Sensing danger: toll-like receptors and outcome in allogeneic hematopoietic stem cell transplantation.

Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) play key roles in initiating innate and adaptive immune responses. Based mainly on animal studies there is growing evidence to suggest that TLRs are involved in the development of chemotherapy-induced mucositis and in the propagation of graft versus host reactions as well as graft versus tumor effects in allogeneic hematopoietic stem cell transplantation (HSCT). In this review we discuss these findings along with the emerging, although still preliminary, clinical evidence, that points to a role of PRRs in determining the outcome of HSCT and new therapeutic perspectives that may be related to this development.

YKL-40 in allogeneic hematopoietic cell transplantation after AML and myelodysplastic syndrome.

YKL-40, also called chitinase-3-like-1 protein, is an inflammatory biomarker that has been associated with disease severity in inflammatory and malignant diseases, including AML, multiple myeloma and lymphomas. The objective of the current study was to assess the prognostic value of pretransplant recipient and donor plasma YKL-40 concentrations in patients with AML (n=624) or myelodysplastic syndrome (n=157) treated with allogeneic hematopoietic cell transplantation (HCT). In recipients, the plasma YKL-40 concentrations were increased when the HCT-comorbidity index was ⩾5 (P=0.028). There were no significant associations between plasma YKL-40 concentrations in recipients and any outcome measures. In donors with YKL-40 plasma concentrations above the age-adjusted 95th percentile, a trend toward increased grade II-IV acute GvHD in recipients was observed (adjusted hazard ratio 1.39 (95% confidence interval 1.00-1.94), P=0.050), with no significant associations with overall survival, treatment-related mortality or relapse. In conclusion, our study shows that YKL-40 does not aid risk stratification of patients undergoing allogeneic HCT, but suggests that YKL-40 may aid donor selection when multiple, otherwise equal, donors are available.

Long-term survival after allogeneic haematopoietic cell transplantation for AML in remission: single-centre results after TBI-based myeloablative and non-myeloablative conditioning.

We report the results of non-myeloablative (NM) and myeloablative (MA) conditioning for haematopoietic cell transplantation in 207 consecutive AML patients at a single institution. A total of 122 patients were transplanted in first CR (CR1) and 67 in second CR (CR2). MA conditioning was given to 60 patients in CR1 and 50 in CR2. NM conditioning was given to 62 patients in CR1 and 17 patients in CR2. MA patients in CR1 experienced more acute GVHD than NM patients, 60.5% versus 22.9%, but the 5-year post transplant cumulative TRM was not different. Relapse incidence at 5 years in CR1 patients was 23.7% which is not statistically different from 28.5% in NM patients. Leukaemia-free survival at 5 years in CR1 patients was 57.7% after MA conditioning and 58.3% after NM conditioning. No statistical difference in overall 5-year survival after MA or NM conditioning was observed in CR1 patients (63.9 versus 64%) and CR2 patients (51.2 versus 64.7%). Durable remission can be obtained in older patients with AML in remission after NM conditioning, which may also be applicable to younger patients.

Haematopoietic cell transplantation with non-myeloablative conditioning in Denmark: disease-specific outcome, complications and hospitalization requirements of the first 100 transplants.

We analysed the outcome and hospitalization requirements of the first 100 patients (Hodgkin's disease (HD), N=13; multiple myeloma (MM), N=14; CLL, N=12; non-Hodgkin's lymphoma (NHL), N=17; myelodysplastic syndrome (MDS), N=18; AML, N=24 and CML, N=2) treated in Denmark with haematopoietic cell transplantation after non-myeloablative conditioning with TBI 2 Gy+/-fludarabine. The cumulative incidence of acute GVHD grade II-IV and extensive chronic GVHD was 67 and 49%. After a median follow-up of 534 days, the overall survival, PFS, relapse-related mortality and treatment-related mortality were 59, 50, 25 and 17%, respectively. Patients with CLL, NHL, AML and MDS with <5% blasts at any time had a favourable outcome with a PFS of 61-71%. Patients with MM, HD and MDS and a history of > or =5% blasts had a less favourable outcome with a PFS of 19-38% (P=0.001). The cumulative incidence of discontinuation of immunosuppression was 37%. During the first and second year post transplant, patients experienced a mean of 41 and 13 outpatient clinic visits, and 53 and 16 days of hospitalization. Sixteen patients were admitted to the intensive care unit, of whom eight are still alive. In conclusion, transplantation outcomes were encouraging, but complications requiring admission and outpatient clinic visits occur frequently post transplant.

The genetic variation of the human HMGB1 gene.

