Infection of the dental pulp occurs as a sequellum of caries, trauma, or operative dental procedures, and may result in pulpal necrosis and the need for endodontic therapy and associated restorative procedures. Both antigen-specific and non-specific immune responses occur in dental pulps and in the periapical region in response to these infections. Information from the literature and our own preliminary studies indicate that antigen- specific responses mediated by T and B lymphocytes do not appear to exert a clear protective role in pulpal immunity. Instead, non-specific immune mechanisms, in particular phagocytic polymorphonuclear leukocytes (PMNs), appear to be a key element in the resistance of the pulp to bacterial invasion and destruction. In the proposed studies, we will rigorously test the hypothesis that non-specific immune mechanisms, in particular PMNs, play a key protective role in the resistance of the pulp/periapical complex to infection.
In AIM I, the role of specific immune responses will be assessed in RAG2 severe combined immunodeficient (SCID) vs. immunologically-intact control mice, using a well-established in vivo model. The inflammatory cell infiltrate and the expression of cytokines potentially important in tissue destruction and in crosstalk between the specific and non-specific systems will be characterized.
In AIM 2, single and double knockout mice deficient in four cell adhesion molecules (CAMs), including P- and E-selectin, ICAM-1, and beta2 integrin (CD18), which are crucial for phagocytic cell adhesion to, and migration through, the endothelial lining of blood vessels, will be tested for effects on pulpal/periapical destruction in vivo. The studies in Aims I and 2 will establish, in a definitive way, the role of the specific vs non-specific arms of the immune response in pulpal protection. The effect of upregulating PMN function with the biological response modifier PGG glucan will be explored, with a focus on the local effects of this immunostimulator (AIM 3). A chamber model which mimics the infected pulp chamber will be utilized to determine the effect of PGG glucan on the emigration, activation, and anti-bacterial function of leukocytes.
In AIM 4, the molecular mechanism(s) by which PGG-glucan upregulates phagocytic cell function-will be determined. Strategies for characterizing gene arrays modulated by PGG glucan will include differential screening and differential display by polymerase chain reaction. The functional relevance of identified gene products will be evaluated in antibody and antisense inhibition experiments. The ultimate goal of these studies is to determine whether protective modalities of the immune response can be manipulated to improve the success of vital pulp therapies, prevent pulpal destruction, and reduce the necessity for endodontic treatment.
Showing the most recent 10 out of 18 publications
