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Biomedical subjects

Hermann Einsele

Publications and source records attributed to Hermann Einsele.

At least 55 records · Page 3Linked to original sources
PubMed2003

Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants.

Adoptive transfer of cytomegalovirus (CMV)-specific T cells can restore long-lasting, virus-specific immunity and clear CMV viremia in recipients of allogeneic stem cell transplants if CD4(+) and CD8(+) CMV-specific T cells are detected in the recipient after transfer. Current protocols for generating virus-specific T cells use live virus, require leukapheresis of the donor, and are time consuming. To circumvent these limitations, a clinical-scale protocol was developed to generate CMV-specific T cells by using autologous cellular and serum components derived from a single 500-mL blood draw. CMV-specific T cells were stimulated simultaneously with CMV-specific major histocompatibility complex class I (MHC I)- restricted peptides and CMV antigen. Activated T cells were isolated with the interferon-gamma (IFN-gamma) secretion assay and expanded for 10 days. In 8 randomly selected, CMV-seropositive donors, 1.34 x 10(8) combined CD4(+) and CD8(+) CMV-specific T cells, on average, were generated, as determined by antigen-triggered IFN-gamma production. CMV-infected fibroblasts were efficiently lysed by the generated T cells, and CMV-specific CD4(+) and CD8(+) T cells expanded if they were stimulated with natural processed antigen. On the other hand, CD4(+) and CD8(+) T cell-mediated alloreactivity of generated CMV-specific T-cell lines was reduced compared with that of the starting population. In conclusion, the culture system developed allowed the rapid generation of allodepleted, highly enriched, combined CD4(+) and CD8(+) CMV-specific T cells under conditions mimicking good manufacturing practice.

Adoptive Transfer↗
PubMed2003

Infectious complications after allogeneic stem cell transplantation: epidemiology and interventional therapy strategies--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

The risk of infection after allogeneic stem cell transplantation is determined by the underlying disease, the intensity of previous treatments and complications that may have occurred during that time, but above all, the risk of infection is determined by the selected transplantation modality (e.g. HLA-match between the stem cell donor and recipient, T cell depletion of the graft, and others). In comparison with patients treated with high-dose chemotherapy and autologous stem cell transplantation, patients undergoing allogeneic stem cell transplantation are at a much higher risk of infection even after hematopoietic reconstitution, due to the delayed recovery of T and B cell functions. The rate at which immune function recovers after hematopoietic reconstitution greatly influences the incidence and type of post-transplant infectious complications. Infection-associated mortality, for example, is significantly higher following engraftment than during the short neutropenic period that immediately follows transplantation.

Humans↗
PubMed2003

Diagnosis and antimicrobial therapy of pulmonary infiltrates in febrile neutropenic patients--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

Patients with severe neutropenia lasting for more than 10 days, who develop fever and pulmonary infiltrates, are at high risk of treatment failure and infection-related death, under conventional broad-spectrum antibiotics. Early supplementation by a systemic antifungal therapy active against Aspergillus spp. has been shown to markedly improve their clinical outcome. Prognosis is significantly influenced by early identification of lung infiltrates by means of high-resolution thoracic computed tomography. Non-culture based diagnostic procedures using a highly sensitive Sandwich ELISA assay to detect circulating galactomannan, or PCR techniques to amplify circulating fungal DNA, may facilitate the diagnosis of invasive pulmonary aspergillosis. CT-directed bronchoscopy and bronchoalveolar lavage using standardized procedures are useful in order to identify causative microorganisms such as filamentous fungi or Pneumocystis carinii. The standard antifungal agent in the treatment of these patients, amphotericin B deoxycholate, has been challenged recently by newly developed antifungals such as voriconazole. It seems important to continue antifungal treatment for at least 14 days before first response assessment. Microbial isolates from blood cultures, bronchoalveolar lavage or respiratory secretions must be critically interpreted with respect to their etiological relevance for pulmonary infiltrates, to avoid inadequate antimicrobial treatment modification.

