[Epidemiology and interventional treatment strategies of infectious complications after allogenic stem-cell transplantation].
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Anti-Bacterial Agents↗
Biomedical subjects
H J Kolb
Publications and source records attributed to H J Kolb.
Second German consensus on immunogenetic donor search for allotransplantation of hematopoietic stem cells.
The present paper summarizes the results of the second German consensus meeting on immunogenetic donor search for allotransplantation of hematopoietic stem cells held in Essen in November 1999 under the auspices of the German Society for Immunogenetics (DGI) and the German Working Party for Blood and Marrow Transplantation (DAG-KBT). Immunogeneticists and transplant physicians from all over the country agreed to update the national standards for: (1) search strategy including the role of unrelated and extended family donor search after unsuccessful core family donor search, (2) histocompatibility loci to be typed, (3) histocompatibility typing techniques to be used (HLA serology vs DNA-based HLA typing, cellular tests, serum cross-match), and (4) acceptable HLA mismatches in the context of a defined underlying disease, donor type, and conditioning regimen.
Aging↗
[Allogeneic transplantation in malignant lymphoma].
INTRODUCTION: Allogeneic transplantation of bone marrow and peripheral blood stem cells is a frequently discussed therapeutic option in the treatment of malignant lymphoma. By analysing the results of our own transplant program in patients with advanced lymphoma we tried to evaluate indications for allogeneic transplantations. METHODS: Data from lymphoma patients treated at the Klinikum Grosshadern between 1985 and 2001 were analysed retrospectively. RESULTS: 56 patients were included. 24 patients had low grade Non-Hogdkin's lymphoma (NHL) (follicular lymphoma: n = 8, mantle cell lymphoma: n = 6) or chronic lymphocytic leukemia (CLL: n = 10), 16 patients had high grade NHL (immunoblastic/lymphoblastic: n = 5; large cell/diffuse: n = 5) and 8 patients suffered from Hodgkins's disease. Median age was 41 years, 34 patients were transplanted from an HLA-identical sibling, 19 from an HLA-id. unrelated donor and three from an HLA-mismatched related donor. 30 patients received bone marrow and 26 peripheral blood stem cells. 22 pat. were treated with an intensive 12 Gy TBI containing conditioning regimen, whereas 34 patients were treated with a dose-intensity reduced conditioning procedere. 25 patients are alive between 2 month and 15 years after transplantation. Overall survival after 2 years is 48 % for patients with low grade NHL (incl. CLL), 9.3 % for patients with high grade lymphoma and 25 % for patients with Hodgkin's disease. 1-year-transplant-related mortality (TRM) was 33.9 % in all patients. Dose-intensity-reduced conditioning was not able to reduce TRM. CONCLUSIONS: Allogeneic bone marrow or stem cell transplantation is able to induce long lasting complete remissions in patients with heavily pretreated malignant lymphoma. Results of allogeneic transplantation are encouraging in patients with follicular and other low grade lymphoma. However transplant-related toxicity is high. At present the impact of reducing the intensity of conditioning is not yet clear.
Adolescent↗
Different types of human leukemias express the message for TNF-alpha and interleukin-10.
Leukemic cells proliferate under the influence of cytokines. In particular, the colony-stimulating factors stimulate the growth and proliferation of myeloid leukemia cells. Under normal conditions, tumor necrosis factor-alpha (TNF-alpha) is produced by activated monocytes, whereas interleukin- 10 (IL-10) is produced by several cell types like monocytes and lymphocytes. The autocrine production of cytokines by leukemic cells may have a pathogenic role in the progression of leukemia or may be an epiphenomenon. In this study, we investigated the expression of TNF-alpha and IL-10 in human leukemic cells by RT-PCR and by a cytoplasmic protein assay. Most cases of acute myelogenous leukemia (AML) (7/8 cases) and all cases of acute lymphoblastic leukemia (ALL) (n = 2), chronic myelogenous leukemia (CML) (n = 5), both in chronic phase and during blast crisis, expressed the mRNA for TNF-alpha and IL-10. A patient whose blasts were positive for IL-10 and negative for TNF-alpha, had high circulating levels of IL-10 and failed to respond to donor lymphocyte infusions. Using a cytoplasmic protein assay, generally low levels of cytoplasmic TNF-alpha and IL-10 were found which increased in case of TNF-alpha following stimulation with lipopolysaccharide. Taken together, our data show that most leukemic cells express the mRNA for a proinflammatory cytokine (TNF-alpha) and an immunosuppressive cytokine (IL-10). More work is necessary to determine under which conditions these cytokines actually paralyze the immune system and thereby permit the progression of leukemia.
