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Faculty Detail    
Name KOHTARO FUJIHASHI
  
Campus Address SDB 801A Zip 0007
Phone  (205) 934-1951
E-mail  kohtarof@uab.edu
Other websites
     


Faculty Appointment(s)
Appointment Type Department Division Rank
Primary  Pediatric Dentistry  Pediatric Dentistry Professor Emeritus
Center  UWIRC Microbiome Center  UWIRC Microbiome Center Professor Emeritus

Graduate Biomedical Sciences Affiliations
Cellular and Molecular Biology Program 
Immunology 
Microbiology 

Biographical Sketch 
Positions and Honors 1980-1982 Pre-Dental Student, Nihon University, School of Dentistry at Matsudo, Chiba, Japan 1982-1986 Dental Student, Nihon University, School of Dentistry at Matsudo, Chiba, Japan 1986 Clinical Fellow, Department of Pedodontics, Nihon University School of Dentistry at Matsudo, Chiba, Japan 1986-1991 Postdoctoral Fellow, Departments of Oral Biology and Microbiology, University of Alabama at Birmingham 1991-1993 Research Associate, Department of Oral Biology, University of Alabama at Birmingham 1993-1997 Research Instructor, Department of Oral Biology, University of Alabama at Birmingham 1994-2002 Visiting Research Fellow, Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Japan 1997-2001 Associate Professor, Department of Oral Biology, University of Alabama at Birmingham, Birmingham, Alabama 2001-2004 Professor, Department of Oral Biology, University of Alabama at Birmingham, Birmingham, Alabama 2003-present Co-Director, The Immunobiology Vaccine Center 2003-present Visiting Professor, Nihon University School of Dentistry at Matsudo, Chiba, Japan 2004-present Professor, Department of Pediatric Dentistry 2004-present Senior Scientist, UAB Arthritis and Musculoskeletal Center

Society Memberships
Organization Name Position Held Org Link
2004-present VA Immunology B Study Section     
2004-present Editorial Board, Current Immunology Reviews     
2001-present American Gastroenterological Association     
1988-1991 American Association of Immunologists (Postdoctoral Member)1988-Present Society for Mucosal Immunology1991-Present American Association of Immunologists (Full Member)1991-Present American Association for Dental Research1991-Present International Association for Dental Research1992-Present Society for Japanese Immunologists2001-Present American Gastroenterological Association  1995-2000 Editorial Board, Infection and Immunity2000-Present Associate Editor, The Journal of Immunology   
 



