Publications by authors named "Joerg Bittenbring"

12 Publications

  • Page 1 of 1

Insertion site of central venous catheter correlates with catheter-related infectious events in patients undergoing intensive chemotherapy.

Bone Marrow Transplant 2021 Jan 23;56(1):195-201. Epub 2020 Jul 23.

Department of Hematology, Oncology, Clinical Immunology, Rheumatology, Saarland University Medical School, Homburg, Germany.

Patients undergoing intensive chemotherapy are usually in need for central venous catheters (CVC). Due to contradictory study results, relation of insertion site and CVC-associated complication rate in these patients is not clear. We therefore retrospectively analyzed CVC-related data of all patients undergoing intensive chemotherapy with high risk of febrile neutropenia according to NCCN criteria, who received a CVC at our bone marrow transplantation unit between May 2016 and December 2019. In total, 210 patients received 281 CVC. CVC were placed via either the subclavian-vein (SCV, n = 58; 20%) or the internal-jugular-vein (IJV, n = 223; 80%). Median duration of CVC-lifetime and neutropenic days per CVC were comparable between the two groups (IJV vs SCV: 23 days vs 21 days (p = 0.16) and 12 days vs 11 days (p = 0.65)). Both, time to CVC removal due to local inflammation and time to central line-associated bloodstream infection was significantly shorter in patients with SCV catheters (p = 0.013 and p = 0.045). CVC placed in the IJV were associated with significantly less catheter-related infectious events compared with CVC placed in the SCV. This difference was consistent across different subgroups including 88 patients undergoing allogeneic stem cell transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01003-0DOI Listing
January 2021

Characterization of an HLA-restricted and human cytomegalovirus-specific antibody repertoire with therapeutic potential.

Cancer Immunol Immunother 2020 Aug 16;69(8):1535-1548. Epub 2020 Apr 16.

José Carreras Center, Saarland University Medical Center, Homburg, Germany.

With an infection rate of 60-90%, the human cytomegalovirus (HCMV) is very common among adults but normally causes no symptoms. When T cell-mediated immunity is compromised, HCMV reactivation can lead to increased morbidity and mortality. HCMV antigens are processed and presented as peptides on the cell surface via HLA I complexes to the T cell receptor (TCR) of T cells. The generation of antibodies against HCMV peptides presented on HLA complexes (TCR-like antibodies) has been described, but is without therapeutic applications to date due to the polygenic and polymorphic nature of HLA genes. We set out to obtain antibodies specific for HLA/HCMV-peptides, covering the majority of HLA alleles present in European populations. Using phage display technology, we selected 10 Fabs, able to bind to HCMV-peptides presented in the 6 different HLA class I alleles A*0101, A*0201, A*2402, B*0702, B*0801 and B*3501. We demonstrate specific binding of all selected Fabs to HLA-typed lymphoblastoid cell lines (EBV-transformed B cells) and lymphocytes loaded with HCMV-peptides. After infection with HCMV, 4/10 tetramerized Fabs restricted to the alleles HLA-A*0101, HLA-A*0201 and HLA-B*0702 showed binding to infected primary fibroblasts. When linked to the pseudomonas exotoxin A, these Fab antibodies induce highly specific cytotoxicity in HLA matched cell lines loaded with HCMV peptides. TCR-like antibody repertoires therefore represent a promising new treatment modality for viral infections and may also have applications in the treatment of cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-020-02564-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347513PMC
August 2020

Progranulin-autoantibodies in sera of rheumatoid arthritis patients negative for rheumatoid factor and anti-citrullinated peptide antibodies.

Clin Exp Rheumatol 2020 Jan-Feb;38(1):94-98. Epub 2019 May 10.

Department of Internal Medicine I, José Carreras Center for Immuno- and Gene Therapy, Saarland University Medical School, Homburg/Saar, Germany.

Objectives: Previously we discovered antibodies against progranulin (PGRN-abs) in a protein array-based screening of sera from various rheumatic diseases. Here we conducted a study to evaluate the prevalence of PGRN-abs in seropositive and seronegative rheumatoid arthritis (RA).