Gene Expression Profiling↗
Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey.
BACKGROUND: Some patients treated by transplantation of haemopoietic stem cells (peripheral blood or bone marrow) become permanently infertile, but others retain or recover fertility. We assessed the outcome of conception in women, and partners of men previously treated by autologous or allogeneic stem cell transplantation (SCT). METHODS: We sent questionnaires to 229 centres of the European Group for Blood and Marrow Transplantation. We sought details about the original disease, transplant procedure, and outcome of conception for both male and female patients. FINDINGS: 199 centres gave information relating to 19412 allogeneic and 17950 autologous transplant patients. 232 (0.6%) patients conceived after SCT. Crude annual birth rate for 4-month survivors of SCT was lower than the national average for England and Wales at 1.7 per 1000 patients. 312 conceptions were reported in 113 patients (74 allograft) and partners of 119 patients (93 allograft). Most pregnancies were uncomplicated and resulted in 271 livebirths. 28 (42%) of 67 allograft recipients had caesarean section compared with 16% in the normal population (difference =26% [95% CI 15-38]), 12 (20%) of 59 had preterm delivery compared with a normal rate of 6% (14% [4-24]), and 12 (23%) of 52 had low birthweight singleton offspring compared with a normal rate of 6% (17% [6-29]). INTERPRETATION: Pregnancy after SCT is likely to have a successful outcome. Pregnancies in allograft patients who have received total body irradiation should be treated as high risk for maternal and fetal complications.
Adolescent↗
Levels of insulin-like growth factor after stem cell transplantation.
Some cytokines, i.e. tumor necrosis factor-, interleukin-6 and soluble interleukin-2 receptors are associated with complications of stem cell transplantation. Insulin-like growth factors (IGFs) are a family of peptides essential for the proliferation of normal and malignant cells. Recently increased levels of IGFs have been associated with the development of malignant tumors. In this communication we report on 96 measurements of insulin-like growth factor-I (IGF-1), insulin-like growth factor-II (IGF-2), and insulin-like growth factor-binding protein-3 (IGFBP-3) performed in 19 patients following stem cell transplants. Seventeen patients had allogeneic and 2 patients autologous transplants. Most IGF determinations were made at days 0, 7, 14, 21 and 28, some at other time points. The baseline values (day 0) of IGF-1 and IGFBP-3 were not different from controls. IGF-2 values were slightly lower than controls. Following transplantation, a consistent increase of IGF-1 was observed in 9/16 patients at days 7 and 14. Later the values decreased again. IGF-2 and IGFBP-3 did not change significantly after transplantation. No direct correlation could be established with the severity of graft-versus-host disease, levels of interleukin-6 and the time to hematopoietic recovery. A potential relevance of IGFs following stem cell transplantation may be the early diagnosis of liver damage and the development of second malignancies. More studies are necessary to investigate the pathophysiology and the clinical relevance of the increase of IGF-1 following stem cell transplantation.
Adolescent↗
[Cell therapy of hematological neoplasms].
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Bone Marrow Transplantation↗
Histological correlation between different centers using the skin explant model to predict graft-versus-host disease following bone marrow transplantation.
Acute graft-versus-host disease (GVHD) remains the major complication of allogeneic stem cell transplantation (SCT) with an incidence of 40-60% and a mortality of up to 50%. Several assays have been developed to try to predict the development of GVHD including the mixed lymphocyte culture reaction, cytotoxic and helper T lymphocyte precursor frequency assays. In the Northern region of England we have used an in vitro skin explant model for predicting GVHD in MHC compatible bone marrow transplant recipients since 1988. The aims of the present study was to test the reproducibility of the model in two other bone marrow transplant centers in Europe. The assay consists of incubating patient skin explants with effector cells from mixed donor versus recipient lymphocyte cultures and the subsequent detection of graft-versus-host reactions by histopathological grading (0-IV) of the skin explants. 503 slides from 134 patients were evaluated. All were graded for negative GVHR grade 0-I or positive grade II-IV. Results from control and test slides significantly correlated between centers to the p value of 0.0001 by Fisher's exact probability test. These results show that the skin explant assay is reproducible between centers and supports the continued use of the assay to predict GVHD in allogeneic stem cell transplant recipients.
Biopsy↗
Ex vivo generation of cytotoxic T lymphocytes specific for one or two distinct viruses for the prophylaxis of patients receiving an allogeneic bone marrow transplant.
