Senior Member of the Staff
Head, Department of Immunology
Professor, Harvard-Forsyth Department of Oral Biology
email:
Brooklyn College, B.S., 1961, Biology
Columbia University, D.D.S., 1965, Dentistry
State University of New York at Buffalo, Ph.D., 1970, Immunology/Oral Biology
Dr. Taubman's laboratory studies immune responses in the two major oral infectious diseases, dental caries and periodontal disease. We are investigating vaccine approaches to stimulate a specific type of immune response for protection against dental caries and for passive immunization to interfere with dental caries. In periodontal disease, significant tissue damage may be perpetrated by the immune system itself, triggered by highly immunogenic microorganisms. Certain types of T cells and immune B cells responding to signals from infecting bacteria and from the host immune system produce the cytokine RANKL, which is a primary contributor to osteoclastogenesis and periodontal bone resorption. The signals that specifically direct these destructive immune cells to inflammatory sites are another important area of research.
One area of emphasis is understanding and optimizing oral immune responses in order to interfere with the inception and progression of dental caries. Early studies in rodents established that immunization with the glucosyltransferase (GTF) enzyme, involved in the molecular pathogenesis of dental caries caused by mutans streptococci, could elicit production of protective mucosal antibody. Clinical trials of oral immunization of humans with GTF indicated that mucosal IgA was induced and could interfere with re-establishment of indigenous mutans streptococci following reduction in bacterial numbers after dental prophylaxis.
We use several approaches to improve GTF-based vaccines. Peptides from functionally significant domains of the enzyme are being examined for use in vaccines. At least two peptides from the catalytic domain and one from the repetitive glucan-binding domain are immunogenic in humans and rodents. Covalent association of two peptide constructs, one from each GTF domain containing complementary B and T cell epitopes, gave rise to antibody and T cell responses in rodents, and provided more protection from experimental dental caries than either one alone. A second strategy involves producing mixed diepitopic molecules containing functional peptide moieties, from GTF and another streptococcal peptide. Such diepitopic constructs are extremely effective in inducing immunity and protecting against dental caries.
We are developing a live, attenuated Salmonella typhi vaccine to initiate mucosal immune responses. In this system, mutans streptococcal GTF peptides are synthesized as carboxyl-terminal fusions with tetanus toxin fragment C, expressed in S. typhi. Production of expressed fusion protein vaccines has been initiated, and response to mutans antigens is generated with diminished mutans colonization and reduced dental caries in the rodent caries model. Experimental vaccines containing conjugated GTF antigens and water soluble glucan show remarkably enhanced antibody levels to the carbohydrate antigen and are protective against caries production.
While periodontal disease is initiated by bacterial infection, host immune responses, particularly the activation of certain T and B lymphocytes responding to both host and bacterial signals, is a primary contributor to tissue destruction. The T and B lymphocytes in disease lesions expressing receptor activator of NFkB ligand (RANKL) seem to be a mature type with abundant surface RANKL that induce osteoclastogenesis and also account for periodontal bone resorption. We are studying the requirements for T and B lymphocyte migration and retention in gingival tissues, using a variety of endothelial cell transmigration models and animal experiments.
We have compared Th1 and Th2 lymphocyte clones specific for an antigen of the periodontopathic bacterium Actinobacillus actinomycetemcomitans (Aa). Th2 clones were found to provide extensive help for antibody production and were protective in rat adoptive transfer systems. Lymphokine profiles of T cells in diseased human gingival tissues indicated a prominance of Th1 type (IFN-g positive, IL-5 negative). These studies support our hypothesis that Th1 lymphocytes are destructive in periodontal disease, as contrasted with the protective effects shown by Th2 cells. While adoptive transfer of Aa-specific Th1 and Th2 clones resulted in antigen-based retention, only the Th1 cells induced bone loss in a rodent model of periodontal bone resorption. A key event is the regulation of T cell transmigration across endothelia, a process we found to be IFN-g, chemokine receptor 5 (CCR5), and RANTES dependent. Adoptive transfer of antigen specific B cells bearing RANKL also induced periodontal bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG), the high affinity decoy receptor for RANK which effectively competes with RANKL. Immunological interference with RANKL expression can interfere with periodontal bone resorption such as blocking the B7 costimulatory molecule. T cells transmigrating across an endothelial barrier can receive a signal from MHC class II, resulting in T cell anergy in the absence of costimulatory signal. This anergy can protect against further disease and may represent a mode of peripheral T cell tolerance and a mechanism to selectively sequester and anergize self-reactive clones. We are currently using immune cell RANKL-dependent and immunologically compromised animal models to study the roles of cytokines, chemokines, adhesion molecules, and ligands in periodontal disease and to inhibit immune cell-mediated periodontal bone resorption. Lymphocytes entering gingivae are selectively regulated by cytokines/chemokines to produce destructive cytokines which are responsible for periodontal disease osteoclastogenesis and bone resorption. We are also studying host response to bacterial whole genomic DNA as an immune protective mechanism in periodontitis.
Ernst CW, Lee JE, Nakanishi T, Karimbux NY, Rezende TM, Stashenko P, Seki M, Taubman MA, Kawai T. Diminished forkhead box P3/CD25 double-postive T regulatory cells are associated with the increased nuclear factor-kappaB ligand (RANKL+) T cells in bone resorption lesion of peridontal disease. Clin Exp Immunol. 2007 May;148(2):271-80.