High-mobility group box 1 protein (HMGB1) is a nuclear DNA-binding protein, which also functions as a pleiotropic cytokine, implicated in the pathology of several different immune-mediated diseases. The purpose of this study was to examine the HMGB1 gene for putative polymorphisms in 103 healthy Caucasian Danish blood donors. A total of six polymorphisms and four mutations were identified in the HMGB1 gene. Subsequent MatInspector estimation revealed that several polymorphisms might have a potential regulatory impact on HMGB1 transcription. This study has characterized genetic variations in the HMGB1 gene locus, which may have a regulating role in the expression of HMGB1, providing the basis for molecular investigations of the HMGB1 gene in different disease settings.

Phenotypic presentation and underlying mutations in carriers of beta-thalassaemia and alpha-thalassaemia in the Danish immigrant population.

OBJECTIVE: The thalassaemia syndromes are the most common hereditary diseases in the world and now appear with relatively high frequency in non-endemic regions. Guidelines recommend the use of mean corpuscular haemoglobin (MCH) alone or in combination with mean corpuscular volume (MCV) in screening for alpha- and beta-thalassaemia. This article deals with the viability of MCV<78 fL alone as screening parameter for thalassaemia in non-endemic regions. MATERIAL AND METHODS: Data from the Center for Haemoglobinopathies, Herlev University Hospital, consist of MCV measurements from 438 patients with alpha-thalassaemia and 450 patients with beta-thalassaemia referred between 1996 and 2005, and simultaneously measured MCV and MCH measurements in 86 patients referred between November 2004 and November 2005. RESULTS: In 450 beta-thalassaemia patients and 117 alpha0-thalassaemia patients diagnosed between 1996 and 2005, only two beta-thalassaemia patients had MCV>or=78 fL. All alpha0-thalassaemia patients had MCV<78 fL. In contrast, 38% of patients with alpha+-thalassaemia had MCV>78 fL. When MCV and MCH were measured simultaneously, one patient with beta-thalassaemia was missed if MCV was used as a screening tool and one patient was missed if MCH was used. Forty-four different beta-thalassaemic mutations were found. CONCLUSIONS: Our data support the notion that the use of MCV<78 fL instead of MCH<27 pg is acceptable as a screening criterion in a non-endemic population. Only 0.5% of the beta-thalassaemia patients were missed and all the patients with alpha0-thalassaemia were diagnosed. Since the racial heterogeneity of the immigrant population in non-endemic regions creates a scenario with a broad spectrum of mutations and haemoglobinopathy, laboratories should be equipped to detect a large variety of mutations.

Pyruvate protects against 3-nitropropionic acid neurotoxicity in corticostriatal slice cultures.

Previously, we have shown that 3-nitropropionic acid (NPA) neurotoxicity in organotypic corticostriatal slice cultures is dependent on glucose and glutamate. Here we studied the neuroprotective potential of agents improving mitochondrial function, including creatine, malate, oxaloacetate, Pyruvate and L-lactate in NPA-treated slice cultures. pyruvate provided the best protection against the loss of glutamic acid decarboxylase activity, depletion of GABA levels, increased propidium iodide uptake and increased glial fibrillary acidic protein levels. ATP levels were significantly reduced by 100 microM NPA (but not by 50 microM) and restored by pyruvate (5 mM). Creatine and L-lactate had no significant protective effect. Protective mechanisms of pyruvate are probably multifold, including stimulation of the citric acid cycle, scavenging and reduction of excitotoxicity.

3-Nitropropionic acid neurotoxicity in organotypic striatal and corticostriatal slice cultures is dependent on glucose and glutamate.

Mitochondrial inhibition by 3-nitropropionic acid (3-NPA) causes striatal degeneration reminiscent of Huntington's disease. We studied 3-NPA neurotoxicity and possible indirect excitotoxicity in organotypic striatal and corticostriatal slice cultures. Neurotoxicity was quantified by assay of lactate dehydrogenase in the medium and glutamic acid decarboxylase in tissue homogenates. 3-NPA toxicity (25-100 microM in 5 mM glucose, 24-48 h) appeared to be highly dependent on culture medium glucose levels. 3-NPA treatment caused also a dose-dependent lactate increase, reaching a maximum of threefold increase above control at 100 microM. Both a high dose of glutamate (5 mM) and glutamate uptake blockade by dl-threo-beta-hydroxyaspartate potentiated 3-NPA neurotoxicity in corticostriatal slice cultures. Furthermore, striatum from corticostriatal cocultures was more sensitive to 3-NPA than striatum without cortex and tetrodotoxin, MK-801, and d-2-amino-5-phosphonopentanoic acid prevented or attenuated 3-NPA neurotoxicity, suggesting that membrane depolarization and/or neuronal activity of the glutamatergic corticostriatal pathway contributes to striatal pathology. The results indicate that in vivo characteristics of 3-NPA toxicity can be reproduced in organotypic corticostriatal slice cultures.