Cell contact-dependent priming and Fc interaction with CD32+ immune cells contribute to the TGN1412-triggered cytokine response

Following inconspicuous preclinical testing, the superagonistic anti-CD28 mAb TGN1412 was applied to six study participants who all developed a devastating cytokine storm. We verified that TGN1412 treatment of fresh PBMCs induced only moderate responses, whereas restoration of tissue-like conditions...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2014-03, Vol.192 (5), p.2091-2098
Main Authors: Bartholomaeus, Patrick, Semmler, Linda Y, Bukur, Thomas, Boisguerin, Valesca, Römer, Paula S, Tabares, Paula, Chuvpilo, Sergey, Tyrsin, Dmitry Y, Matskevich, Alexey, Hengel, Hartmut, Castle, John, Hünig, Thomas, Kalinke, Ulrich
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal, Humanized - immunology
Antibodies, Monoclonal, Humanized - pharmacology
Cytokines - immunology
Female
Gene Expression Profiling
Gene Expression Regulation - drug effects
Gene Expression Regulation - immunology
Humans
Immunoglobulin Fc Fragments - immunology
Immunoglobulin Fc Fragments - pharmacology
Immunoglobulin G - immunology
Immunoglobulin G - pharmacology
Male
Receptors, IgG - immunology
Transcriptome - drug effects
Transcriptome - immunology
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Summary:Following inconspicuous preclinical testing, the superagonistic anti-CD28 mAb TGN1412 was applied to six study participants who all developed a devastating cytokine storm. We verified that TGN1412 treatment of fresh PBMCs induced only moderate responses, whereas restoration of tissue-like conditions by high-density preculture (HDC) allowed vigorous cytokine production. TGN1412 treatment of T cells isolated from HDC-PBMCs induced moderate cytokine responses, which upon additional anti-IgG crosslinking were significantly boosted. Moreover, coincubation of TGN1412-treated T cells with B cells expressing the intermediate affinity Fcγ receptor IIB (CD32B), or coincubation with CD32B(+) transfectants, resulted in robust T cell activation. This was surprising because TGN1412 was expressed as an Ig of the subclass 4 (IgG4), which was shown before to exhibit only minor affinity to FcγRs. Transcriptome analysis of TGN1412-treated T cells revealed that similar gene signatures were induced irrespective of whether T cells derived from fresh or HDC-PBMCs were studied. Collectively, these data indicate that HDC-PBMCs and HDC-PBMC-derived T cells mount rapid TGN1412 responses, which are massively boosted by FcγR crosslinking, in particular by CD32-expressing B cells. These results qualify HDC-PBMCs as a valuable in vitro test system for the analysis of complex mAb functions.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1302461