(550g) Preclinical Evaluation of Treg Recruiting Microparticles for the Treatment of Periodontitis

Periodontal disease (gum disease) affects an
estimated 78 million Americans, and is the leading cause of tooth loss
according to the American Dental Association^[1].  Current
treatments for periodontal diseases focus on the removal of invasive bacterial
species through non-surgical scaling and root planing procedures (sometimes
accompanied by antibiotics)^[2].  Although bacteria initiate the disease,
tissue destruction in the periodontium (ligament and tooth supporting bone) is
perpetuated by the inflammatory immune response.  Recently, a subset of lymphocytes known
as regulatory T cells (Tregs) has been shown to play a critical role in the
regulation of harmful inflammatory immune responses^[3].  Furthermore,
the presence or absence of Tregs has been correlated with the presence or
absence of aggressive periodontitis^[4].  Therefore, we
hypothesized that resolution of inflammatory conditions through the recruitment
of Tregs may alleviate periodontal disease symptoms and prevent alveolar bone
loss.

In support of this hypothesis, here we show
Treg recruitment to poly(lactic-co-glycolic) acid
microparticles encapsulating CCL22 placed in the subgingival
pocket, lead to the resolution of periodontal disease symptoms in both a murine
and canine model.  Specifically,
upon injection of CCL22 loaded microparticles in the mouse model, we observed
an increase in the expression of FOXP3 (Treg transcription factor), and
anti-inflammatory cytokines IL-10 and TGFβ. 
Indeed, we also observed a corresponding decrease in the expression of
inflammatory cytokines IL-1, TNF, and IFNγ, without affecting the protective host
response (we observed comparable bacterial loads, Fig. 1A).  Furthermore, in the most widely accepted
preclinical model for periodontitis (dog model), we observed decreased clinical
scores for inflammation, probing depth (Fig. 1B), and bleeding on probing.  In addition, we observed a marked
decrease in alveolar bone loss in the CCL22 treated animals (observed and
quantified using microCT, Fig. 1C).

[1]       P. I. Eke, R. J. Genco, Journal of Periodontology 2007, 78, 1366.

[2]       R. C. Williams, D. W. Paquette,
S. Offenbacher, D. F. Adams, G. C. Armitage, K. Bray, J. Caton, D. L. Cochran,
C. H. Drisko, J. P. Fiorellini, W. V. Giannobile, S. Grossi, D. M. Guerrero, G.
K. Johnson, I. B. Lamster, I. Magnusson, R. J. Oringer, G. R. Persson, T. E.
Van Dyke, L. F. Wolff, E. A. Santucci, B. E. Rodda, J. Lessem, Journal of Periodontology 2001, 72, 1535.

[3]       Q. Tang, J. A. Bluestone, Nature Immunology 2008, 9, 239.

[4]       G. P. Garlet, C. R. Cardoso, F.
S. Mariano, M. Claudino, G. F. de Assis, A. P. Campanelli, M. J. Avila-Campos,
J. S. Silva, Journal of Clinical
Periodontology 2010, 37, 591.