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Introduction Toll-like receptors ( TLRs) detect invading pathogens through several pattern-recognition mechanisms and play a central role in the regulation of the immune system. In allogeneic hematopoietic stem cell transplantation ( HSCT), the frequent opportunistic fungal infections remain an important cause of mortality and morbidity in these highly immunocompromised patients. Methods We analyzed 154 patients after allogeneic HSCT for acute leukemia for TLR4 gene variants 1063A/G (D299G) and 1363C/T (T399I) with their respective donors, and correlated the results with the incidence of invasive aspergillosis ( IA) infection after transplant. Results Probable and proven IA in recipients was significantly increased if either recipients or donors exhibited one of the two TLR4 gene variants. In addition, recipients with TLR gene variants and IA showed a delayed T cell and NKT cell immune reconstitution after transplant. Increased susceptibility for IA was not associated with an increased rate of death-in-remission or decreased estimate for overall survival. Conclusion These findings reinforce the importance of genetic variants in innate immunity and IA among the recipients of allogeneic HSCT. [ABSTRACT FROM AUTHOR]

Growth factor-independent 1B ( GFI1B) is a transcription factor essential for the development and differentiation of erythroid and megakaryocytic lineages. We evaluated the GFI1B expression in erythroleukaemia and megakaryocytic leukaemia, as well as in patients with other subtypes of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), myelodysplastic syndrome (MDS), severe aplastic anaemia (SAA), myelofibrosis with myeloid metaplasia (MMM) and in healthy volunteers. GFI1B expression was increased at least threefold in patients with erythroleukaemia ( P < 0·01 compared with controls) and megakaryocytic leukaemia ( P < 0·05) as well as in their corresponding leukaemic cell lines HEL, K562, CMK and M-07e. Patients with undifferentiated or monocytic AML, ALL, MMM, MDS and CML had no significantly altered GFI1B expression, whereas GFI1B expression was decreased 10-fold in patients with SAA ( P < 0·0001 compared with controls). Silencing GFI1B by transfection with small interfering RNA (siRNA) markedly reduced the proliferation rate in the leukaemic cell lines HEL, K562 and NB4 ( P < 0·01). Concomitantly, we observed a two- to threefold increase in the apoptosis rate in these cells after transfection with siRNA towards GFI1B. Our data indicate that GFI1B plays a major role in AML-M6 and AML-M7 and qualifies as a target for anti-leukaemic strategies in these malignancies. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the outcome following myeloablative allogeneic hematopoietic stem cell transplantation (SCT) among patients older than 50 yr of age. A total of 215 patients with a median age of 57 yr underwent allogeneic hematopoietic SCT for early (41%) or advanced (59%) hematologic malignancies. After a median follow-up of 36 months a 10-yr survival estimate of 56 ± 6% could be assessed for patients in early disease stages while patients with advanced diseases showed a significantly decreased survival probability of 31 ± 5% (p < 0.0002). Transplant related mortality (TRM) at day 100 and 365 post-transplant was 13% and 30% for early but increased to 21% and 49% for advanced disease stages. As major determinants of TRM advanced disease stage (p < 0.0001) and occurrence of grades II–IV graft-vs.-host disease (GVHD) (p < 0.0001) were identified. These results show that hematopoietic SCT following myeloablative conditioning is also applicable to elderly patients whereas disease stage and high-grade GVHD represent the essential prognostic factors for outcome. [ABSTRACT FROM AUTHOR]

The mortality rate associated with respiratory failure due to invasive fungal infections after allogeneic hematopoietic stem cell transplantation (HSCT) is exceedingly high. We present a retrospective analysis of 4 HSCT recipients who survived long-term artificial respiration subsequent to pulmonary mycosis, and compare our current findings with historic data. Several clinical parameters indicate a remarkable improvement in the clinical courses of those patients in recent years: weaning time, extubation rate, and improvement of additional organ failures were all significantly better in patients treated after the emergence of new antimycotic agents, resulting in prolonged overall survival. We propose that our observations reflect an improved management of these patients, mainly because of the use of new antimycotics with alternative mechanisms of action and decreased toxicity, allowing for earlier, more aggressive, and more effective antifungal treatment approaches. In addition, the optimized use of new technologies designed to augment spontaneous breathing efforts by patients, mechanical ventilation, as well as the advantages of early tracheotomy will contribute to better outcomes in the treatment of respiratory failure due to pulmonary mycoses following allogeneic HSCT. [ABSTRACT FROM AUTHOR]

