SOS) is unclear and there is a need to exclude other diagnoses (1C).
It is recommended that liver biopsies are undertaken using the transjugular approach in order to reduce the risks associated with the procedure (1C).
It is suggested that the role of plasminogen activator inhibitor 1 levels remains an area for further research but that these levels should not form part of the routine diagnostic work‐up for VOD (SOS) at present (2C).
Risk factors
It is recommended that patients are assessed for risk factors for VOD (SOS) and that these risk factors are addressed prior to haematopoietic stem cell transplantation (1A).
Prophylaxis
Defibrotide is recommended at a dose of 6·25 mg/kg intravenously four times daily for the prevention of VOD (SOS) in children undergoing allogeneic stem cell transplantation with the following risk factors: pre‐existing hepatic disease, second myeloablative transplant, allogeneic transplant for leukaemia beyond second relapse, conditioning with busulfan‐containing regimens, prior treatment with gemtuzumab ozogamicin, diagnosis of primary haemophagocytic lymphohistiocytosis, adrenoleucodystrophy or osteopetrosis (1A).
Defibrotide is suggested at a dose of 6·25 mg/kg intravenously four times daily for the prevention of VOD (SOS) in adults undergoing allogeneic stem cell transplantation with the following risk factors: pre‐existing hepatic disease, second myeloablative transplant, allogeneic transplant for leukaemia beyond second relapse, conditioning with busulfan‐containing regimens, prior treatment with gemtuzumab ozogamicin, diagnosis of primary haemophagocytic lymphohistiocytosis, adrenoleucodystrophy or osteopetrosis (2B).
Prostaglandin E1 is not recommended in the prophylaxis of VOD (SOS) due to lack of efficacy and toxicity (1B).
Pentoxifylline is not recommended in the prophylaxis of VOD (SOS) due to lack of efficacy (1A).
Ursodeoxycholic acid is suggested for use in the prophylaxis of VOD (SOS) (2C).
Heparin (unfractionated and low molecular weight) is not suggested for use in the prophylaxis of VOD (SOS) due to the risk of increased toxicity (2B).
Antithrombin is not suggested for the prophylaxis of VOD (SOS) due to lack of efficacy (2B).
Treatment
Defibrotide is recommended in the treatment of VOD (SOS) in adults and children (1B).
Tissue plasminogen activator is not recommended for use in the treatment of VOD (SOS) due to the associated risk of haemorrhage (1B).
N‐acetylcysteine is not routinely recommended for use in the treatment of veno‐occlusive disease due to lack of efficacy (1A).
Methylprednisolone may be considered for use in the treatment of veno‐occlusive disease with the appropriate caveats of caution regarding infection (2C).
Judicious clinical care, particularly in the management of fluid balance, is recommended in the management of VOD (SOS) (1C).
Early discussion with critical care specialists and a specialist hepatology unit is recommended in the management of VOD (SOS) and other treatment options including transjugular intrahepatic portosystemic shunt or hepatic transplantation may be considered (1C).
Summary
A joint working group established by the Haemato‐oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of veno‐occlusive disease of the liver following haematopoietic stem cell transplantation (HSCT). This guideline includes recommendations for both prophylaxis and treatment of the condition and includes recommendations for children and adults undergoing HSCT.
Human marrow stromal cells (MSCs) can be isolated from bone marrow and differentiate into multiple tissues in vitro and in vivo. These properties make them promising tools in cell and gene therapy. ...The lack of a specific MSC marker and the low frequency of MSCs in bone marrow necessitate their isolation by in vitro expansion prior to clinical use. This may severely reduce MSC proliferative capacity to the point that the residual proliferative potential is insufficient to maintain long‐term tissue regeneration upon reinfusion. In this study we determined the effect of in vitro expansion on the replicative capacity of MSCs by correlating their rate of telomere loss during in vitro expansion with their behavior in vivo. We report that even protocols that involve minimal expansion induce a rapid aging of MSCs, with losses equivalent to about half their total replicative lifespan.
Mucopolysaccharidosis type I–Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Although hematopoietic cell transplantation ...(HCT) has been performed in these patients for more than 30 years, large studies on the long-term outcome of patients with MPS-IH after HCT are lacking. The goal of this international study was to identify predictors of the long-term outcome of patients with MPS-IH after successful HCT. Two hundred seventeen patients with MPS-IH successfully engrafted with a median follow-up age of 9.2 years were included in this retrospective analysis. Primary endpoints were neurodevelopmental outcomes and growth. Secondary endpoints included neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic, and endocrinologic outcomes. Considerable residual disease burden was observed in the majority of the transplanted patients with MPS-IH, with high variability between patients. Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant. A normal α-l-iduronidase enzyme level obtained post-HCT was another highly significant predictor for superior long-term outcome in most organ systems. The long-term prognosis of patients with MPS-IH receiving HCT can be improved by reducing the age at HCT through earlier diagnosis, as well as using exclusively noncarrier donors and achieving complete donor chimerism.