Methods: PGRN-abs were determined in the sera from 257 RA patients being seropositive for RF-IgM and/or ACPA-IgG and from 224 seronegative RA patients who were prospectively included in this study (total RA cohort n=481). All serum samples from the included participants were tested for RF-IgM as well as for ACPA-IgG, and PGRN-abs were determined using a previously described ELISA. Statistics was performed using the χ2 test for evaluating differences in clinical data; to evaluate independent statistical effects on the frequency of PGRN-abs status a logistic regression model with Wald-test was performed.

Results: PGRN-abs were detected in 25.3% from seropositive RA and in 21.0% from RF- and ACPA-negative RA resulting in a prevalence of 23.7% for both cohorts together. Comparing mean DAS28 values in the PGRN-abs positive cohort with the PGRN-abs negative cohort, the DAS28 value was significantly higher in PGRN-abs positive RA patients (3.81 vs. 3.50, p=0.038). A trend for higher frequencies of PGRN-abs in sera of RA patients with unfavourable characteristics such as erosive disease or requiring TNFi medication was observed.

Conclusions: These data suggest that the determination of PGRN-abs in seronegative RA patients may reduce their seronegative status. Further studies are required to evaluate PGRN-abs as a potential diagnostic marker in RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2020

Determination of optimum vitamin D3 levels for NK cell-mediated rituximab- and obinutuzumab-dependent cellular cytotoxicity.

Cancer Immunol Immunother 2018 Nov 21;67(11):1709-1718. Epub 2018 Aug 21.

Department of Internal Medicine I, Saarland University Medical Center, Kirrberger Strasse 100, 66421, Homburg, Saarland, Germany.

Vitamin D3 (25-OH-D3) deficiency impairs rituximab-dependent cellular cytotoxicity and the outcome of patients with diffuse large B-cell and follicular lymphomas (DLBCL). Since the optimum 25-OH-D3 serum levels for NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) are unknown, we determined the 25-OH-D3 serum levels associated with maximum NK cell-mediated ADCC. CD20 antibody-loaded CD20 B-cell lymphoma cell lines were cultured with NK cells and ADCC activity was determined by lactate dehydrogenase release assays. Using a newly developed formula, pre-defined 25-OH-D3 serum levels were achieved with high individual precision over a wide range. NK cells from 20 healthy individuals killed antibody-treated CD20 lymphoma cells in a concentration- and E:T ratio-dependent manner with obinutuzumab displaying a stronger ADCC activity than rituximab. Maximum NK-cell activity and ADCC were observed at 65 ng/ml 25-OH-D3, the middle of the normal range (30-100 ng/ml). 25-OH-D3 serum levels around this range should be the target in interventional trials aiming at improving NK cell-mediated ADCC by 25-OH-D3 substitution. Lower levels do not provide significant ADCC improvements in individuals with 25-OH-D3 deficiency or insufficiency and might result in the failure of interventions with 25-OH-D3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-018-2224-yDOI Listing
November 2018

Extracorporeal Photopheresis for Non-skin GvHD.

Anticancer Res 2016 Mar;36(3):1395-6

Department of Dermatology, Saarland University Hospital, Homburg, Germany.

Graft versus host disease (GvHD) is one of the most feared adverse events of allogeneic hematopoietic stem cell transplantation. In severe grades of GvHD patients die from infections due to impairment of their immune defense or therapy-refractory involvement of intestines, liver and lung. Extracorporeal photopheresis is an effective treatment for acute and chronic graft versus host disease without severe impairment of the recipient's immune system. It is generally better known for its effect on skin GvHD but all other manifestations of GvHD can respond as well. Herein we report a brief review of its history and give an overview of the current knowledge of extracorporeal photopheresis in non-skin GvHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2016

Elevated serum free light chains do not predict outcome of elderly patients with aggressive CD20(+) B-cell lymphomas.

Br J Haematol 2014 Nov 27;167(3):430-4. Epub 2014 Jun 27.

Department of Internal Medicine I, Oncology, Haematology, Clinical Immunology and Rheumatology, Saarland University Medical School, Homburg, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.13001DOI Listing
November 2014

The impact of Fc-γ receptor polymorphisms in elderly patients with diffuse large B-cell lymphoma treated with CHOP with or without rituximab.

Blood 2011 Oct 7;118(17):4657-62. Epub 2011 Sep 7.

Saarland University Medical School, Homburg, Germany.

