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 of the mouth, 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 a cytokine, 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.
Research in the Taubman laboratory is directed toward exploring the role of immunological phenomena in the two major infectious diseases of the oral cavity, dental caries and periodontal disease.
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.
Passive Immunity to Dental Caries
Streptococci was mediated by phage display selected human B cell clones selected from libraries of 2.7 X 1010 members from 57 donors. We have screened and isolated about 200 clones and selected the most immunologically active clones by inhibition of GTF and inhibition of biofilm formation. Most active clones will be tested for passive oral effect on dental caries in animals. Such studies are currently under observation.
GTF Conjugate Vaccines
We have developed GTF vaccines where the carbohydrate product of GTF; glucan is chemically conjugated to GTF. While carbohydrate vaccines are usually most immunogenic in children conjugation for protein a T cell helper function provides immunogenicity. Such conjugate vaccines induce IgA antibody to the GTF protein and the glucan carbohydrate. Such vaccines are more effective than simple GTF vaccine in providing protection vs. mutans streptococcal induced caries. This vaccine has been tested in pre-clinical trials and we are seeking support for vaccine manufacture and clinical trials.
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 accounts 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-γ 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-γ, 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.
Importantly, immune cell responses are responsible for immune-mediated periodontal bone loss. We are developing immune antibody responses to several immune factors that contribute to periodontal disease. We have developed several immune responses to various component factors that can ameliorate periodontal disease in animal immune-mediated periodontal disease models.
Han X, Lin X, Seliger AR, Eastcott J, Kawai T, Taubman MA. (2009) Expression of receptor activator of nuclear factor-kB ligand by B cells in response to oral bacteria. Oral Microbiol. Immunol. 24(3):190-196.
Nogueira RD, King WF, Gunda G, Culshaw S, Taubman MA, Mattos-Graner RO, Smith DJ. (2008) Mutans streptococcal infection induces salivary antibody to virulence proteins and associated functional domains. Infect. Immun. 76(8):3606-3613.
Rezende TM, Vieira LQ, Sobrinho AP, Oliveira RR, Taubman MA, Kawai T. (2008) The influence of mineral trioxide aggregate on adaptive immune responses to endodontic pathogens in mice. J. Endod. 34(9):1066-1071.
Komatsuzawa H, Ouhara K, Kawai T, Yamada S, Fujiwara T, Shiba H, Kurihara H, Taubman MA, Sugai M. (2007) Susceptibility of periodontopathogenic and cariogenic bacteria to defensins and potential therapeutic use of defensins in oral diseases. Curr. Pharm. Des. 13(30):3984-3095.
Culshaw S, Han X, La Rosa K, Eastcott JW, Smith DJ, Taubman MA. (2007) Assessment of human immune response to mutans streptococcal glucosyltransferase peptides selected by MHC Class II binding probability. Int. J. Pept. Res. Ther. 13(4):525-531.
Culshaw S, LaRosa K, Tolani H, Han X, Eastcott JW, Smith DJ, Taubman MA. (2007) Immunogenic and protective potential of mutans streptococcal glucosyltransferase peptide constructs selected by MHC class II allele binding. Infect. Immun. 75(2):915-923.
Taubman MA, Han X, LaRosa KB, Socransky SS, Smith DJ. (2007) Periodontal bacterial DNA suppresses immune response to mutans streptococcal glucosyltransferase. Infect. Immun. 75(8):4088-4096.
Ernst CWO, Lee JE, Nakanishi T, Karimbux NY, Rezende TMB, Stashenko P, Seki M, Taubman MA, Kawai T. (2007) Diminished forkhead box P3/CD25 double-positive T regulatory cells are associated with the increased nuclear factor K-B ligand (RANKL) T Cells in bone resportion lesion of periodontal disease. Clin. Exp. Immunol. 148(2):271-280
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):208-215.
Taubman MA, Kawai T, Han X. (2007) The new concept of periodontal disease pathogenesis requires new and novel therapeutic strategies. J. Clin. Periodontol. 34(5):367-369.
Han X, Kawai T, Taubman MA. (2007) Interference with immune-cell-mediated bone resorption in periodontal disease. Periodontol. 2000 45(1):76-94.
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.
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. 146(2):218-225.
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):5211-5220.
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(11-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.
Xiaozhe Han, D.D.S., Ph.D.
Hiroyuki Kanzaki, D.D.S., Ph.D.