Research/Clinical Interest
Title
The Cellular and Molecular Mechanisms for Mucosal Immunity in the Elderly; Molecular and Cellular Mechanisms for the Induction and Regulation of Mucosally Induced Tolerance; A Mucosal Internet Of gd, ab T Cells and Epithelial Cells for Mucosal Immunity; Mucosal Immunity in Murine Models of IBD
Description
The mucosal immune system is an internet of tissues, cells and biologic mediators which regulate host responses to the environment. Over 80 % of this immune system occurs in the gastrointestinal (GI) tract and the three major manifestations, e.g., mucosal immunity, inflammation and tolerance can be most conveniently studied there. For example, immunoglobulin A (IgA) is the major antibody isotype found in higher mammals, and represents 70 - 90 % or > 95 % of humoral mucosal immunity in the GI tract of humans and mice, respectively. How do higher mammals regulate this distinct isotype pattern and allow predominant secretory IgA (S-IgA) responses at mucosal sites ? It is noteworthy that ingestion (or inhalation) of soluble proteins, peptides and haptens most often leads to a state of systemic unresponsiveness to parenteral immunization with these molecules, and this condition is now termed mucosally-induced tolerance. The results which are emerging are that the manner in which antigens are encountered by the mucosal immune system can determine the outcome, e.g., mucosal and systemic T cell and antibody responses versus tolerance. What is the role of antigen presentation for induction of regulatory cells and cytokines which determine whether mucosal immunity or tolerance will develop ? It is now clear that infection, allergies as well as immune diseases can result in significant mucosal inflammation. Specific examples include induction of CD4+ Th2 cells secreting IL-4 with regulation of mucosal IgE synthesis and mast cell-mediated, type I hypersensitivity. Recently developed murine models of inflammatory bowel disease (IBD), e.g, TCRa, or IL-2 or IL-10 knockout mice spontaneously develop either colonic inflammation or more generalized intestinal inflammatory disease. Further, various types of human Periodontal Diseases (PD) are caused by certain anaerobic bacteria, and the specific gingival cell types are similar to those which occur in IBD. What are the regulatory cells and cytokines responsible for development of mucosal IBD and PD ? The broad research interests discussed above have significant clinical applications which range from development of mucosal vaccines, to studies of mucosal allergies, inflammation or the development of tolerance to self antigens to prevent autoimmune diseases. A number of research projects are underway in our group and these NIH-funded studies involve a number of significant collaborations both at UAB as well as with other Universities and Research Institutes. Specifically, individual projects include 1) The Cellular and Molecular Mechanisms for Mucosal Immunity in the Elderly; 2) Molecular and Cellular Mechanisms for Induction and Regulation of Mucosal Tolerance. 3) A Mucosal Internet of gd, ab T Cells and Epithelial Cells for Mucosal Immunity ; and 4) Mucosal Immunity in Murine Models of IBD. 1. The Cellular and Molecular Mechanisms for Mucosal Immunity in the Elderly It is well established that immune dysregulation of T cells occur in the elderly in terms of their phenotype, mitogenic responses and cytokine expression. Thus, it is likely that these age-related T cell responses exhibit altered help for B cell and antibody (Ab) responses. Indeed, it was shown that T cells from aged mice down regulate B cell responsiveness. Further, increased numbers of splenic CD5+ B cells producing IL-10 were found in aged mice. Despite these age-associated changes as well as recent advances in cellular and molecular analysis of induction and regulation of mucosal immune responses, the precise nature of mucosal immune responses which occur in the elderly remain poorly defined. In this regard, we have examined the cellular and molecular mechanisms involved in the induction of mucosal immune responses in aging mice given mucosal vaccines. Our studies showed that mucosal immunity was impaired in one-year-old mice which had been orally immunized with ovalbumin (OVA) and native cholera toxin (nCT) as mucosal adjuvant. Recently, we queried if similar immune dysregulation was also present in mucosal compartments of mice immunized by the nasal route. Both one-year-old and young adult mice were immunized weekly with three nasal doses of OVA and nCT or with a non-toxic chimeric enterotoxin [mutant CT-A E112K/ LT-B] from Brevibacillus choshinensis. Elevated levels of OVA-specific IgG antibodies (Abs) in plasma and secretory-IgA (S-IgA) Abs in mucosal secretions (nasal washes, saliva, and fecal extracts) were noted in both young adult and one-year-old mice given nCT or chimeric enterotoxin as mucosal adjuvants. Significant levels of OVA-specific CD4+ T cell proliferative and OVA-induced Th1- and Th2-type cytokine responses were noted in cervical lymph nodes and spleen of one-year-old mice. In this regard, CD4+, CD45RB+ T cells were detected in greater numbers in the nasopharyngeal-associated lymphoreticular tissues (NALT) of one-year-old mice than of young adult mice, but the same did not hold true for PeyerŐs patches or spleen. This result reinforced our findings that age-associated immune alterations occur first in GALT, and thus nasal delivery of vaccines for NALT-based mucosal immunity offers an attractive possibility to protect the elderly. 2. Molecular and Cellular Mechanisms for the Induction and Regulation of Mucosally Induced Tolerance The prolonged oral or nasal administration of soluble T dependent antigens induces two distinct immune responses in mucosal and systemic compartments where antigen-specific S-IgA and unresponsiveness are seen, respectively. In order to maintain these two different immune functions in mucosal and systemic sites, we hypothesized that a specific subset of T cells (e.g., gd T cells) in mucosa-associated tissues may play an important role for induction and maintenance of antigen-specific IgA responses in the presence of systemic unresponsiveness. Thus, we have shown that gd T cells isolated from intestinal epithelium of orally-tolerized mice were capable of abrogating systemic unresponsiveness and supported immune responses following adoptive transfer to syngeneic mice with mucosally-induced tolerance. In order to further establish a direct role for gd T cells, we are currently using both gd