Anti-Bacterial Agents↗
PubMed2003

Treatment of fungal infections in hematology and oncology--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

The Infectious Diseases Working Party of the German Society of Haematology and Oncology presents their guidelines for the treatment of fungal infections in patients with hematological and oncological malignancies. These guidelines are evidence-based, considering study results, case reports and expert opinions, using the evidence criteria of the Infectious Diseases Society of America (IDSA). The recommendations for major fungal complications in this setting are summarized here. The primary choice of therapy for chronic candidiasis should be fluconazole, reserving caspofungin or amphotericin B (AmB) for use in case of progression of the Candida infection. Patients with candidemia (except C. krusei or C. glabrata) who are in a clinically stable condition without previous azole prophylaxis should receive fluconazole, otherwise AmB or caspofungin. Voriconazole is recommended for the first-line treatment of invasive aspergillosis. The benefit of a combination of AmB and 5-flucytosine has not been demonstrated except in patients with cryptococcal meningitis. Mucormycosis is relatively rare. The drug therapy of choice consists of AmB, desoxycholate or liposomal formulation, in the highest tolerable dosage. Additional surgical intervention has been shown to achieve a lower fatality rate than with antifungal therapy alone. The role of interventional strategies, cytokines/G-CSF, and granulocyte transfusions in invasive fungal infections are further reviewed. These guidelines offer actual standards and discussions on the treatment of oropharyngeal and esophageal candidiasis, invasive candidiasis, cryptococcosis and mould infections.

Hematology↗
PubMed2003

Antimicrobial therapy of febrile complications after high-dose chemo-/radiotherapy and autologous hematopoietic stem cell transplantation--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

Infectious complications occur in 60-100% of patients following high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (HSCT), and are commonly caused by Gram-negative aerobic bacteria (such as Pseudomonas aeruginosa and enterobacteriacea e) and Gram-positive cocci (such as enterococci, streptococci and staphylococci), which should be covered by empiric first-line antibiotic therapy. Less frequently, infections are caused by fungi and anaerobic bacteria, and initial therapy does not necessarily have to cover coagulase-negative staphylococci, oxacillin-resistant S. aureus (MRSA), anaerobic bacteria and fungi. Patients who already receive antibiotics and develop pulmonary infiltrates should immediately be treated with systemic antifungals. Patients with fever and diarrhea or other signs and symptoms of gastrointestinal or perianal infection should be treated with antibiotics covering anaerobic bacteria and enterococci. Clinically stable patients with skin infections or central venous catheter-related infections can be treated with standard empiric antibiotic therapy including a beta-lactam active against Pseudomonas aeruginosa with or without an aminoglycoside, and should only receive glycopeptides if they do not respond to first-line therapy within 72 hours, become clinically unstable, have severe mucositis, or when resistance against the empiric antibiotics is demonstrated. Recombinant hematopoietic growth factors should not be added routinely but may be considered in life-threatening situations such as invasive pulmonary mycoses or sepsis.

Anti-Bacterial Agents↗
PubMed2003

Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis.

Cytomegalovirus (CMV) has been a major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). The importance of the recipient's serologic status is paramount. However, the importance of the donor's serologic status in CMV-seropositive recipients is controversial. We analyzed the influence of the donor's CMV status in a large cohort of patients. A total of 7018 patients seropositive for CMV reported to the European Group for Blood and Marrow Transplantation (EBMT) were included; 5910 patients had undergone HLA-identical sibling SCT and 1108 patients had undergone unrelated donor SCT. Univariate and multivariate proportional hazards models were constructed for survival, event-free survival, transplant-related mortality, and relapse incidence. Patients receiving grafts from CMV-seropositive HLA-identical sibling donors had the same survival as patients grafted from seronegative donors (hazard ratio [HR], 1.04; P =.37; 95% confidence interval [CI], 0.95-1.14). However, unrelated donor stem cell (SC) transplant recipients receiving grafts from CMV-seropositive donors had an improved 5-year survival (35% versus 27%; HR = 0.8; P =.006), an improved event-free survival (30% versus 22%; HR = 0.8; P =.01), and a reduced transplant-related mortality (49% versus 62%; HR = 0.7; P <.001). There was no influence on the relapse incidence. The effects of donor CMV status remained in multivariate analyses. The effect of donor status was different among different disease categories. In patients with chronic myelogenous leukemia (CML), T-cell depletion abrogated the beneficial effect of donor status, suggesting that the effect is mediated through transfer of donor immunity. Our data suggest that donor CMV status influences outcome of unrelated SCT. For a CMV-seropositive patient, a seropositive donor might be preferable.

Adolescent↗
PubMed2003

Specific infectious complications after stem cell transplantation.

