0000000000654460
AUTHOR
Karl-josef Kallen
showing 7 related works from this author
A bioactive designer cytokine for human hematopoietic progenitor cell expansion
1997
Efficient expansion of hematopoietic progenitor cells requires, at least, the simultaneous stimulation of the receptors c-kit and gp130. While c-kit is activated by SCF; gp130, in cells which do not express sufficient amounts of IL-6R, can be activated by the complex of soluble IL-6R (sIL-6R) and IL-6. The therapeutic use of IL-6/sIL-6R, however, has been hampered by the high concentrations of the sIL-6R protein required. We have designed a fusion protein of sIL-6R and IL-6, linked by a flexible peptide chain, that was expressed to high levels. On gp130 expressing cells the fusion protein turned out to be fully active at 100 to 1,000-fold lower concentration than the combination of unlinked…
Factors affecting the amount and the mode of merocyanine 540 binding to the membrane of human erythrocytes. A comparison with the binding to leukemia…
1995
Abstract In the presence of albumin Merocyanine 540 (MC540) exhibits a very limited binding to the outer surface of the membrane of normal erythrocytes, whereas pronounced binding is observed to leukemia cells. To find out whether this difference is due to differences in the composition or structural organization of the cell membrane we analyzed effects of a number of covalent and non-covalent perturbations of the red cell membrane on the binding and fluorescence characteristics of membrane-bound MC540. It is shown that exposure of the cells to cationic chlorpromazine, neuraminidase or photodynamic treatment with AlPcS 4 as sensitizer caused a limited increase (30–50%) of MC540 binding, tog…
Receptor Recognition Sites of Cytokines Are Organized as Exchangeable Modules
1999
Interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) are "4-helical bundle" cytokines of the IL-6 type family of neuropoietic and hematopoietic cytokines. IL-6 signals by induction of a gp130 homodimer (e.g. IL-6), whereas CNTF and leukemia inhibitory factor (LIF) signal via a heterodimer of gp130 and LIF receptor (LIFR). Despite binding to the same receptor component (gp130) and a similar protein structure, IL-6 and CNTF share only 6% sequence identity. Using molecular modeling we defined a putative LIFR binding epitope on CNTF that consists of three distinct regions (C-terminal A-helix/N-terminal AB loop, BC loop, C-terminal CD-loop/N-terminal D-helix). A corresponding gp130-bindin…
Immunoadhesins of interleukin-6 and the IL-6/soluble IL-6R fusion protein hyper-IL-6.
1999
Signal transduction in response to interleukin-6 (IL-6) results from homodimerization of gp130. This dimerization occurs after binding of IL-6 to its surface receptor (IL-6R) and can also be triggered by the complex of soluble IL-6R and IL-6. We fused IL-6 to the constant region of a human IgG1 heavy chain (Fc). IL-6Fc was expressed in COS-7 cells and purified via Protein A Sepharose. Using three different assays we found that the biological activity of this dimeric IL-6 protein is comparable with monomeric IL-6. Recently, we described the designer cytokine Hyper-IL-6 (H-IL-6) in which soluble IL-6R and IL-6 are connected via a flexible peptide linker. This molecule turned out to be 100-100…
A New Type of Cytokine Receptor Antagonist Directly Targeting gp130
1998
The interleukin-6-type family of cytokines bind to receptor complexes that share gp130 as a common signal-transducing subunit. So far, receptor antagonists for interleukin-6-type cytokines have been constructed that still bind to the specific ligand binding subunit of the receptor complex, but have lost the ability to stimulate gp130. Such receptor antagonists compete for a specific receptor of a member of the cytokine family. Interleukin-6 only binds to gp130 when complexed with the interleukin-6 receptor that exists as a membrane bound and soluble molecule. Here we have constructed fusion proteins that consist of the soluble form of the human interleukin-6 receptor covalently linked to in…
New developments in IL-6 dependent biology and therapy: where do we stand and what are the options?
2005
Interleukin-6 (IL-6) is a four-helical protein which, on target cells, binds to a specific IL-6-receptor and two molecules of the promiscuous signal transducing protein gp130. Structure-function analysis defined three molecular contact sites between IL-6 and its receptor subunits. Using this information, competitive antagonistic proteins as well as hyperagonistic proteins were developed. Possible therapeutic applications of IL-6 antagonists are in IL-6 dependent haematological disorders (Castleman's disease, POEMS syndrome, multiple myeloma) and bone diseases (Paget's disease, osteoporosis). Designer IL-6 antagonists could suppress inflammatory activity in rheumatic and autoimmune diseases …
Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells.
2005
CD4(+)CD25(+) regulatory T cells (Treg) are important mediators of peripheral immune tolerance; however, whether Treg participate also in hepatic immune tolerance is not clear. Therefore, we tested the potential of Treg to suppress stimulation of CD4(+) T cells by liver sinusoidal endothelial cells (LSEC), Kupffer cells (KC), or hepatocytes. In the absence of Treg, all 3 types of liver cells could stimulate CD4(+) T cell proliferation; in the presence of Treg, however, CD4(+) T cell proliferation was suppressed. Interaction with KC even stimulated the expansion of the Treg population; LSEC or hepatocytes, in contrast, could not induce proliferation of Treg. Because liver inflammation can be…