T cell receptor (TCR) and ab TCR knockout mice for these studies. In addition, different cytokine knockout mice including IFN-g-/-, IL-4-/- and IL-10-/- are also employed in this project in order to examine the possible role of Th1 and Th2 type cells in mucosally-induced tolerance. Studies in OVA transgenic mice showed significant increases in transgenic T cells in Peyer's patches of mice which had been tolerized by low or high OVA doses, suggesting the importance of this mucosal inductive tissue in the development of oral tolerance. Further support for a requirement of GALT in oral tolerance induction was provided by in vivo treatment with flt3 ligand. This treatment resulted in an expansion of dendritic cells in Peyer's patches with enhanced oral tolerance induction. In order to precisely address the role of Peyer's patches in the induction of oral tolerance, we have generated mice which lack PeyerŐs patches, but which possess brachial, cervical, mesenteric and sacral lymph nodes by administration of LTbR-Ig fusion protein to pregnant mice in utero. We have compared the immune responses in offspring of LTbR-Ig fusion protein-treated and control mice given high oral doses of either OVA or trinitrobenzene sulfonic acid (TNBS) prior to systemic challenge. The differences in responses to these two forms of antigen are discussed from the standpoint that GALT are major sites for macromolecular protein uptake in maintenance of immunologic homeostasis between the mucosal and systemic compartments of the host. These studies are important for a more precise understanding of molecular and cellular mechanisms of mucosally-induced tolerance for possible clinical applications such as the treatment and prevention of allergy and autoimmune diseases. 3. A Mucosal Internet Of gd, ab T Cells and Epithelial Cells for Mucosal Immunity Our group has shown that higher frequencies of CD4+ Th2 cytokine producing T cells occur in mucosal effector sites (e.g., the intestinal lamina propria, the salivary glands and the mammary glands) and more recently have established that CD4+, ab T cells isolated from murine submandibular glands (SMG) expressed high message levels for Th2 cytokines. Further, this fraction contains IL-5 and IL-6 producing CD4+ Th cells which are capable of supporting IgA B cell responses in cultures containing PP B cells. However, it is important to note that relatively high numbers of IFN-g producing Th1 type cells were also seen in these IgA effector tissues including those of SMG and small intestine. Thus, the IFN-g specific message was also increased in mRNA isolated from SMG and small intestinal CD4+ T cells. The occurrence of high IFN-g production could be an important accessory event for the enhancement of cell-to-cell interactions between Th2 type CD4+ T cells and sIgA+ B cells via the TCR-CD3 and MHC class II-peptide complexes for the terminal differentiation of sIgA+ B cells into IgA producing plasma cells under the influence of IL-5 and IL-6, since IFN-g can up regulate MHC class II expression on antigen presenting cells (APC). Interestingly, mRNA isolated from SMG gd T cells harbored high levels of IL-5 and IL-6 as well. This finding suggested that gd T cells which reside in IgA effector tissues are also committed to the Th2 phenotype. Therefore, it is important to examine whether these gd T cells can directly regulate IgA responses in mucosal effector sites such as the GI tract and salivary glands. Our recent findings have shown that removal of gd T cells from mucosa-associated tissues, i.e., the disruption of a specific gene for d chain of T cell receptor (TCRd-/-) resulted in reduction of the IgA response. These gd T cells direct a mucosal cell internet with ab T cells and epithelial cells via cytokines and cytokine receptors (R) for the regulation of mucosal immune responses. As a result of these findings, we have postulated that resident gd T cells in mucosal effector tissues (e.g., salivary glands and the GI tract) are key regulatory T cells which are of central importance for the formation of a triad cell internet with ab T cells and acinar cells / epithelial cells in the salivary gland for the induction and regulation of IgA immune responses in mucosal effector sites. 4. Mucosal Immunity in Murine Models of IBD The development of human IBD is characterized by frequent episodes of diarrhea, abdominal pain, blood in the stool and weight loss over a period of months to years ; however, the initiating events are still unknown. This has led to studies of small animal models of IBD in order to determine early events in the disease process for evaluation of new treatments. One of these models is based on the local exposure of colonic mucosa to the contact-sensitizing agent, trinitrobenzene sulfonic acid (TNBS) first established in rats, and more recently in mice. Contact sensitizing agents such as TNBS are covalently reactive compounds that attach to autologous proteins and stimulate a delayed-type hypersensitivity (DTH) response to hapten (TNP)-modified self antigens, a reaction that involves and is regulated by complex interactions among various functional subsets of CD4+ T cells. Another IBD model is the spontaneous colitis type that has been described in the C3H/HeJBir substrain of mice developed by investigators at the Jackson Laboratories and by Dr. Elson and colleagues at the University of Alabama at Birmingham (UAB). The development of colitis in these mice was genetically determined and was caused by dysregulation of the mucosal immune system. Finally, other studies of knockout mice have indicated that chronic intestinal inflammation can result from the deletion of certain cytokines or T cells. For example, TCR a chain KO (TCRa-/-) mice that develop nonfunctional b TCR+ T cells but do have B cells, develop chronic colitis. Chronic intestinal inflammation also develops in IL-2-/- mice ; these mice show abnormal B cell responses including colon autoantibodies. IL-10-/- mice develop severe focal inflammation in both small and large intestine and have an elevated production of the Th1 cytokine IFN-g. Taken together, these results suggest that different immune pathways can lead to chronic intestinal inflammation with features of human IBD and that mice are excellent models to study these processes. The overall hypothesis being followed by our group is that in the normal state a balanced Th1 and Th2 profile is seen in the GI tract ; however, in the various murine IBD models a dysregulation occurs with the development of a major CD4+ Th1-type response.

