Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells.
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The administration of the immunosuppressive humanized monoclonal antibody CAMPATH 1-H, which recognizes CD52 on lymphocytes and monocytes, is associated with a first-dose cytokine-release syndrome involving TNFalpha, IFNgamma, and IL-6 clinically. In vitro models have been used to establish the cellular source and mechanism responsible for cytokine release, demonstrating that cytokine release is isotype dependent, with the rat IgG2b and human IgG1 isotype inducing the highest levels of cytokine release, which was inhibited with antibody to CD16, the low affinity Fc-receptor for IgG (FcgammaR). Cross-linking antibody opsonized CD4 T lymphocytes failed to stimulate TNFalpha release, which together with the observation that TNFalpha release by purified natural killer (NK) cells stimulated by fixed autologous CAMPATH 1-H-opsonized targets was inhibited with anti-CD16, indicates that cytokine release results from ligation of CD16 on the NK cells, rather than Fc-receptor (FcR)-dependent cross-linking of CD52 on the targeted cell. Since the hierarchy of isotypes inducing cytokine release in these cultures matches that seen clinically, we conclude that ligation of CD16 on NK cells is also responsible for cytokine release after injection of CAMPATH 1-H in vivo.
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TGN1412 stimulates CD4+ T-cells to undergo lymphoproliferation and release pro-inflammatory cytokines, whereas Campath-1H and Rituximab stimulate cytokine release from NK and CD8+, but not CD4+, T-cells.
“It was established that TGN1412 stimulates CD4+ T-cells to undergo lymphoproliferation and release pro-inflammatory cytokines (Stebbings et al., 2007).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Wing et al., 1996
The results section on CD16-dependent TNF-α release (page not provided) identifies NK cells, rather than the tested T lymphocytes, as the source of CAMPATH 1-H-induced cytokine release; purified CD4+ cells also failed to release TNF-α under the tested conditions. The paper does not address Rituximab, CD8+ T-cell cytokine release, or TGN1412. The supplied verbatim citing sentence attributes the TGN1412 point to Stebbings et al., not to this source. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThis mechanism of cytokine release likely involves engagement of CD16 (FcgammaRIII) on NK cells by the Fc component of immobilized therapeutic mAbs.
“This mechanism of cytokine release would likely involve engagement of CD16 (FcgammaRIII) on NK cells by the Fc component of immobilized therapeutic mAbs 25 .”
From Severity of the <scp>TGN</scp>1412 trial disaster cytokine storm correlated with <scp>IL</scp>‐2 release (2013) · cites this paper as [25]
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- Authors
- Wing, M. G., Moreau, T., Greenwood, J., Smith, R. M., Hale, G., Isaacs, J., Waldmann, H., Lachmann, P. J., & Compston, A.
- Affiliations
- Medical Research Council (GB)
- University of Cambridge (GB)
- University of Oxford (GB)
- Venue
- Journal of Clinical Investigation
- Published
- 1996-12-15
- Volume
- 98
- Issue
- 12
- Pages
- 2819-2826
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC507749
- OpenAlex
- W2069219892
- Cited by
- 257
- References
- 43
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 5 · 2021: 11 · 2020: 12 · 2019: 15 · 2018: 11 · 2017: 11 · 2016: 11 · 2015: 7 · 2014: 8 · 2013: 12 · 2012: 8
- FWCI
- 1.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- cytokine release syndrome, CD52, natural killer cells, CD16, Fc gamma receptor I, LFA-1, CD11a/CD18, antibody isotypes, TNF-α, interferon-gamma, interleukin-6
- MeSH terms
- Alemtuzumab, Antibodies, Monoclonal, Antibodies, Neoplasm, Enzyme-Linked Immunosorbent Assay, Humans, Immunoglobulin G, Immunoglobulin M, Interferon-gamma, Killer Cells, Natural, Leukocytes, Tumor Necrosis Factor-alpha, CD4-Positive T-Lymphocytes, Interleukin-6, Cytokines, Receptors, IgG, CD11 Antigens, Antibodies, Monoclonal, Humanized
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