Kenneth S. Tung

Education

  • MBBS, Melbourne University, Melbourne, Australia
  • Resident, Melbourne University, Melbourne, Australia
  • Resident, Cleveland Clinic, Cleveland, Ohio
  • Fellowship, Scripps Clinic & Res. Fdn., La Jolla, CA

Primary Appointment

  • Professor, Pathology

Contact

Research Interest(s)

Mechanisms of Tolerance and Autoimmunity to Gonad-Specific Antigens

Research Description

Tolerance and Autoimmunity: My laboratory explores the fundamental mechanisms of prevention and induction of autoimmune disease of clinical relevance, under four major topics.

First, we investigate how Ag specific regulatory T cells bearing Foxp3 (Treg) control physiological self tolerance in normal mice. We discovered that regional lymph nodes of normal mice accumulate highly active Treg that suppress autoimmunity of the organ draining to it. We now want to know whether in this strategic location, Treg maintain self tolerance by preventing autoimmune disease triggered by endogenous "danger signal".

Second, we study sperm granuloma in unilaterally-vasectomized mice as endogenous "danger signal". Unexpectedly, vx mice develop tolerance to testis Ag, which is terminated by depletion of Treg, leading to severe testis autoimmune disease. We want to know how Treg normally control the choice between tolerance and autoimmune pathogenesis in autoimmune response. [The project is clinically relevant and of global significance, since the annual rate of vasectomy in the US alone is 0.5 million and rising.]

Third, we developed a model of spontaneous autoimmune disease in a mice expressing transgenic ovalbumin as male germ cell autoantigen and transgenic TCR specific for OVA peptide. [The model elucidates how human autoimmune diseases progress from preclinical to clinical stage, from remission to relapse, and design of appropriate therapy.] We discovered that transferred autoantibody rapidly forms immune complexes with OVA, which, contrary to current dogma, is not sequestered behind the blood-testis barrier. The immune complexes attract and activate Ag presenting cells and Ag specific T cells in a unique testis micro-environment, expanding pathogenic Th17 cells. We want to know the molecular mechanisms responsible for the events.

Fourth, we discover that maternal autoantibody, nonpathogenic in adults, induces pathogenic innate response, as well as de novo pathogenic T cell response in the progeny, leading to severe neonatal autoimmunity. Notably, antibody needs to reach the pups within but not beyond, the first 5 days of life. We found that the neonatal propensity for autoimmune disease is explicable by the functional supremacy of neonatal NK cell and FcgRIII+ cells over adult counterparts. [This is a model of congenital heart block: a serious human disease that occurs in the newborn of mothers suffering from Sjogren's disease, a type of lupus.] 

Selected Publications

  • Coquery C, Wade N, Loo W, Kinchen J, Cox K, Jiang C, Tung K, Erickson L. Neutrophils contribute to excess serum BAFF levels and promote CD4+ T cell and B cell responses in lupus-prone mice. PloS one. 2014;9(7): e102284. PMID: 25010693 | PMCID: PMC4092127
  • Rival C, Wheeler K, Jeffrey S, Qiao H, Luu B, Tewalt E, Engelhard V, Tardif S, Hardy D, del Rio R, Teuscher C, Tung K. Regulatory T cells and vasectomy. Journal of reproductive immunology. 2013;100(1): 66-75. PMID: 24080233 | PMCID: PMC3965253
  • Mauldin I, Tung K, Lorenz U. The tyrosine phosphatase SHP-1 dampens murine Th17 development. Blood. 2012;119(19): 4419-29. PMID: 22438258 | PMCID: PMC3362360
  • Tewalt E, Cohen J, Rouhani S, Guidi C, Qiao H, Fahl S, Conaway M, Bender T, Tung K, Vella A, Adler A, Chen L, Engelhard V. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood. 2012. PMID: 22993390 | PMCID: PMC3520619
  • Carroll V, Lundgren A, Wei H, Sainz S, Tung K, Brown M. Natural killer cells regulate murine cytomegalovirus-induced sialadenitis and salivary gland disease. Journal of virology. 2011;86(4): 2132-42. PMID: 22156514 | PMCID: PMC3302420
  • Ernst P, Erickson L, Loo W, Scott K, Wiznerowicz E, Brown C, Torres-Velez F, Alam M, Black S, McDuffie M, Feldman S, Wallace J, McKnight G, Padol I, Hunt R, Tung K. Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice. American journal of physiology. Gastrointestinal and liver physiology. 2011;302(1): G105-15. PMID: 21921286 | PMCID: PMC3345967
  • Ernst P, Wiznerowicz E, Feldman S, Tung K. Pathogenesis of gastritis in ileitis-prone SAMP1/Yit mice. The Keio journal of medicine. 2011;60(2): 65-8. PMID: 21720202
  • Jiang C, Loo W, Greenley E, Tung K, Erickson L. B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus. Journal of immunology (Baltimore, Md. : 1950). 2011;186(11): 6136-47. PMID: 21536804 | PMCID: PMC3181142
  • Wheeler K, Tardif S, Rival C, Luu B, Bui E, Del Rio R, Teuscher C, Sparwasser T, Hardy D, Tung K. Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(18): 7511-6. PMID: 21502500 | PMCID: PMC3088630
  • Cohen J, Guidi C, Tewalt E, Qiao H, Rouhani S, Ruddell A, Farr A, Tung K, Engelhard V. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. The Journal of experimental medicine. 2010;207(4): 681-8. PMID: 20308365 | PMCID: PMC2856027
  • Case L, Del Rio R, Bonney E, Zachary J, Blankenhorn E, Tung K, Teuscher C. The postnatal maternal environment affects autoimmune disease susceptibility in A/J mice. Cellular immunology. 2009;260(2): 119-27. PMID: 19914609 | PMCID: PMC2795069
  • Guth A, Detanico T, Smith D, Tung K, Bonorino C, Wysocki L. Spontaneous autoimmunity in mice that carry an IghV partial transgene: a required arginine in VHCDR3. Lupus. 2009;18(4): 299-308. PMID: 19276297 | PMCID: PMC2892212
  • Wheeler K, Samy E, Tung K. Cutting edge: normal regional lymph node enrichment of antigen-specific regulatory T cells with autoimmune disease-suppressive capacity. Journal of immunology (Baltimore, Md. : 1950). 2009;183(12): 7635-8. PMID: 19923458 | PMCID: PMC2872190
  • Chavali A, Gianchandani E, Tung K, Lawrence M, Peirce S, Papin J. Characterizing emergent properties of immunological systems with multi-cellular rule-based computational modeling. Trends in immunology. 2008;29(12): 589-99. PMID: 18964301
  • Samy E, Wheeler K, Roper R, Teuscher C, Tung K. Cutting edge: Autoimmune disease in day 3 thymectomized mice is actively controlled by endogenous disease-specific regulatory T cells. Journal of immunology (Baltimore, Md. : 1950). 2008;180(7): 4366-70. PMID: 18354156
  • Samy E, Setiady Y, Ohno K, Pramoonjago P, Sharp C, Tung K. The role of physiological self-antigen in the acquisition and maintenance of regulatory T-cell function. Immunological reviews. 2006;212 170-84. PMID: 16903914