Human adenovirus (AdV) infection and EBV-lymphoproliferative disease (LPD) are serious complications following allogeneic stem cell transplantation. In the healthy individual these viruses cause minor, self-limiting diseases but in the immunocompromised patient they are responsible for significant morbidity and mortality. The limitations of anti-viral drugs and a better understanding of the cellular immune response to viral pathogens have prompted interest in developing adoptive immunotherapy for transplant patients. Ex vivo expanded cytotoxic T lymphocytes (CTLs) specific for EBV have been used effectively both as prophylaxis against EBV-LPD and as treatment of established EBV+ lymphoma. To generate CTLs specific for AdV, we infected immature dendritic cells with virus, in the presence of lipid, and subsequently used these cells to stimulate PBMNCs. Cytotoxicity assays showed that the resulting CTLs specifically lysed AdV-expressing targets and that this was mediated predominantly by CD4+ T cells. To generate CTLs specific for both AdV and EBV, we developed a CD40 ligand co-culture system to infect B-lymphoblastoid cell lines (LCLs) with high efficiency. PBMNCs from healthy AdV-seropositive donors were stimulated weekly with autologous AdV+-LCLs. Chromium release assays demonstrated that the resultant CTLs had specificity against both EBV and AdV and that this was mediated by both CD4+ and CD8+ T cells. Our findings have potential implications for post-transplant AdV and EBV immunotherapy in recipients of allogeneic stem cell transplants.
Adenoviridae↗
Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia.
It has been proposed that adoptive immunotherapy, for the treatment of relapsed AML, with cytotoxic T lymphocytes which show a relative specificity for the leukemic cells may have the advantage of maximizing the beneficial anti-leukemic effect whilst minimizing the probability of graft-versus-host disease. In this study we differentiated peripheral blood AML cells in vitro into functional dendritic cells (DCs), as demonstrated by cell morphology, immunophenotype and functional activity, in the presence of GM-CSF, IL-4, TNF-alpha and FLT3 ligand. Such DCs could be differentiated from 77% of AML patients, irrespective of their FAB classification and clinical status and, in all cases tested, the DCs were shown to derive from the leukemic clone by FISH analysis. Importantly, from >60% of AML patients, autologous T lymphocytes stimulated with these in vitro generated leukemic DCs displayed specific cytotoxic activity against AML blasts but low reactivity against autologous non-leukemic targets and HLA-matched normal PBMNCs therefore suggesting that the CTLs were AML-specific. The use of FLT3 ligand in our system resulted in a significantly higher number of leukemic DCs as compared to cultures from which FLT3 ligand was omitted which is obviously advantageous if large numbers of specific CTLs are to be generated in the shortest possible time.
Acute Disease↗
Growth inhibition in giant growth hormone transgenic mice by overexpression of insulin-like growth factor-binding protein-2.
To clarify the role of insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) in postnatal growth regulation, we crossed hemizygous CMV-IGFBP-2 transgenic mice with hemizygous PEPCK-bGH transgenic mice, which are characterized by serum GH levels in the range of 2 microgram/ml. Four genetic groups were obtained: animals carrying both transgenes (GB), the GH (G) or the IGFBP-2 transgene (B), and nontransgenic controls (C). Male offspring were analyzed for serum levels of IGF-I, for serum and tissue levels of IGFBP-2, and for body and organ growth. Serum IGF-I levels were 2- to 3-fold increased (P < 0.001) in the GH-overexpressing groups, with no difference between G and GB mice. Serum IGFBP-2 levels were 4- to 9-fold (P < 0.001) increased both in B and GB vs. C and G mice. Western immunoblot analysis did not reveal differences in tissue IGFBP-2 levels between B and GB mice. IGFBP-2 levels were highest in pancreas, followed by skeletal muscle, heart, kidney, brain, skin, and spleen. No elevation of IGFBP-2 was found in the liver. Body weight gain of G and GB mice was significantly increased vs. C and B mice, resulting in almost 2-fold increased body weights at the age of 15 weeks. However, there was a significant reduction in body weight of GB vs. G mice (17%; P < 0.001) and of B vs. C mice (13%; P < 0.05). This was primarily caused by a marked reduction of carcass weight (GB vs. G, 27%; B vs. C, 21%; P < 0.001). Measurements of nose-rump-length, organ (brain, heart, spleen, liver, pancreas, kidney), and tissue weights (skin, carcass, abdominal fat) in 5- and 15-week-old mice revealed several indications that the growth-inhibiting effect of IGFBP-2 overexpression was more marked in high-GH/IGF-I mice: 1) At 5 weeks of age, GB mice displayed a significant reduction of all growth parameters except for the weight of abdominal fat, when compared with G mice, whereas only brain weight was significantly reduced in B vs. C mice. 2) In 15-week-old animals, a significant reduction in all growth parameters, except for spleen and abdominal fat weights, was seen in GB vs. G mice, whereas only nose-rump-length and the weights of carcass and brain were significantly reduced in B vs. C mice. Our study demonstrates, for the first time, the potential of IGFBP-2 to inhibit GH-stimulated growth in giant transgenic mice, providing further evidence for an inhibitory effect of this IGFBP in vivo.