Fcγ receptor (FcγR) polymorphisms have been shown to affect rituximab-mediated antibody-dependent cellular cytotoxicity. Of 512 patients with diffuse large B-cell lymphoma treated in the RICOVER-60 trial, carriers of FcγRIII 158 valine homozygous receptors (V/V) presented with a slightly decreased incidence of B-symptoms (158 V/V: 26%, V/F: 35%, phenylalanine receptors [F/F]: 42%; P = .037). Survival curves of all FcγR single nucleotide polymorphisms were superimposable after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); but after CHOP with rituximab (R-CHOP), event-free survival (EFS) and progression-free survival (PFS), but not overall survival, of FcγRIIIa 158 F/F had a trend to be lower than those of 158 V/F and 158 V/V: 3-year EFS: FcγRIIIa 158 F/F: 64.5%, 158 V/F: 70.2%, 158 V/V: 76.9% (log-rank test: P = .224 F/F vs V/V; P = .285 F/F vs V/F + V/V); 3-year PFS: FcγRIIIa 158 F/F: 68.3%, V/F: 76.1%, V/V: 80.5% (log-rank test: P = .233 for F/F vs V/V; P = .185 for F/F vs V/F + V/V). By multivariate analysis adjusting for International Prognostic Index factors, relative risk of F/F compared with V/F plus V/V was 1.80 (P = .052) for PFS and 1.55 (P = .120) for EFS. The interaction of R-CHOP, but not CHOP with FcγRIIIa polymorphisms, indicates a window of opportunity for CD20 antibodies designed to mediate enhanced antibody-dependent cellular cytotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-04-346411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208281PMC
October 2011

Hyperphosphorylation of autoantigenic targets of paraproteins is due to inactivation of PP2A.

Blood 2011 Sep 26;118(12):3340-6. Epub 2011 Jul 26.

José-Carreras Center for Immuno- and Gene Therapy, Department Internal Medicine I, Saarland University Medical School, Homburg (Saar), Germany.

Paratarg-7, a frequent autoantigenic target, and all other autoantigenic targets of human paraproteins molecularly defined to date are hyperphosphorylated in the respective patients compared with healthy controls, suggesting that hyperphosphorylation of autoantigenic paraprotein targets is a general mechanism underlying the pathogenesis of these paraproteins. We now show that hyperphosphorylation of paratarg-7 occurs because of an additional phosphorylation of Ser17, which is located within the paraprotein-binding epitope. Coimmunoprecipitation identified phosphokinase C ζ (PKCζ) as the kinase responsible for the phosphorylation of most, and phosphatase 2A (PP2A) as the phosphatase responsible for the dephosphorylation of all hyperphosphorylated autoantigenic targets of paraproteins. Single-nucleotide polymorphisms (SNPs) or mutations of PKCζ and PP2A were excluded. However, PP2A was inactivated by phosphorylation of its catalytic subunit at Y307. Stimulation of T cells from healthy carriers of wild-type paratarg-7 induced a partial and transient hyperphosphorylation between days 4 and 18, which was maintained by incubation with inhibitors of PP2A, again indicating that an inactivation of PP2A is responsible for the hyperphosphorylation of autoantigenic paraprotein targets. We conclude that the genetic defect underlying the dominantly inherited hyperphosphorylation of autoantigenic paraprotein targets is not in the PP2A itself, but in genes or proteins controlling PP2A activity by phosphorylation of its catalytic subunit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-04-351668DOI Listing
September 2011

Analysis of the antibody repertoire of patients with mantle cell lymphoma directed against mantle cell lymphoma-associated antigens.

Ann Hematol 2009 Oct 24;88(10):999-1003. Epub 2009 Feb 24.

Jose-Carreras-Center, Saarland University Medical School, Homburg, Saar, Germany.