Novotny JR, Rosenthal C, Elmaagacli AH, Dürig J, Beelen DW, Dührsen U. Disease- or therapy-related bone marrow damage cannot be overcome by changes in stem cell source or dose in allogeneic transplantation. Eur J Haematol 2004: 73: 1–9. © Blackwell Munksgaard 2004. To test whether the functional impairment of the host bone marrow (BM) microenvironment pre-existing at the time of transplantation could be overcome by the increased content of immature cells in allogeneic peripheral blood stem cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). Cobble stone area forming cells (CAFC) were assayed in normal BM and BM after allogeneic BMT and PBSCT after stable engraftment. Groups were compared by two-tailed t-test. While BM from 11 normal controls contained an average of 778.8 CAFC-d35 per 106 low density bone marrow cells (LDBMC, range 453–1231 per 106 LDBMC), BM from patients after BMT contained an average of 123.7 CAFC-d35 per 106 LDBMC (range 38–257) per 106 LDBMC. BM from patients transplanted with PBSC after myeloablative conditioning contained 128.3 (range 46–305) CAFC-d35 per 106 LDBMC ( P = 0.89 compared with BMT). Similar results were obtained when patients after PBSCT with non-myeloablative conditioning were included ( P = 0.62 compared with BMT). CAFC numbers in patients transplanted in early stages of myeloid leukaemia (acute myeloid leukaemia first remission, chronic myeloid leukaemia first chronic phase) were significantly higher than CAFC numbers in patients transplanted in more advanced stages ( P = 0.008) or myelodysplastic syndrome ( P = 0.023). The lowest CAFC numbers were found in two cases of retransplantation. Our findings indicate that the functional state of the BM microenvironment rather than stem cell dose or source is limiting for the homing and engraftment of immature haemopoietic cells in clinical transplantation. [ABSTRACT FROM AUTHOR]

Abstract Indoleamine 2,3-dioxygenase (IDO) is an interferon-γ (IFN-γ)-induced enzyme, which is suggested to play an important role in the prevention of allogeneic fetal rejection. IDO effects the suppression of T-cell activity by catabolizing the essential amino acid l-tryptophan. We studied IDO expression by reverse transcription polymerase chain reaction (RT-PCR) in dendritic cells and by real-time RT-PCR in monocytes of patients undergoing allogeneic transplantation for leukaemia, who developed acute graft-versus-host disease (aGvHD), and compared the IDO expression with that of pregnant women and healthy volunteers. A spontaneous IDO expression was detected in the monocytes of 20 pregnant women with an IDO/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ratio at a median of 1.0%, whereas none of 15 healthy volunteers or patients after allogeneic transplant had any detectable spontaneous IDO expression. The IDO expression increased by in vitro IFN-γ stimulation in pregnant women (median 116%), healthy volunteers (median 11.7%) and patients with a low-grade aGvHD (grades 0–II) 28 days after transplant (median 433%) but not in patients with a severe aGvHD (grades III–IV) (median 0%), which was highly significant (P < 0.01). IDO expression was also measured in dendritic cells by qualitative RT-PCR, where a spontaneous IDO expression was detected in 16 of 31 (52%) pregnant women versus none of 17 healthy volunteers and none of 62 studied patients after transplant. IFN-γ-induced IDO expression was detected in all pregnant women, all volunteers and 47 of 49 (96%) patients with a low-grade aGvHD (grades 0–II) after transplant, whereas only in two of 13 (16%) patients with aGvHD grade III–IV was IFN-γ-induced IDO expression observed. These data suggest that IDO expression might be involved in the development of allogeneic immune tolerance. [ABSTRACT FROM AUTHOR]

We have used a new single-step real-time reverse transcription polymerase chain reaction (RT-PCR) method to quantify BCR-ABL transcripts, thereby estimating the relapse stage in chronic myeloid leukaemia patients after allogeneic transplants. In 402 samples from 172 patients, BCR-ABL expression was determined and normalized, using the GAPDH housekeeping gene product as an endogenous reference. In our real-time RT-PCR assay, serial dilutions of RNA of the K562 cell line remained positive down to 7·5 pg. The median normalized BCR-ABL amount differed significantly (P < 0·001) between the various disease stages and was 0·06% (range 0·001–1·55%), 3·2% (range 1·4–5·6%) and 21·5% (range 6·8 -827%) in 17 patients with a molecular relapse, in eight patients with a cytogenetic relapse and in 10 patients with a haematological relapse respectively. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Clinical course and molecular features in 21 patients with atypical chronic myeloid leukemia" in January 2012 issue.

The article focuses on a report by Hao et al. which deals with the possible role of the indolamine 2,3 dioxygenase (IDO)-aryl hydrocarbon receptor (AhR) axis in maternal-foetal tolerance. It was hypothesized that AhR mediates the kynurenine-induced differentiation of regulatory T cells at the feto-maternal interface. The mechanisms that may contribute to reduction of alloreactivity during pregnancy is discussed.

Presents a letter to the editor on the role of interferon in the induction of allogeneic immune tolerance in pregnant women, published in the 2005 issue of "Scandinavian Journal of Immunology."