Selected Publications 
Publication PUBMEDID
Kawamura YI, Kawashima R, Shirai Y, Kato R, Hamabata T, Yamamoto M, Furukawa K, Fujihashi K, McGhee JR, Hayashi H, Dohi T.
Cholera toxin activates dendritic cells through dependence on GM1-ganglioside which is mediated by NF-kappaB translocation.
Eur J Immunol. 2003 Nov;33(11):3205-12.
 		 14579289 
Boyaka PN, Tafaro A, Fischer R, Fujihashi K, Jirillo E, McGhee JR.
Therapeutic manipulation of the immune system: enhancement of innate and adaptive mucosal immunity.
Curr Pharm Des. 2003;9(24):1965-72. Review.
 		 12871182 
Dohi T, Fujihashi K, Koga T, Shirai Y, Kawamura YI, Ejima C, Kato R, Saitoh K, McGhee JR.
T helper type-2 cells induce ileal villus atrophy, goblet cell metaplasia, and wasting disease in T cell-deficient mice.
Gastroenterology. 2003 Mar;124(3):672-82.
 		 12612906 
Kato H, Fujihashi K, Kato R, Dohi T, Fujihashi K, Hagiwara Y, Kataoka K, Kobayashi R, McGhee JR.
Lack of oral tolerance in aging is due to sequential loss of Peyer's patch cell interactions.
Int Immunol. 2003 Feb;15(2):145-58.
 		 12578844 
Hagiwara Y, McGhee JR, Fujihashi K, Kobayashi R, Yoshino N, Kataoka K, Etani Y, Kweon MN, Tamura S, Kurata T, Takeda Y, Kiyono H, Fujihashi K.
Protective mucosal immunity in aging is associated with functional CD4+ T cells in nasopharyngeal-associated lymphoreticular tissue.
J Immunol. 2003 Feb 15;170(4):1754-62.
 		 12574339 
Boyaka PN, Ohmura M, Fujihashi K, Koga T, Yamamoto M, Kweon MN, Takeda Y, Jackson RJ, Kiyono H, Yuki Y, McGhee JR.
Chimeras of labile toxin one and cholera toxin retain mucosal adjuvanticity and direct Th cell subsets via their B subunit.
J Immunol. 2003 Jan 1;170(1):454-62.
 		 12496431 
Kweon MN, Yamamoto M, Watanabe F, Tamura S, Van Ginkel FW, Miyauchi A, Takagi H, Takeda Y, Hamabata T, Fujihashi K, McGhee JR, Kiyono H.
A nontoxic chimeric enterotoxin adjuvant induces protective immunity in both mucosal and systemic compartments with reduced IgE antibodies.
J Infect Dis. 2002 Nov 1;186(9):1261-9. Epub 2002 Oct 03.