•Patients with Hurler syndrome show significant residual disease burden despite HCT.•Early referral for HCT, using noncarrier donors and regimens designed to achieve full-donor chimerism, offers the best long-term prognosis.
Patient 4 (sibling to patient 3) was well until he presented with inflammatory colitis and Hodgkin lymphoma (inguinal and para-aortic region) at age 16 years. Because of his sibling's history, CTLA4 ...haploinsufficiency was confirmed by both genetic and protein level testing, the only patient in this cohort to have an identified mutation before HSCT. In summary, 4 of 8 patients experienced GvHD despite having well-matched donors and receiving alemtuzumab in 3 out of 4 cases.\n9 (5.4-16.8)IgA 0.27 (0.74-2.61)IgM 0.84 (0.40-1.95)Preimmunoglobulin therapyPre-RTX 23 y Interstitial lung disease ("nodular lymphoid hyperplasia") Transverse myelitis Recurrent white matter and brainstem lesions with oligoclonal bands and elevated IgG index Arthritis Father:ITPSister:Patient no. 7 Table I Patients' characteristics ABVD, Adriamcyin (Doxorubicin), bleomycin, vinblastine, dacarbazine; naive CD4, CD3+CD4+CD27+CD45RA+; naive CD8, CD3+CD4-CD27+CD45RA+; Euronet PHL-C1, Euronet pediatric Hodgkin lymphoma-C1; F, female; IDDM, insulin-dependent diabetes mellitus; ITP, idiopathic thrombocytopenic purpura; M, male; NK, natural killer; PN, parenteral nutrition; RTX, rituximab.
Homing of bone marrow stromal cells (MSCs) to bone and bone marrow after transplantation, important for the correction of conditions such as metabolic storage disorders, can occur but with poor ...efficiency. Substantial improvements in engraftment will be required in order to derive a clinical benefit from MSC transplantation. Chemokines are the most important factors controlling cellular migration. Stromal-derived factor-1 (SDF-1) has been shown to be critical in promoting the migration of cells to the bone marrow, via its specific receptor CXCR4. The aim of our study was to investigate CXCR4 expression on MSCs and its role in mediating migration to bone marrow. We show that CXCR4, although present at the surface of a small subset of MSCs, is important for mediating specific migration of these cells to bone marrow. (Blood. 2004; 104:2643-2645)
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very ...broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies.
A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus.
Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT.
This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases.
Hematopoietic stem cell transplantation (HSCT) has been established as an effective therapy for selected inborn errors of metabolism. The success of HSCT in metabolic disease is best exemplified ...through the treatment of Hurler's syndrome, a lysosomal storage disease. Through the collaborative effort of several international centers, factors that predict successful patient and transplant outcomes have been identified. In this review, we discuss the principles that underlie the use of HSCT in metabolic diseases. We consider the clinical indications, conditioning regimens, and disease-specific follow-up for HSCT in different metabolic diseases. We highlight persisting challenges in HSCT to delay progression of certain organ systems that remain refractory to HSCT and the relatively high rates of aplastic graft failure. Finally, we evaluate the variable applicability of these principles to other inherited metabolic disorders including peroxisomal, mitochondrial, and other lysosomal storage diseases.
Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; ...cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access.
We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT-multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition.
We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.
PURPOSE OF REVIEWThis review summarizes the main results of haematopoietic stem cell transplantation (HSCT) in selected inborn errors of metabolism (IEMs).
RECENT FINDINGSEarly diagnosis and ...immediate referral to an IEM specialist is of paramount importance to improve clinical outcomepatients who are transplanted early or in their presymptomatic phase generally achieve better correction of their somatic symptoms and neurocognitive development. Long-term outcome in children with Hurler syndrome is influenced by age at HSCT, baseline clinical status and post-HSCT enzyme levels. Myeloablative Busulfan-based conditioning regimens with therapeutic drug monitoring are recommended to achieve full donor engraftment and more robust enzyme delivery after HSCT. Gene therapy can lead to production of supranormal enzyme levels, and preliminary clinical results are also promising in IEMs historically not responsive to allogeneic HSCT.
SUMMARYAllogeneic HSCT has largely contributed to the improved survival and quality of life of many children affected by IEMs. Neonatal screening could enable earlier HSCT, and this might significantly reduce residual disease burden and improve clinical outcome. Novel strategies, such as gene therapy, have shown encouraging clinical results in selected IEMs and might become more widely available in the future, with potentially better enzyme delivery and reduced transplant-related toxicity.
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