Animals↗
Risk assessment in patients with Ph+ chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: an EBMT retrospective analysis. The Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
Patients with Ph+ chronic myelogenous leukemia who relapse after a first allogeneic stem cell transplant still have a possibility of long-term survival. To assess the value of the individual therapeutic options, the factors predicting outcome should be identified. We investigated data from 500 patients who relapsed before July 1996; follow-up was updated during 1998. The actuarial survival from relapse was 34.2% (95% confidence interval [CI]: 29. 9%-38.5%) at 5 years and 23.4% (95% CI: 18.9%-27.9%) at 10 years. Survival after relapse was significantly related to 5 factors: time from diagnosis to transplant (< 2 years vs >/= 2 years), disease phase at transplant (first chronic phase vs other), disease stage at relapse (cytogenetic or chronic phase vs advanced phase), time from transplant to relapse (< 1 year vs >/= 1 year), and donor type (HLA-identical sibling vs volunteer unrelated donor). The effects of individual adverse risk factors were cumulative: The probability of survival at 10 years decreased stepwise from 42% (0 factors), 32% (1 factor), 14% (2 factors), 3% (3 factors), to 0% (4 or 5 factors). Novel strategies for high-risk patients are warranted. We conclude that these 5 factors should be taken into account when comparing results of salvage therapies in patients with Ph+ chronic myeloid leukemia relapsing after allogeneic stem cell transplant.
Actuarial Analysis↗
Overexpression of insulin-like growth factor-binding protein-2 results in increased tumorigenic potential in Y-1 adrenocortical tumor cells.
Increased concentrations of insulin-like growth factor-binding protein-2 (IGFBP-2) have been observed in human malignancies including adrenocortical carcinomas. To elucidate the functional consequences of IGFBP-2 overexpression, we have stably transfected the cDNA of murine IGFBP-2 in mouse adrenocortical tumor cells (Y-1). Long-term overexpression of IGFBP-2 was associated with significant morphological alterations, enhanced cell proliferation, and increased cloning efficiency as compared with mock transfected control cells. The enhanced proliferation of IGFBP-2 secreting clones was independent of exogenous insulin-like growth factors (IGFs). These data suggest that elevated levels of IGFBP-2 may contribute to the highly malignant phenotype of adrenocortical cancer by a thus far unknown, presumably IGF-independent, mechanism.
Adrenal Cortex Neoplasms↗
In vitro-generated stem cell leukaemia showing altered cell cycle progression with distinct signalling of the tyrosine-phosphorylated rasGAP-associated p62(dok) protein.
In an attempt to gain more insight into the events of leukaemic transformation, a cell line overexpressing MHC class II (DR) was generated by transfecting an early CD34-negative haematopoietic progenitor stem cell line with the appropriate constructs. The stable transfection with genes for DR antigens leads to cellular transformation. The DR(+) transformed cell clones express a tyrosine-phosphorylated DR heterodimer and show a significantly different morphology. DR(+) clones present the morphology of an immature myeloid neoplasia expressing alpha-naphthyl-acetate-esterase (ANAE), but neither myeloperoxidase nor CD34. While D064 cells predominately grow adherent as fibroblast-like cells, the DR(+) clones display a decrease in adherent growth. Although both cell lines express similar amounts of the interleukin-6 (IL-6) signal transducer gp130, the DR-transfected cells still show activation of STAT factors by IL-6, whereas D064 cells do not. Although the transformed clones present acceleration of cell-cycle transition and growth, the G(0)/G(1) progression inhibitor p27(kip-1) is up-regulated, while the expression of proteins involved in the S/G(2) phase transition, such as cyclin B and cdc2 (p34), is suppressed. Instead cyclin D3, one of the G(0)/G(1) progression factors, is up-regulated, as well as tyrosine-phosphorylated p62(dok), suggesting dysregulation of cell cycle-controlling proteins. In addition, DR(+) leukaemia-like cells also overexpress Bcl-2, while bax expression is suppressed, compared with the wild-type (wt) parental haematopoietic stem cell line.
Acute Disease↗
Quiescence of CD34-negative haematopoietic stem cells is mediated by downregulation of Cyclin B and no stat activation.