 		 12402195 
Fujihashi K, Koga T, van Ginkel FW, Hagiwara Y, McGhee JR.
A dilemma for mucosal vaccination: efficacy versus toxicity using enterotoxin-based adjuvants.
Vaccine. 2002 Jun 7;20(19-20):2431-8. Review.

 		 12057597 
Ohmura M, Yamamoto M, Kiyono H, Fujihashi K, Takeda Y, McGhee JR.
Highly purified mutant E112K of cholera toxin elicits protective lung mucosal immunity to diphtheria toxin.
Vaccine. 2001 Dec 12;20(5-6):756-62.
 		 11738739 
Fujihashi K, Kato H, van Ginkel FW, Koga T, Boyaka PN, Jackson RJ, Kato R, Hagiwara Y, Etani Y, Goma I, Fujihashi K, Kiyono H, McGhee JR.
A revisit of mucosal IgA immunity and oral tolerance.
Acta Odontol Scand. 2001 Oct;59(5):301-8. Review.
 		 11680650 
Wormley FL Jr, Steele C, Wozniak K, Fujihashi K, McGhee JR, Fidel PL Jr.
Resistance of T-cell receptor delta-chain-deficient mice to experimental Candida albicans vaginitis.
Infect Immun. 2001 Nov;69(11):7162-4.
 		 11598094 
Jones HP, Hodge LM, Fujihashi K, Kiyono H, McGhee JR, Simecka JW.
The pulmonary environment promotes Th2 cell responses after nasal-pulmonary immunization with antigen alone, but Th1 responses are induced during instances of intense immune stimulation.
J Immunol. 2001 Oct 15;167(8):4518-26.
 		 11591779 
ohi T, Rennert PD, Fujihashi K, Kiyono H, Shirai Y, Kawamura YI, Browning JL, McGhee JR.
Elimination of colonic patches with lymphotoxin beta receptor-Ig prevents Th2 cell-type colitis.
J Immunol. 2001 Sep 1;167(5):2781-90.
 		 11509623 
Kato H, Kato R, Fujihashi K, McGhee JR.
Role of mucosal antibodies in viral infections.
Curr Top Microbiol Immunol. 2001;260:201-28. Review. No abstract available.
 		 11443875 
Yuki Y, Byun Y, Fujita M, Izutani W, Suzuki T, Udaka S, Fujihashi K, McGhee JR, Kiyono H.
Production of a recombinant hybrid molecule of cholera toxin-B-subunit and proteolipid-protein-peptide for the treatment of experimental encephalomyelitis.
Biotechnol Bioeng. 2001 Jul 5;74(1):62-9.
 		 11353411 
Fujihashi K, Dohi T, Rennert PD, Yamamoto M, Koga T, Kiyono H, McGhee JR.
Peyer's patches are required for oral tolerance to proteins.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3310-5.
 		 11248075 
Byun Y, Ohmura M, Fujihashi K, Yamamoto S, McGhee JR, Udaka S, Kiyono H, Takeda Y, Kohsaka T, Yuki Y.
Nasal immunization with E. coli verotoxin 1 (VT1)-B subunit and a nontoxic mutant of cholera toxin elicits serum neutralizing antibodies.
Vaccine. 2001 Feb 28;19(15-16):2061-70.
 		 11228378 
Kato H, Fujihashi K, Kato R, Yuki Y, McGhee JR.
Oral tolerance revisited: prior oral tolerization abrogates cholera toxin-induced mucosal IgA responses.
J Immunol. 2001 Mar 1;166(5):3114-21.
 		 11207263  
Boyaka PN, Tafaro A, Fischer R, Leppla SH, Fujihashi K, McGhee JR.
Effective mucosal immunity to anthrax: neutralizing antibodies and Th cell responses following nasal immunization with protective antigen.
J Immunol. 2003 Jun 1;170(11):5636-43.
 		 12759444 
 

Keywords
Mucosal Immunology, Oral Tolerance, Salivary IgA Antibody