Kawai T, Paster BJ, Komatsuzawa H, Ernst CW, Goncalves RB, Sasaki H, Ouhara K, Stashenko PP, Sugai M, Taubman MA. 2007. Cross-reactive adaptive immune response to oral commensal bacteria results in an induction of receptor activator of nuclear factor-kappaB ligand (RANKL)-dependent periodontal bone resorption in a mouse model. Oral Microbiol Immunol. 22(3):208-15.
Hosokawa I, Hosokawa Y, Komatsuzawa H, Goncalves RB, Karimbux N, Napimoga MH, Seki M, Ouhara K, Sugai M, Taubman MA, Kawai T. 2006. Innate immune peptide LL-37 displays distinct expression pattern from beta-defensins in inflamed gingival tissue. Clin. Exp. Immunol. In press.
Harada Y, Han X, Yamashita K, Kawai T, Eastcott JW, Smith DJ, Taubman MA. 2006. Effect of adoptive transfer of antigen-specific B cells on periodontal bone resorption. J. Periodontal Res. 41 (2) :101–1 07.
Ouhara K, Komatsuzawa H, Shiba H, Uchida Y, Kawai T, Sayama K, Hashimoto K, Taubman MA, Kurihara H, Sugai M. (2006) Actinobacillus actinomycemcomitans OMP 10 triggers innate immunity, ß-defensin and CAP18 (LL37) production, through the Fibronectin integrin pathway in human gingival epithelial cells. Infect. Immun. 74(9):521 1–5220.
Kawai T, Matsuyama T, Hosokawa Y, Makihira S, Seki M, Karimbux NY, Gonclaves RG, Valverde P, Dibart S, Li YP, Miranda LA, Ernst CWO, Izumi Y, Taubman MA. 2006. B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease. Am. J. Pathol. 169 (3) :987–998.
Taubman MA, Nash, DA. 2006. The scientific and public health imperative for a vaccine against dental caries. Nat. Rev. Immunol. 6(7):555–563.
Harada Y, Han X, Yamashita K, Kawai T, Eastcott JW, Smith DJ, Taubman MA. 2006. Effect of adoptive transfer of antigen-specific B cells on periodontal bone resorption. J. Periodontal Res. 41 (2):101–107.
Han X, Kawai T, Eastcott JW, Taubman MA. 2006. Bacterial-responsive B lymphocytes induce periodontal bone resorption. J. Immunol. 176(1 ):625–631.
Taubman MA, Smith DJ, Kawai T, Valverde P, Han X. 2005. Host-biofilm interface interactions lead to oral infectious diseases and contain promise for disease amelioration. International Congress Series 1284:93–102.
Taubman MA, Valverde P, Han X, Kawai T. 2005. Immune response: The key to bone resorption in periodontal disease. J. Periodontol. 76(1 1-s):2033–2041.
Valverde P, Kawai T, Taubman MA. 2005. Potassium channel-blockers as therapeutic agents to interfere with periodontal bone resorption. J. Dent. Res. 84(6):488–499.
Matsuyama T, Kawai T, Izumi Y, Taubman MA. 2005. Expression of major histocompatibility complex class II and CD80 by gingival epithelial cells induces activation of CD4+ T cells in response to bacterial challenge. Infect. Immun. 73 (2) :1044–1051.
Smith DJ, King WF, Rivero J, Taubman MA. 2005. Immunological and protective effects of diepitopic subunit dental caries vaccines. Infect. Immun. 73(5) :2797–2804.
Peacock ZS, Barnes LA, King WF, Trantolo DJ, Wise DL, Taubman MA, Smith DJ. 2005. Influence of micro-particle formulation on immunogenicity of SYI, a synthetic peptide derived from Streptococcus mutans GbpB. Oral Microbiol. Immunol. 20(1):60–64.
Sasaki H, Okamatsu Y, Kawai T, Kent R, Taubman M, Stashenko P. 2004. The interleukin-10 knockout mouse is highly susceptible to Porphyromonas gingivalis-induced alveolar bone loss. J. Periodontal Res. 39(6):432–441.
Kawai T, Makihira S, Hosokawa Y, Seki M, Taubman MA. 2004. Association of activated T and B lymphocytes on the host tissue destruction in periodontal disease. Inflamm. Immunol. 12(4):45–53.
Russell MW, Childers NK, Michalek SM, Smith DJ, Taubman MA. 2004. A caries vaccine? The state of the science of immunization against dental caries. Caries Res. 38(3):230–235.
Taubman MA, DePaola DP, Smith DJ. 2004. A vaccine is needed to prevent tooth infection. Dent. Abstr. 49(1):4–5.
Valverde P, Kawai T, Taubman MA. 2004. Selective blockade of voltage-gated potassium channels reduces inflammatory bone resorption in experimental periodontal disease. J. Bone Miner. Res. 19 (1) :155–1 64.
Asakawa R, Komatsuzawa H, Kawai T, Yamada S, Goncalves RB, Izumi S, Fujiwara T, Nakano Y, Suzuki N, Uchida Y, Ouhara K, Shiba H, Taubman MA, Kurihara H, Sugai M. 2003. Outer membrane protein 100, a versatile virulence factor of Actinobacillus actinomycetemcomitans. Mol. Microbiol. 50 (4) :1125–1139.
Xiaozhe Han, D.D.S., Ph.D.
Jean W. Eastcott, Ph.D.
