Signaling signatures and functional properties of anti-human CD28 superagonistic antibodies
| Autor: | Linda Y. Sender, Ulrich Kalinke, Matthias Gunzer, Zoe Waibler, Burkhart Schraven, Camilla Merten, Stefanie Kliche, Peter Reichardt, Roland Hartig |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Quinuclidines
T-Lymphocytes Blotting Western Immunology Medizin lcsh:Medicine Biology Antibodies Monoclonal Humanized Lymphocyte Activation T-Lymphocytes Regulatory Interferon-gamma Immunology/Leukocyte Signaling and Gene Expression CD28 Antigens Calcium flux Animals Humans Cytotoxic T cell lcsh:Science PI3K/AKT/mTOR pathway Cell Proliferation Calcium signaling Multidisciplinary Tumor Necrosis Factor-alpha T-cell receptor lcsh:R Antibodies Monoclonal CD28 Flow Cytometry TGN1412 Macaca mulatta Cell biology Macaca fascicularis src-Family Kinases Immunology/Leukocyte Activation Interleukin-2 Phosphorylation Calcium lcsh:Q Signal Transduction Research Article |
| Zdroj: | PLoS ONE, Vol 3, Iss 3, p e1708 (2008) PLoS ONE |
| Popis: | Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 supergonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naive and memory CD4⁺ T cells but not in cynomolgus T lymphocytes. The sustained Ca⁺⁺ -signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation or Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells. © 2008 Waibler et al. |
| Databáze: | OpenAIRE |
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