Infectious complications continue to be a leading cause of morbidity and mortality after stem cell transplantation (SCT). The most important determinants for risk and outcomes are the stem cell source and the time after transplantation that the infection occurs. More recent developments in preparative regimens and graft manipulations, as well as the control of some important infectious complications after SCT by the introduction of effective prophylaxis and preemptive treatment strategies, have had a great impact on the timing and the epidemiology of infections posttransplantation. Better control of infectious complications posttransplantation has resulted in a reduced transplant-related mortality.

Cytomegalovirus Infections↗
PubMed2003

Improvement of inflammatory bowel disease after allogeneic stem-cell transplantation.

Because causes of inflammatory bowel disease (IBD) remain obscure and a curative therapy is still lacking, the influence of stem-cell transplantation (SCT) on IBD is of major interest. We retrospectively analyzed the course of seven patients with Crohn's disease and four patients with idiopathic ulcerative colitis who underwent allogeneic SCT between July 1994 and August 2002 for acute and chronic myeloid leukemia and myelodysplastic syndrome. After a median follow-up of 34 months posttransplantation, 10 patients are alive. None of the patients showed IBD activity after SCT, except one patient with mild persistent symptoms of Crohn's disease early after transplant. Colonoscopy after complete discontinuation of prophylactic posttransplant immunosuppression revealed no pathologic findings. These observations imply that host immune dysregulation plays a central role in the perpetuation of IBD. It may be influenced by the implementation of a new allogeneic immune system resulting from the transplantation of hematopoietic stem cells.

Acute Disease↗
PubMed2003

A CTL epitope from human cytomegalovirus IE1 defined by combining prediction of HLA binding and proteasomal processing is the target of dominant immune responses in patients after allogeneic stem cell transplantation.

OBJECTIVE AND METHODS: In an attempt to define HCMV IE1-derived, HLA-A(*)0201-restricted epitopes, an advanced computer-based epitope prediction combining HLA binding and proteasomal cleavages in silico was performed. RESULTS: This prediction algorithm clearly confirmed VLEETSVML to be the most likely CTL epitope. By tetramer staining, HCMV pp65 NLVPMVATV-specific CD8(+) T cells were detectable in 18/24 HCMV seropositive HLA-A(*)0201-expressing individuals (median frequency 0.58%; range 0.1%-4.7%), and IE1 VLEETSVML-specific CD8(+) T cells in 5/24 (median frequency 2.1%; range 0.1%-4.3%), respectively (p<0.01). Also in recipients of an allogeneic SCT, VLEETSVML- and NLVPMVATV-specific CD8(+) T cells were detectable in comparable frequencies, but again the number of patients with detectable pp65-specific CD8(+) T cells was higher (p=0.014). In 4/15 individuals, all demonstrating IE1 VLEETSVML-specific CD8(+) T cells prior to peptide stimulation, VLEETSVML-specific T cell lines (purity of 42.6%-98.6% of all CD3(+)/CD8(+) T cells) were successfully generated after 2-4 weeks of culture using the IFN-gamma secretion assay. CONCLUSION: In conclusion, this novel prediction strategy efficiently predicted an immunodominant viral T-cell epitope.

Adult↗
PubMed2003

Development and evaluation of the nuclisens basic kit NASBA for the detection of RNA from Candida species frequently resistant to antifungal drugs.

We describe a Nucleic Acid Sequence Based Amplification (NASBA) protocol to detect 6 different Candida species (Candida krusei, Candida glabrata, Candida inconspicua, Candida dubliniensis, Candida norvegensis, Candida lusitaniae) and compare it to a PCR assay. NASBA showed a sensitivity of 1 Colony Forming Unit and detected RNA from all 6 Candida species within 1 working day. All 5 patients with documented candidiasis showed identical results by both methods. This assay offers a sensitive, specific and fast possibility to detect yeast RNA.

Antifungal Agents↗
PubMed2003

Myeloablative intensified conditioning regimen with in vivo T-cell depletion (ATG) followed by allografting in patients with advanced multiple myeloma. A phase I/II study of the German Study-group Multiple Myeloma (DSMM).

