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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent
Shinsuke Inuki1,2, Natsumi Hirata1, Emi Kashiwabara1
1Graduate School of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan.
Insights
New α-GalCer derivatives act as potent CD1d ligands, activating natural killer T cells. Derivative 3 shows promise in treating ulcerative colitis by modulating immune responses.
Area of Science:
- Immunology
- Medicinal Chemistry
- Glycolipid Research
Background:
- CD1d is a nonpolymorphic glycoprotein presenting glycolipid antigens like α-GalCer.
- CD1d-ligand complexes activate natural killer T cells, inducing cytokine secretion (IFN-γ, IL-4, IL-17A).
Purpose of the Study:
- To conduct structure-activity relationship studies of α-GalCer derivatives.
- To identify novel CD1d ligands with enhanced immune-modulating properties.
- To evaluate the therapeutic potential of selected derivatives in an inflammatory disease model.
Main Methods:
- Synthesis and characterization of α-GalCer derivatives with varied lipid acyl chains.
- Immunological evaluation of CD1d ligand binding and cytokine induction.
- In vivo efficacy studies in a DSS-induced model of ulcerative colitis.
Main Results:
- Several α-GalCer derivatives were identified as potent CD1d ligands.
- Lipid moiety flexibility impacts binding affinity and cytokine profiles.
- Derivative 3, exhibiting Th2- and Th17-biasing responses, significantly protected against intestinal inflammation in vivo.
Conclusions:
- Structure-activity relationship studies identified potent CD1d ligands with tunable cytokine responses.
- Derivative 3 demonstrates therapeutic potential for ulcerative colitis via modulation of Th2 and Th17 immunity.
Abstract:
The MHC class I-like molecule CD1d is a nonpolymorphic antigen-presenting glycoprotein, and its ligands include glycolipids, such as α-GalCer. The complexes between CD1d and ligands activate natural killer T cells by T cell receptor recognition, leading to the secretion of various cytokines (IFN-γ, IL-4, IL-17A, etc.). Herein, we report structure-activity relationship studies of α-GalCer derivatives containing various functional groups in their lipid acyl chains. Several derivatives have been identified as potent CD1d ligands displaying higher cytokine induction levels and/or unique cytokine polarization. The studies also indicated that flexibility of the lipid moiety can affect the binding affinity, the total cytokine production level and/or cytokine biasing. Based on our immunological evaluation and investigation of physicochemical properties, we chose bisamide- and Bz amide-containing derivatives 2 and 3, and evaluated their in vivo efficacy in a DSS-induced model of ulcerative colitis. The derivative 3 that exhibits Th2- and Th17-biasing responses, demonstrated significant protective effects against intestinal inflammation in the DSS-induced model, after a single intraperitoneal injection.
