Tailored design of NKT-stimulatory glycolipids for polarization of immune responses
| Autor: | Alice L. Yu, Jung-Tung Hung, Jing-Rong Huang |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Endocrinology Diabetes and Metabolism Clinical Biochemistry Review Lymphocyte Activation Medical and Health Sciences Mice 0302 clinical medicine 2.1 Biological and endogenous factors Pharmacology (medical) alpha-galactosylceramide Aetiology Cancer Immunity Cellular α-galactosylceramide education.field_of_study General Medicine Biological Sciences Natural killer T cell Cell biology Infectious Diseases Biochemistry CD1D lipids (amino acids peptides and proteins) Myeloid-derived suppressive cell Biochemistry & Molecular Biology Population Galactosylceramides chemical and pharmacologic phenomena Biology Vaccine Related 03 medical and health sciences Immune system Glycolipid Biodefense Information and Computing Sciences Animals Humans Avidity education Molecular Biology Biochemistry medical Prevention Biochemistry (medical) T-cell receptor Immunity Cell Biology carbohydrates (lipids) Emerging Infectious Diseases 030104 developmental biology Anergy iNKT cell biology.protein Myeloid-derived Suppressor Cell Natural Killer T-Cells Cellular 030215 immunology |
| Zdroj: | Journal of biomedical science, vol 24, iss 1 Journal of Biomedical Science |
| ISSN: | 1423-0127 |
| Popis: | Natural killer T (NKT) cell is a distinct population of T lymphocytes that can rapidly release massive amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with glycolipids presented by CD1d. The secreted cytokines can promote cell-mediated immunity to kill tumor cells and intracellular pathogens, or suppress autoreactive immune cells in autoimmune diseases. Thus, NKT cell is an attractive target for developing new therapeutics to manipulate immune system. The best-known glycolipid to activate NKT cells is α-galactosylceramide (α-GalCer), which has been used as a prototype for designing new NKT stimulatory glycolipids. Many analogues have been generated by modification of the galactosyl moiety, the acyl chain or the phytosphingosine chain of α-GalCer. Some of the analogues showed greater abilities than α-GalCer in polarizing immune responses toward Th1 or Th2 dominance. Among them, several analogues containing phenyl groups in the lipid tails were more potent in inducing Th1-skewed cytokines and exhibited greater anticancer efficacy than α-GalCer. Analyses of the correlation between structure and activity of various α-GalCer analogues on the activation of iNKT cell revealed that CD1d-glycolipid complexes interacted with the same population of iNKT cell expressing similar T-cell receptor Vβ as α-GalCer. On the other hand, those phenyl glycolipids with propensity for Th1 dominant responses showed greater binding avidity and stability than α-GalCer for iNKT T-cell receptor when complexed with CD1d. Thus, it is the avidity and stability of the ternary complexes of CD1d-glycolipid-iNKT TCR that dictate the polarity and potency of immune responses. These findings provide a key to the rationale design of immune modulating glycolipids with desirable Th1/Th2 polarity for clinical application. In addition, elucidation of α-GalCer-induced anergy, liver damage and accumulation of myeloid derived suppressor cells has offered explanation for its lacklustre anti-cancer activities in clinical trials. On other hand, the lack of such drawbacks in glycolipid analogues containing phenyl groups in the lipid tails of α-GalCer coupled with the greater binding avidity and stability of CD1d-glycolipid complex for iNKT T-cell receptor, account for their superior anti-cancer efficacy in tumor bearing mice. Further clinical development of these phenyl glycolipids is warranted. |
| Databáze: | OpenAIRE |
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