We investigated toxicity and efficacy of in vivo T-cell depletion with anti-thymocyte globulin (ATG) as part of an intensified myeloablative conditioning regimen followed by allogeneic stem cell transplantation in patients with advanced multiple myeloma. The conditioning regimen consisted of modified total body irradiation, busulfan and cyclophosphamide (n=15) or in the case of prior dose-limiting radiotherapy of busulfan and cyclophosphamide (n=3). The median age was 44 years (range, 29-53) and the median time from diagnosis to transplant was 12 months (range, 6-144). Grade II-IV acute graft-versus-host disease (GvHD) occurred in six patients (35%). Severe grade III/IV GvHD developed in one patient (6%). Three patients died of therapy-related causes (17%). A complete remission (CR) with negative immunofixation after allogeneic transplantation was seen in eight of the evaluable patients (53%). After a median follow-up of 41 months (range, 8-84), the estimated overall survival at 6 years for all patients is 77% (CI 95%: 58-96%). The estimated progression-free survival at 6 years for all patients is 31% (CI 95%: 2-59%) and 46% (CI 95%: 9-83%) for patients with CR. In vivo T-cell depletion with ATG resulted in a low rate of severe GvHD with low treatment-related mortality, and a substantial number of long-term survivors.

Acute Disease↗
PubMed2003

Antigen-specific T cells for the treatment of infections after transplantation.

Considerable progress has been made in our understanding of the immunobiology of infections in immunocompromised hosts. Insights derived from animal model and human studies have provided the rationale for investigating immunotherapy with alphabeta+ T cells to restore responses considered essential for protective immunity to cytomegalovirus and Epstein-Barr virus. Future studies will address the role of adoptive immunotherapy in the prevention and treatment of adenovirus and invasive fungal infection. The use of genetically modified T cells has already been evaluated clinically and offers the potential for improving safety and efficacy and removing obstacles to successful immunotherapy. Although these studies are in the early stages and present considerable technical challenges, the results suggest that cellular immunotherapy will be a fruitful area for investigation in future years.

Adenoviridae Infections↗
PubMed2003

Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning.

Allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning was evaluated in 22 patients (median age 53, range 36-66 years) with multiple myeloma with progression after an autologous SCT. Seven patients received a transplant from a human leucocyte antigen (HLA)-identical sibling and 15 patients (68%) from an unrelated donor [including 3/22 (14%) from a HLA-mismatched unrelated donor]. Graft-versus-host disease (GVHD) prophylaxis consisted of serotherapy with antithymocyte globulin (ATG) and cyclosporine (CSA) (n = 12) or CSA plus mycophenolate mofetil (n = 10). Despite of heavy pretreatment, the transplant-related mortality (TRM) for all grafted patients was acceptable at 5/22 patients (23%). Seven of 21 patients (33%) that were evaluated developed grade II GVHD and one (5%) patient developed grade III/IV acute GVHD. Seven patients developed chronic GVHD (cGVHD), but only one was extensive. Eleven patients died of progressive disease within a median of 7 months (2-19 months) post transplant. Thirteen of all 22 patients (59%) achieved a partial or complete remission with six of these 13 patients (46%) remaining event free at a median of 24 months (range 8-36 months) post allografting. Estimated 2 year overall and event-free survival was, respectively, 25.5% and 22.0% for the whole patient group, and 62.5% and 57.1% for patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation (P = 0.0182) and absence of cGVHD (P = 0.069) were associated with shorter event-free survival. Thus long-term disease control can be achieved, but is restricted to patients responding to prior salvage chemotherapy.

Acute Disease↗
PubMed2003

Value of comparative genomic hybridization and fluorescence in situ hybridization for molecular diagnostics in multiple myeloma.

Chromosomal abnormalities, such as 13q deletions, are emerging as important prognostic factors in multiple myeloma. Fluorescence in situ hybridization (FISH) using specific DNA probes is the technique most widely used for the determination of genomic aberrations in this disease. The utility of comparative genomic hybridization (CGH) for molecular diagnostics in plasma cell malignancies has not been systematically analysed. We investigated tumour samples of patients with multiple myeloma (n = 43) or plasma cell leukaemia (n = 3) using CGH and FISH with five DNA probes localized to chromosome bands 1p22, 6q21, 11q22-q23, 13q14 and 17p13. By CGH, the most frequent genomic changes were gains on chromosomes 1q, 9q and 11q, as well as losses on chromosomes 13q, 6q, Xp and Xq. By FISH, trisomy 11q was identified at a similar frequency to the 13q deletion (42%). Compared with FISH data, the sensitivity of CGH was 80.7% and the specificity was 97.5%. Thirty-two aberrations found by FISH were not identified by CGH, mostly as a result of the proportion of cells carrying the respective aberrations, or because of the limited spatial resolution of CGH. Our data indicate that, for clinical molecular diagnostics in multiple myeloma, FISH with a disease-specific DNA probe set is superior to CGH analysis.

