An in silico approach for modelling T-helper polarizing iNKT cell agonists.
Many analogues of the glycolipid alpha-galactosylceramide (α-GalCer) are known to activate iNKT cells through their interaction with CD1d-expressing antigen-presenting cells, inducing the release of Th1 and Th2 cytokines. Because of iNKT cell involvement and associated Th1/Th2 cytokine changes in a broad spectrum of human diseases, the design of iNKT cell ligands with selective Th1 and Th2 properties has been the subject of extensive research. This search for novel iNKT cell ligands requires refined structural insights. Here we will visualize the chemical space of 333 currently known iNKT cell activators, including several newly tested analogues, by more than 3000 chemical descriptors which were calculated for each individual analogue. To evaluate the immunological responses we analyzed five different cytokines in five different test-systems. We linked the chemical space to the immunological space using a system biology computational approach resulting in highly sensitive and specific predictive models. Moreover, these models correspond with the current insights of iNKT cell activation by α-GalCer analogues, explaining the Th1 and Th2 biased responses, downstream of iNKT cell activation. We anticipate that such models will be of great value for the future design of iNKT cell agonists.
Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Anton
A
De Spiegeleer
Drug Quality and Registration (DruQuaR) Group, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Evelien
E
Wynendaele
Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Matthias
M
Vandekerckhove
Drug Quality and Registration (DruQuaR) Group, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Sofie
S
Stalmans
Drug Quality and Registration (DruQuaR) Group, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Maxime
M
Boucart
Geriatrics Unit, Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Nele
N
Van Den Noortgate
Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Koen
K
Venken
Laboratory of Medicinal Chemistry, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Serge
S
Van Calenbergh
Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Sandrine
S
Aspeslagh
Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Dirk
D
Elewaut
D000818:Animals; D003198:Computer Simulation; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D018448:Models, Immunological; D015394:Molecular Structure; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D025341:Principal Component Analysis; D012372:ROC Curve; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D005699:Galactosylceramides; D018793:Interleukin-13; D007376:Interleukin-2; C493154:alpha-galactosylceramide; D015847:Interleukin-4; D007371:Interferon-gamma