IADR Abstract Archives
Th17 Cells as Drivers and Therapeutic Targets in Periodontitis
Objectives: Periodontitis is a common human disease characterized by inflammatory bone destruction. T helper (Th) cells and specifically Th17 have been identified as important constituents of inflammatory lesions in periodontitis. However, whether Th17 cells play a causative role in periodontitis or simply serve as disease markers has not been yet addressed. Our aim was to evaluate whether Th17 drive inflammatory pathology and if their pharmacological inhibition could inhibit alveolar bone loss.
Methods: For this study, we clinically evaluated and obtained research biopsies from healthy controls, patients with periodontitis and patients with a primary immunodeficiency linked to defects in the differentiation of Th17 cells (Autosomal Dominant Hyper IgE; AD-HIES, n=32 per group). For complementary mechanistic studies we subjected mice with genetic defects affecting Th17 differentiation (CD4creStat3flox/flox and LckcreRorcflox/flox) to ligature induced periodontitis. For relevant preclinical translational studies, we targeted Th17 cells by inhibiting their master transcription factor ROR-γt in the setting of experimental periodontitis.
Results: Patients with Th17 defects (AD-HIES) presented with reduced periodontal inflammation and bone loss not only as compared to age/gender-matched periodontitis patients but also to healthy volunteers, suggesting a causative link between Th17 and periodontitis. Mirroring human findings, Th17 cells significantly expanded and ample bone loss developed in wild-type mice subjected to experimental periodontitis. In contrast, mice with targeted mutations in Stat3 or Rorc within the CD4 compartment completely lacked Th17 cells and presented with significantly reduced inflammatory bone loss. Importantly, small molecule inhibition of ROR-γt was effective in limiting periodontal bone loss.
Conclusions: Our work uncovers the pathogenic potential of Th17 cells in periodontal inflammatory bone loss and suggests their pharmacologic inhibition in the treatment of this common inflammatory disease.
Methods: For this study, we clinically evaluated and obtained research biopsies from healthy controls, patients with periodontitis and patients with a primary immunodeficiency linked to defects in the differentiation of Th17 cells (Autosomal Dominant Hyper IgE; AD-HIES, n=32 per group). For complementary mechanistic studies we subjected mice with genetic defects affecting Th17 differentiation (CD4creStat3flox/flox and LckcreRorcflox/flox) to ligature induced periodontitis. For relevant preclinical translational studies, we targeted Th17 cells by inhibiting their master transcription factor ROR-γt in the setting of experimental periodontitis.
Results: Patients with Th17 defects (AD-HIES) presented with reduced periodontal inflammation and bone loss not only as compared to age/gender-matched periodontitis patients but also to healthy volunteers, suggesting a causative link between Th17 and periodontitis. Mirroring human findings, Th17 cells significantly expanded and ample bone loss developed in wild-type mice subjected to experimental periodontitis. In contrast, mice with targeted mutations in Stat3 or Rorc within the CD4 compartment completely lacked Th17 cells and presented with significantly reduced inflammatory bone loss. Importantly, small molecule inhibition of ROR-γt was effective in limiting periodontal bone loss.
Conclusions: Our work uncovers the pathogenic potential of Th17 cells in periodontal inflammatory bone loss and suggests their pharmacologic inhibition in the treatment of this common inflammatory disease.