Adult↗
PubMed2003

Idiotype vaccination of multiple myeloma patients using monocyte-derived dendritic cells.

BACKGROUND AND OBJECTIVES: Dendritic cells (DC) pulsed with multiple myeloma (MM) patient-specific idiotype (Id) protein can induce MM-specific T-cell responses. DESIGN AND METHODS: We established serum-free culture conditions to generate monocyte-derived DC for clinical use to circumvent anti-xenogenic immune responses with repetitive vaccinations. In a clinical phase I trial twelve patients responsive to high dose chemotherapy (HDT) were vaccinated with autologous Id pulsed DC vaccines followed by Id/keyhole limpet hemocyanin (Id/KLH) booster immunizations co-injected with granulocyte-macrophage colony-stimulating factor as adjuvant. RESULTS: In vitro studies showed that serum-free-generated DC were equally effective in the induction of specific T-cell responses as were DC generated with fetal calf serum. On average 4.5 x 10(6) DC of >60% purity were generated from peripheral blood monocytes obtained 3-6 months after HDT and autologous stem cell transplantation. Ten of twelve patients received all planned vaccines without serious toxicity. Two patients developed Id-specific T-cell proliferative responses, in one patient an Id-specific cytotoxic T lymphocyte (CTL) response was measured. Id-specific TH1 cytokine secretion was found in one of the T-cell responding patients. All patients who received at least three Id/KLH vaccines mounted strong KLH specific T-cell and delayed antibody responses. Two patients remain in clinical partial response at 25 and 29 months after the start of the vaccination and ten patients have progressed, six of whom have died from progressive disease or infectious complications. INTERPRETATION AND CONCLUSIONS: Serum-free DC vaccines induce Id-specific T-cell responses in MM patients.

Adjuvants, Immunologic↗
PubMed2002

Quantification of T-cell receptor excision circle DNA using fluorescence resonance energy transfer and the LightCycler system.

T-cell receptor excision circles (TRECs) are circular, stable extrachromosomal DNA fragments and are generated during V(D)J gene recombination, a process responsible for diversity of the T-cell receptor repertoire. Here we describe a sensitive, rapid and easy to perform real-time PCR assay based on the LightCycler technique for the quantification of TRECs among peripheral blood cells and a comparison of this assay with conventional PCR-ELISA. By LightCycler, a sensitivity of 20 copies of plasmid deltaRec-psiJalpha Signal Joint TREC DNA was achieved whereas by PCR-ELISA, a detection limit of 2 copies was demonstrated. In blood samples from healthy individuals (n=52) a median TREC count of 1.6x10(4) copies [range 2x10(1) to 2x10(5)]/2x10(5) peripheral blood mononuclear cells (PBMNCs) and in cord blood, a median TREC count of 1.45x10(5) copies [range 1.2x10(5) to 1.6x10(5)]/2x10(5) PBMNCs) could be detected. No significant difference was found in 15 individuals when unfractionated PBMNCs (median count of 1.1x10(5) copies/2x10(5) PBMNCs) or magnetic associated cell sorter (MACS)-sorted CD45RA+ T-cells (median count of 2.5x10(5) copies/2x10(5) cells) were analyzed for TREC counts. In addition, we examined the number of deltaRec-psiJalpha Signal Joint TREC in paediatric (n=6) and adult patients (n=7) after allogeneic stem cell transplantation. In children, we observed a median TREC count of 5.7x10(4) copies/2x10(5) PBMNCs after 1x10(4) and 5.6x10(4) copies/2x10(5) PBMNCs after 2 years, and in adults, a median count of 3.6x10(4) copies/2x10(5) PBMNCs after 1x10(4) and 1.1x10(4) copies/2x10(5) PBMNCs after 2 years. In conclusion, the LightCycler-based real-time PCR assay described offers a very sensitive and rapid tool for the quantification of TREC DNA.

Adolescent↗