Treatment results of mantle cell lymphomas (MCL) are not satisfactory and novel therapeutic approaches are warranted. Because "shared" tumor antigens like the group of cancer testis antigens are only rarely expressed in MCL, we applied serological analysis of antigens using recombinant expression cloning (SEREX) to a complementary DNA library derived from five cases of MCL using the sera of eight patients with MCL in order to define MCL-associated antigens that are immunogenic in these patients and might be used as vaccines for patients with MCL. Five antigens were detected by SEREX. Four of the five detected antigens (hypothetical protein FLK10233, recombining binding protein suppressor, a chromosomal sequence, and interleukin-1 receptor associated kinase) are also expressed by a wide spectrum of normal human cells, excluding their use as vaccines. In contrast, the expression of CD52, which was detected by antibodies in the serum of an MCL patient, is restricted to hematopoietic cells. Interestingly, anti-CD52 antibodies were detected in this patient before and >2 years after allogeneic transplantation, indicating that both the autologous as well as the allogeneic immune system recognized CD52. Since the anti-CD52 monoclonal antibody alemtuzumab has shown activity in MCL, a vaccine consisting of recombinant CD52 alone or combined with passive immunotherapy using alemtuzumab warrants furthers clinical and immunological evaluation in MCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-009-0711-0DOI Listing
October 2009

Spontaneous high-titered IgG antibody responses against BCL-2 in patients with aggressive lymphomas.

J Cancer Res Clin Oncol 2009 Sep 21;135(9):1207-13. Epub 2009 Feb 21.

Innere Medizin I, Jose-Carreras Center for Immuno- and Genetherapy, Saarland University Medical School Homburg, 66421 Homburg, Saar, Germany.

Purpose: Molecules which are exclusively or preferentially expressed by malignant cells are potential targets for immunotherapeutic approaches to the treatment of cancer.

Methods: We therefore tested serum samples of 95 patients with aggressive B-cell lymphomas for antibodies against lymphoma-associated molecules using SEREX for antibodies against BCL-2, BCL-XL, MCL-1, survivin, BCL-6, CD20, LM02, PDE4B, cyclin-D2, actinin-alpha1, SCYA3, PKCbeta2, E2IG3, and HGAL.

Results: One patient had low-titered (1:100) antibodies against PKCbeta2. Antibodies against BCL-2 were detected in the sera of five patients (5.3%), with responses found more frequently in follicular lymphoma grade 3 (3/26 or 11.5%) than in diffuse large B-cell lymphomas (2/67 or 3%). Anti-BCL-2 antibodies were of the IgG class and titers ranged from 1:1,000 to 1:100,000 with highest titers before treatment and decreasing slowly during remission.

Conclusion: The spontaneous immunogenicity of BCL-2 makes this molecule a prime candidate for vaccine approaches in BCL-2 positive B-cell lymphomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-009-0561-0DOI Listing
September 2009

MDM2 gene SNP309 T/G and p53 gene SNP72 G/C do not influence diffuse large B-cell non-Hodgkin lymphoma onset or survival in central European Caucasians.

BMC Cancer 2008 Apr 23;8:116. Epub 2008 Apr 23.

Internal Medicine I and Josè Carreras Research Center, University of Saarland Medical School, Homburg-Saar, Germany.

Background: SNP309 T/G (rs2279744) causes higher levels of MDM2, the most important negative regulator of the p53 tumor suppressor. SNP72 G/C (rs1042522) gives rise to a p53 protein with a greatly reduced capacity to induce apoptosis. Both polymorphisms have been implicated in cancer. The SNP309 G-allele has recently been reported to accelerate diffuse large B-cell lymphoma (DLBCL) formation in pre-menopausal women and suggested to constitute a genetic basis for estrogen affecting human tumorigenesis. Here we asked whether SNP309 and SNP72 are associated with DLBCL in women and are correlated with age of onset, diagnosis, or patient's survival.

Methods: SNP309 and SNP72 were PCR-genotyped in a case-control study that included 512 controls and 311 patients diagnosed with aggressive NHL. Of these, 205 were diagnosed with DLBCL.

Results: The age of onset was similar in men and women. The control and patients group showed similar SNP309 and SNP72 genotype frequencies. Importantly and in contrast to the previous findings, similar genotype frequencies were observed in female patients diagnosed by 51 years of age and those diagnosed later. Specifically, 3/20 female DLBCL patients diagnosed by 51 years of age were homozygous for SNP309 G and 2/20 DLBCL females in that age group were homozygous for SNP72 C. Neither SNP309 nor SNP72 had a significant influence on event-free and overall survival in multivariate analyses.

Conclusion: In contrast to the previous study on Ashkenazi Jewish Caucasians, DLBCL in pre-menopausal women of central European Caucasian ethnicity was not associated with SNP309 G. Neither SNP309 nor SNP72 seem to be correlated with age of onset, diagnosis, or survival of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2407-8-116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2375899PMC
April 2008