Dynamics of a Cytokine Storm

Six volunteers experienced severe inflammatory response during the Phase I clinical trial of a monoclonal antibody that was designed to stimulate a regulatory T cell response. Soon after the trial began, each volunteer experienced a "cytokine storm", a dramatic increase in cytokine concent...

Celý popis

Uložené v:

Podrobná bibliografia
Vydané v:	PloS one Ročník 7; číslo 10; s. e45027
Hlavní autori:	Yiu, Hao Hong, Graham, Andrea L., Stengel, Robert F.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 01.10.2012 Public Library of Science (PLoS)
Predmet:	Analysis Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - adverse effects Antigens B cells Biology Cluster analysis Cytokine storm Cytokines Cytokines - blood Cytokines - metabolism Data processing Dendritic cells Differential equations Drug dosages Empirical analysis Gene Expression Regulation - drug effects Gene Expression Regulation - immunology Humans Immunoassay Immunology Infections Inflammation Inflammatory response Influenza Initial conditions Interferon Interferon-gamma Interleukin 1 Interleukin 10 Interleukin 12 Interleukin 2 Interleukin 4 Interleukin 6 Interleukin 8 Lymphocytes Lymphocytes - drug effects Lymphocytes T Mathematical models Mathematics Models, Biological Monoclonal antibodies Monocytes Monocytes - drug effects Neutrophils Ordinary differential equations Parameter identification Pathogens Principal Component Analysis Principal components analysis Regulation Respiratory system agents System dynamics T cells Time Factors Tumor necrosis factor-TNF Tumor necrosis factor-α γ-Interferon United States > US New Jersey
ISSN:	1932-6203, 1932-6203
On-line prístup:	Získať plný text
Tagy:	Pridať tag Žiadne tagy, Buďte prvý, kto otaguje tento záznam!

Popis
Shrnutí:	Six volunteers experienced severe inflammatory response during the Phase I clinical trial of a monoclonal antibody that was designed to stimulate a regulatory T cell response. Soon after the trial began, each volunteer experienced a "cytokine storm", a dramatic increase in cytokine concentrations. The monoclonal antibody, TGN1412, raised serum concentrations of both pro- and anti-inflammatory cytokines το very hiγh values during the first day, while lymphocyte and monocyte concentrations plummeted. Because the subjects were healthy and had no prior indications of immune deficiency, this event provided an unusual opportunity to study the dynamic interactions of cytokines and other measured parameters. Here, the response histories of nine cytokines have been modeled by a set of linear ordinary differential equations. A general search procedure identifies parameters of the model, whose response fits the data well during the five-day measurement period. The eighteenth-order model reveals plausible cause-and-effect relationships among the cytokines, showing how each cytokine induces or inhibits other cytokines. It suggests that perturbations in IL2, IL8, and IL10 have the most significant inductive effect, while IFN-γ and IL12 have the greatest inhibiting effect on other cytokine concentrations. Although TNF-α is a major pro-inflammatory factor, IFN-γ and three other cytokines have faster initial and median response to TGN1412 infusion. Principal-component analysis of the data reveals three clusters of similar cytokine responses: [TNF-α, IL1, IL10], [IFN-γ, IL2, IL4, IL8, and IL12], and [IL6]. IL1, IL6, IL10, and TNF-α have the highest degree of variability in response to uncertain initial conditions, exogenous effects, and parameter estimates. This study illuminates details of a cytokine storm event, and it demonstrates the value of linear modeling for interpreting complex, coupled biological system dynamics from empirical data.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: HHY ALG RFS. Performed the experiments: HHY RFS. Analyzed the data: HHY RFS. Contributed reagents/materials/analysis tools: HHY RFS. Wrote the paper: HHY RFS. Suggestions, corrections, revision, and review: ALG.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0045027