Tung2007

Kenneth S. K. Tung, M.D.

Professor, Renal Pathology

EDUCATION:

Medical School: Melbourne University, 1959, M.B.B.S.
Internship: Cleveland Clinic, Intern, 1962
Residency: Cleveland Clinic, Anatomical and Clinical Pathology 1963 - 1967
Fellowship: Fellowship in Immunology. Scripps Clinic and Research Foundation, 1968 - 1970

CLINICAL:
Renal immunopathology

RESEARCH:
Tolerance and Autoimmunity: My laboratory explores the fundamental mechanisms of prevention and induction of autoimmune diseases of clinical relevance. We study four major topics in autoimmune disease models. First, regulatory T cells bearing CD25 have the critical role of autoimmune disease prevention in normal adults. Their depletion leads to of autoimmune disease triggered by endogenous antigens. We now discovered that continuous endogenous antigenic stimulation is required to maintain both antigen-specific CD25 T cell function and the tolerance state. When the self antigen is added or deleted, the CD25+ T cells that prevent the development of the corresponding disease is gained or lost within 10 days. Second, we have discovered that maternal autoantibody, nonpathogenic in adults, induces de novo pathogenic T cell response in the progeny within the first 5 days of life, leading to severe neonatal autoimmunity. The neonatal susceptibility to autoimmune disease due not to CD25+ T cell deficiency, but to neonatal resistance to CD25+ regulatory T cell action, explicable by the unusual innate neonatal response. This results supports a general theme of our research: namely, stimulation by antigen and environmental cofactors early in life induces autoimmune disease rather than self tolerance. Third, while autoantibody can induce neonatal T cell response, we have shown that a pure T cell peptide can elicit autoantibodies in adults against multiple distant determinants of the antigen that contains the peptide and to neighboring autoantigens. This phenomenon depends on the apoptotic rate of the antigen positive target cells and interestingly, on the MHC haplotype. The antibodies, by binding to native self antigen, re-target distribution of Th1 or Th2 cell-mediated inflammation, leading to target organ destruction. Fourth, we are studying two transgenic mice expressing different levels (x40) of ovalbumin in testis germ cell autoantigen after puberty. By studying these mice crossed to those with transgenic TCR to ovalbumin, we are investigating the cellular and molecular basis of tolerance and spontaneous autoimmune disease in the testis.

REFERENCES:

  • Sharp C, Thompson C, Samy ET, Noelle R, Tung KSK. CD40 ligand in pathogenesis of autoimmune ovarian disease of day 3-thymectomized mice: Implication for CD40 ligand antibody therapy.   J. Immunol. 170: 1667-1674, 2003.   
  • Wright PW, Bolling LC, Calvert ME, Sarmento OF, Berkeley EV, Shea MC, Hao Z, Jayes FC, Bush LA, Shetty J, Shore AN, Reddi PP, Tung KS, Samy E, Allietta MM, Sherman NE, Herr JC, Coonrod SA.  ePAD, an oocyte and early embryo-abundant peptidylarginine deiminase-like protein that localizes to egg cytoplasmic sheets.  Dev Biol. 256: 74-89, 2003.
  • Setiady Y, Samy E, Tung KSK.  Maternal autoantibody triggers de novo T cell mediated neonatal autoimmune disease.  J. Immunol.170: 4656-4664, 2003.
  • Roper R, McAllister RD , Biggins JE, Michael SD, Min SH, Tung KSK, Call SB, Gao J, Teuscher. Aod1 controlling day 3 thymectomy-induced autoimmune ovarian dysgenesis in mice encompasses two linked quantitative trait loci with opposing allelic effects on disease susceptibility.  J Immunol. 170: 5886-5891, 2003.
  • Waters S.T., McDuffie M., Bagavant H., Deshmukh U.S. , Gaskin F., Tung KSK., Fu S.M.  Breaking tolerance to double stranded DNA, nucleosome and other nuclear antigens is not required for the pathogenesis of lupus glomerulonephritis.  J. Exp. Med. 199:255-264, 2004.
  • SetiadyYY, Promoonjago P, Tung KSK.  Requirements of NK cells and proinflammatory cytokines in T cell-dependent neonatal autoimmune ovarian disease triggered by immune complex.  J. Immunol. 173: 1051-1058, 2004. 
  • Carter JD, Ellett JD, Chen M, Smith KM, Fialkow LB, McDuffie MJ, Tung KS, Nadler JL, Yang Z.  Viral IL-10-mediated immune regulation in pancreatic islet transplantation.  Molecular therapy 12: 360-368, 2005.
  • Bagavant H, Tung KSK.  Failure of CD25+ T cells from lupus-prone mice to suppress lupus glomerulonephritis and sialoadenitis.  J. Immunol.,175: 944-950, 2005
  • Samy ET, Parker LA, Sharp CP, Tung KSK.  Continuous control against spontaneous autoimmunity in regional lymph nodes by CD4+CD25+ regulatory T cells.   J.  Exp.  Med. 202: 771-781, 2005.
  • Kharel Y, Lee SD, Snyder AH, Sheasley-O'Neill SL, Morris MA, Setiady Y, Zhu R, Zigler MA, Burcin TL, Ley K, Tung KSK, Engelhard VH, Macdonald TL, Lynch KR.  Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720.  J. Biol. Chem. 280:36865-72, 2005 
  • Setiady Y, Agersborg S, Samy E, Lewis J, Tung KSK.  Neonatal autoimmune disease: Influence of CD4+CD25+ regulatory T cells.  Intern. Rev Immunol. 24: 227-245, 2005. 
  • Tung KSK, Setiady Y, Samy E, Lewis J, Teuscher C.  Autoimmune ovarian disease in day 3-thymectomized mice: The neonatal time window, antigen specificity of disease regulation, genetic control.  In Suri-Payer E. and Kyewski B. Eds.  Regulatory T cells.  Current advances in Microbiology and Immunology, 2005, p 209. 
  • Setiady YY, Ohno K, Samy ET, Bagavant H, Qiao H, Sharp C, She JX, Tung KSK.  Physiological self antigen rapidly capacitates disease-specific polyclonal CD4+CD25+ T cells in autoimmune disease suppression.  Blood 107:1056-62, 2006. 
  • Samy ET, Setiady YY, Tung KSK.  Regulatory T cells in acquisition and maintenance of self tolerance.  Immun. Rev.  212:170-184, 2006.
  • Luborsky JL, Tung KSK.  Oophoritis.  In Rose NR, Mackay IR eds.  The Autoimmune diseases (4th Ed), Elsevier, 2006, p.841
  • Lustig L, Tung KSK.  Autoimmune orchitis and male infertility.  In Rose NR, Mackay IR eds.  The Autoimmune diseases (4th Ed), Elsevier, 2006, p.849.
  • Setiady YY, Tung KSK.  Novel mechanisms of autoantibody induction and pathogenesis in experimental autoimmunity.  In KM. Pollard, ed.  Autoantibodies and autoimmunity.  Wiley-VCH press, 2006, p.495.

A list of Dr. Tung's journal publications can be obtained from PubMed.