The CD34-negative, adherent growing, fibroblast-like canine haematopoietic stem cell line D064 was recently identified as the earliest progenitor population in the bone marrow. D064 cells are predominately quiescent. Quiescence is mediated by the accumulation of the cyclin-dependent kinase inhibitor p27(kip-1)and in parallel, by the downregulation of Cyclin B, leading to an accumulation of quiescent cells in the G(0)/G(1)-phase of the cell cycle. Stem cell factor (SCF), the ligand for the tyrosine kinase receptor c-kit, usually induces differentiation of the CD34-negative stem cells into CD34-positive haematopoietic precursors. SCF also suppresses the expression of c-myc-dependent Cyclin E, which is not transcribed initially, but expression occurs later on. Interleukin 6 (IL-6) instead rather promotes proliferation, but fails to induce proliferation in the majority of CD34-negative stem cells due to no STAT activation in quiescent cells. Nevertheless, the potential of quiescent D064 cells to proliferate eventually, becomes apparent by the low-level expression of IL-6 dependent STAT factors. D064 cells also spontaneously start to express Bax, while Bcl-2 is downregulated in parallel. In summary, CD34-negative haematopoietic stem cells dwell in the marrow or other niches as quiescent cells, until they can respond to autocrine or paracrine growth factor-mediated signals.
Animals↗
Transplant activities in Germany in 1998--a survey facilitated by the National Registry for Hemopoietic Stem Cell Transplantation.
To improve the infrastructure of hemopoietic stem-cell transplantations in our country, the German Registry for Hemopoietic Stem-Cell Transplantations (DRST) was established in 1998. The present paper summarizes the current status of the DRST and gives a survey of transplant activities in Germany in 1998 in terms of transplant units, transplant types, transplant frequencies and underlying diseases.
Blood Cells↗
The clinical-chemical screen in the Munich ENU Mouse Mutagenesis Project: screening for clinically relevant phenotypes.
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Animals↗
[Fractional flow reserve as a deciding criterion for intervention in patients with 50% coronary stenoses and impaired myocardial perfusion].
BACKGROUND: A fractional flow reserve (FFRmyo) < 0.75 is a well validated parameter for significance of coronary stenoses in cases of normal myocardial function. We used the FFRmyo limit in patients with impaired myocardial perfusion by myocardial infarction and/or hypertension for intermediate stenoses of the LAD for decision to PTCA and checked the indication by clinical follow-up. METHODS: In 20 pts (5 women) with chest pain and visual 50 D% LAD stenoses, the FFRmyo was obtained by using a RADI-Pressure-Wire, the CFR by a densitometric technique (HODGSON), and the geometry of stenosis (minimal lumen diameter and diameter stenosis) by quantitative coronary angiography (QCA). EF and the kinetics of the anterolateral wall (expressed as radial shortening fraction) were measured by laevography. RESULTS: The mean age of our 20 pts. was 59.4 years: 13 of the pts. (65%) had a history of hypertension, 9 (45%) pts. a history of myocardial infarction. The mean diameter stenosis was 50.8%. The mean value of CFR was 2.9. The FFRmyo ranged from 0.66 to 0.90, the mean value was 0.78. The 12 pts. with FFRmyo > or = 0.75 (60%, group A) were treated with the usual anti-anginal medications. A PTCA was performed only in patients with FFRmyo < 0.75 (N = 8 (40%), group B). Except for one pt. with instent restenosis, in the 7 pts. with denovo stenoses stent implantation was performed. Significant differences between the groups A and B were seen only for the total number of myocardial infarctions (8/12 vs. 1/8) and diameter stenosis (48.5% vs. 54.3%). All lesions of group B had a diameter stenosis of 50% or higher. CFR correlated significantly with the radial shortening fraction (r = 0.75), minimal lumen diameter (r = -0.51) and diameter stenosis (r = -0.46). FFRmyo correlated with diameter stenosis (r = -0.47) only. All pts. treated with PTCA were primarily free of pain or reduced angina at least 1 CCS stage; only one developed an angina due to a restenosis (74 D%) 2 months after PTCA and stent implantation. The pts. of group A did not get worse, nor were they readmitted within 6 to 13 months after catheterization. CONCLUSIONS: Pts. with 50 D% stenoses, impaired myocardial perfusion and FFRmyo < 0.75 had a good long-term benefit concerning clinical and angiographic result. No pts. with FFRmyo < 0.75 had a D% lower than 50; therefore, the PTCA of intermediate stenoses without quantification must be avoided. CFR is not helpful for a decision to PTCA in such cases, because a normal value of CFR is relevant only.
Aged↗