0000000000291921
AUTHOR
Stefan Klein
Mixed Epidermal Cell Lymphocyte Reaction: HLA-DR+ Cells Exhibit a Greater Immunostimulatory Activity than CD1a+ Cells
Induction and expression of immunity depends upon processing and presentation of antigens to T-cells by bone marrow derived HLA-DR+ antigen presenting cells (APC). In the induction of immunity to cutaneous antigens, the initial stages of this process begin within the skin itself, and both epidermis and dermis contain bone-marrow derived cells that have the capability of processing and presenting antigens. In normal epidermis, HLA-DR expression is believed to be confined to Langerhans cells with Birbeck granules and indeterminate cells without Birbeck granules. In diseased skin, particularly the inflammatory dermatoses, HLA-DR is commonly expressed by keratinocytes and has been related to th…
Changes in Immunosuppressive Treatment of Chronic Graft-versus-Host Disease: Comparison of 2 Surveys within Allogeneic Hematopoietic Stem Cell Transplant Centers in Germany, Austria, and Switzerland.
Abstract Chronic graft-versus-host disease (cGVHD) remains the leading cause of late morbidity and mortality. Despite the growing number of treatment options in cGVHD, evidence remains sparse. The German-Austrian-Swiss GVHD Consortium performed a survey on clinical practice in treatment of cGVHD among transplant centers in Germany, Austria, and Switzerland in 2009 and 2018 and compared the results. The survey performed in 2009 contained 20 questions on first-line treatment and related issues and 4 questions on second-line scenarios followed by a survey on all systemic and topic treatment options known and applied, with 31 of 36 transplant centers (86%) responding. The survey in 2018 repeate…
Improved Safety with the Use of Subcutaneous Bortezomib in Combination with Panobinostat and Dexamethasone: Preliminary Data from a Panobinostat Global Expanded Treatment Protocol
Abstract Introduction: Panobinostat (PAN) is a potent pan-deacetylase inhibitor that targets multiple myeloma (MM) cells via its epigenetic effects as well as its effect on the aggresome. In the PANORAMA 1 phase 3 trial, the combination of PAN, bortezomib (BTZ), and dexamethasone (Dex; PAN+BTZ+Dex) significantly increased progression-free survival compared with placebo plus BTZ and Dex, leading to approval in Europe of the combination for the treatment of patients with MM who have received ≥ 2 prior regimens, including BTZ and an immunomodulatory agent. The purpose of this expanded treatment protocol (ETP) is to further evaluate safety and to provide panobinostat prior to commercial availab…
Clinical Validation of a Novel Elispot-Based Diagnostic Assay: Monitoring Cytomegalovirus-Specific Cell-Mediated Immunity and Risk Stratification in Hematopoietic Stem Cell Transplant Recipients
Increasing evidence suggests that impaired cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) is a major cause of uncontrolled CMV reactivations and associated complications in hematopoietic stem cell transplantation (HSCT). No reliable test exists to predict patients at risk of primary and/or recurrent CMV reactivations following HSCT. Accurately assessing CMV-CMI might therefore improve the risk stratification of patients and allow optimizing and individualizing patient care. This study aimed to evaluate the suitability of a novel IFN-γ ELISpot assay (T-Track® CMV), based on the stimulation of peripheral blood mononuclear cells with T-activated® pp65 and IE-1 CMV proteins, to…
The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis
T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression w…
Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation with Venetoclax, Hypomethylating Agents and DLI - a Retrospective Multi Center Study
Introduction: The most common cause of treatment failure after allogeneic hematopoetic stem cell transplantation (aHSCT) is relapse. The combination of venetoclax and the hypomethylating agents (HMA) azacitidine (AZA) or decitabine (DAC) have shown promising efficacy in elderly patients with AML. We here present clinical data on 32 patients, who were treated with an HMA/venetoclax combination therapy (HMAClax) for relapse of a myeloid malignancy after aHSCT, collected retrospectively from 11 German centers. Results: Sixteen patients (50%) were male, median age was 54 years (30.8-71.5). Diagnoses at aHSCT were 25 AML (17 primary, 8 emerging from MDS, CMML or OMF), 5 MDS, 1 CMML and one atypi…
Dissecting the role of ADAM10 as a mediator of Staphylococcus aureus α-toxin action
Staphylococcus aureus is a leading cause of bacterial infections in humans, including life-threatening diseases such as pneumonia and sepsis. Its small membrane-pore-forming α-toxin is considered an important virulence factor. By destroying cell–cell contacts through cleavage of cadherins, the metalloproteinase ADAM10 (a disintegrin and metalloproteinase 10) critically contributes to α-toxin-dependent pathology of experimental S. aureus infections in mice. Moreover, ADAM10 was proposed to be a receptor for α-toxin. However, it is unclear whether the catalytic activity or specific domains of ADAM10 are involved in mediating binding and/or subsequent cytotoxicity of α-toxin. Also, it is not k…
Donor Genetic Determinant of Thymopoiesis rs2204985 Impacts Clinical Outcome after Single HLA Mismatched HSCT
Abstract Introduction: A common genetic variant within the TCRA-TCRD locus has been recently identified as a predictive factor of thymic function and T cell repertoire diversity (Clave et al., 2018). Specifically it was shown in a mouse model that transplantation of rs2204985 AA human hematopoietic stem cells (HSC) into immunodeficient mice led to lower thymocyte counts and poorer TCR diversity. T cell mediated pathways are known to play a significant role in immunological processes affecting HSCT outcome like GvL, GvH and infection. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient's outcome after unrelated HSCT. Methods: The study included 2,…
Matching for the MICA-129 polymorphism is beneficial in unrelated hematopoietic stem cell transplantation.
Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a highly polymorphic ligand of the activating NKG2D receptor on natural killer (NK) cells, γδ-T cells, and NKT cells. MICA incompatibilities have been associated with an increased graft-versus-host disease (GVHD) incidence, and the MICA-129 (met/val) dimorphism has been shown to influence NKG2D signaling in unrelated hematopoietic stem cell transplantation (uHSCT). We investigated the effect of MICA matching on survival after uHSCT. We sequenced 2172 patients and their respective donors for MICA. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n = 1379), 9/10 (n = 636), or 8/10 (n…