Biomedical subjects

Ulrich Kalinke

Publications and source records attributed to Ulrich Kalinke.

22 records · Page 2Linked to original sources

PubMed2003

Combinatorial immunoglobulin light chain variability creates sufficient B cell diversity to mount protective antibody responses against pathogen infections.

To analyze how combinatorial light (L) chain diversity influences the B cell repertoire, we studied mice with a homozygous immunoglobulin-heavy-chain null mutation (mu MT), in which the B cell developmental block was overridden by the expression of a transgenic immunoglobulin mu heavy (H) chain derived from a vesicular stomatitis virus Indiana serotype (VSV-IND)-neutralizing Ab (T11 mu MT mice). The randomly integrated transgene could not undergo secondary rearrangements and was expressed in combination with endogenous kappa or lambda chains. T11 mu MT mice had a skewed B cell repertoire as evidenced by 30-60% VSV-IND-specific peripheral B cells and spontaneous VSV-IND-neutralizing serum titers. Upon immunization, T11 mu MT mice mounted specific IgM antibody responses against VSV-IND but, interestingly, they also responded against VSV New Jersey serotype (VSV-NJ), lymphocytic choriomeningitis virus, poliovirus and Salmonella typhi porins. Variable-region sequence analysis revealed that VSV-NJ-specific antibodies expressed numerous L chains in combination with the transgenic H chain, which was devoid of hypermutations. Thus, in T11 mu MT mice combinatorial L chain variability alone is able to build up a sufficiently complex B cell repertoire to mount protective immunoglobulin responses against a variety of pathogens.

Animals↗

PubMed2002

Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin beta in mesenteric lymph node genesis.

The recently described tumor necrosis factor (TNF) family member LIGHT (herpes virus entry mediator [HVEM]-L/TNFSF14), a ligand for the lymphotoxin (LT)beta receptor, HVEM, and DcR3, was inactivated in the mouse. In contrast to mice deficient in any other member of the LT core family, LIGHT(-/-) mice develop intact lymphoid organs. Interestingly, a lower percentage of LIGHT(-/-)LTbeta(-/-) animals contain mesenteric lymph nodes as compared with LTbeta(-/-) mice, whereas the splenic microarchitecture of LIGHT(-/-)LTbeta(-/-) and LTbeta(-/-) mice shows a comparable state of disruption. This suggests the existance of an additional undiscovered ligand for the LTbeta receptor (LTbetaR) or a weak LTalpha(3)-LTbetaR interaction in vivo involved in the formation of secondary lymphoid organs. LIGHT acts synergistically with CD28 in skin allograft rejection in vivo. The underlying mechanism was identified in in vitro allogeneic MLR studies, showing a reduced cytotoxic T lymphocyte activity and cytokine production. Detailed analyses revealed that proliferative responses specifically of CD8+ T cells are impaired and interleukin 2 secretion of CD4+ T cells is defective in the absence of LIGHT. Furthermore, a reduced 3[H]-thymidine incorporation after T cell receptor stimulation was observed. This for the first time provides in vivo evidence for a cooperative role for LIGHT and LTbeta in lymphoid organogenesis and indicates important costimulatory functions for LIGHT in T cell activation.

Animals↗

PubMed2002

Virus-induced interferon alpha production by a dendritic cell subset in the absence of feedback signaling in vivo.

An effective type I interferon (IFN-alpha/beta) response is critical for the control of many viral infections. Here we show that in vesicular stomatitis virus (VSV)-infected mouse embryonic fibroblasts (MEFs) the production of IFN-alpha is dependent on type I IFN receptor (IFNAR) triggering, whereas in infected mice early IFN-alpha production is IFNAR independent. In VSV-infected mice type I IFN is produced by few cells located in the marginal zone of the spleen. Unlike other dendritic cell (DC) subsets, FACS((R))-sorted CD11c(int)CD11b(-)GR-1(+) DCs show high IFN-alpha expression, irrespective of whether they were isolated from VSV-infected IFNAR-competent or -deficient mice. Thus, VSV preferentially activates a specialized DC subset presumably located in the marginal zone to produce high-level IFN-alpha largely independent of IFNAR feedback signaling.

Animals↗

PubMedDate not supplied

Manufacturing and quality control of cell-based tumor vaccines: a scientific and a regulatory perspective.

Tumor vaccines play an increasingly important role in the therapy of various malignant diseases. The efficacy of these new products is currently being explored in many clinical trials all over the world. Cell-based tumor vaccines can be classified as somatic cell therapy, or, depending on whether genetic modifications have been applied, as gene-transfer medicinal products. Few specific guidance documents are available to standardize the development and production of cell-based tumor vaccines. Here, we review the different types of cell-based cancer vaccines that are currently being used in clinical trials. Furthermore, we discuss regulatory guidance documents available in the European Union and describe methods that have been applied so far to ensure that the cell-based vaccines meet acceptable standards, including potency assays.

Cancer Vaccines↗