Immunomodulation of Inflammatory Bone Resorption

宿主对微生物病原体的最佳抗性需要选择性激活特定细胞的体液免疫应答。 由Th 1细胞介导的迟发型超敏反应需要对抗专性细胞内生物体的感染，而Th 2细胞在细胞外生物体（包括口腔病原体）的感染中是有益的。 我们和其他人开发的新的免疫策略在引导对Th 1或Th 2表型的反应方面显示出巨大的希望。牙髓感染会导致牙髓坏死和尖周骨吸收。 在之前的研究期间，我们发现牙髓感染主要是Th 1型促炎反应，根尖周骨吸收被内源性表达的抗炎性Th 2细胞因子IL-10显著抑制。在拟议的研究中，我们将测试的假设，这些新的免疫策略可用于倾斜对模式生物牙龈卟啉单胞菌向Th 2表型的反应，导致IL-10的表达增加，根尖周骨吸收减少。 在目标1中，将鉴定对牙龈卟啉单胞菌诱导的根尖周骨吸收具有遗传易感性或抗性的小鼠品系。 来自抗性菌株的T细胞系将用于使用表达克隆来鉴定优先刺激IL-10应答的牙龈卟啉单胞菌抗原（目的2）。目的3：研究牙龈卟啉单胞菌抗原免疫能否抑制根尖周骨吸收。牙龈卟啉单胞菌抗原诱导IL-10应答的机制将在目的4中表征。 这些研究的目的是设计通过优先诱导IL-10来免疫调节促炎途径和骨吸收的新方法。

Optimal host resistance to microbial pathogens requires the selective activation of a particular cellular of humoral immune response. Delayed-type hypersensitivity responses medicated by Th1 cells are required to combat infection with obligate intracellular organisms, whereas Th2 cells are beneficial in infections with extracellular organisms, including oral pathogens. New immunization strategies developed by us and others show great promise in directing responses toward either a Th1 or Th2 phenotype. Infections of the dental pulp result in pulpal necrosis and the resorption of periapical bone. During the prior grant period, we found that pulpal infection elicits predominantly Th1-type pro-inflammatory responses, and that periapical bone resorption is dramatically inhibited by the endogenously expressed anti-inflammatory Th2 cytokine IL-10. In the proposed studies, we will test the hypothesis that these novel immunization strategies can be used to skew responses against the model organism P.gingivalis toward a Th2 phenotype, resulting in increased IL-10 expression and reduced periapical bone resorption. In Aim 1, mouse strains that are genetically susceptible or resistant to P. gingivalis-induced periapical bone resorption will be identified. T cell lines from a resistant strain will be used to identify P.gingivalis antigens that preferentially stimulate IL-10 responses, using expression cloning (Aim 2). Aim 3 will determine if immunization with P. gingivalis antigens can inhibit periapical bone resorption in vivo. The mechanism(s) by which P.gingivalis antigens induce IL-10 responses will be characterized in Aim 4. The goal of these studies is to devise new methods for immunomodulating proinflammatory pathways and bone resorption via preferential induction of IL-10.