Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

The Department of ImmunologyMechanisms and Treatment of AutoimmunityTHE TUOHYLABORATORYOur laboratory focus involves (1) understanding the complex self-recognition events thatlead to progression of autoimmune diseaseand (2) developing novel therapeutic strategies thatprevent disease progression. Our laboratory has along-standing history ofresearch on multiplesclerosis (MS) and hasdeveloped a widely usedmouse model calledexperimental autoimmuneencephalomyelitis (EAE)that mimics many of thefeatures of MS. Our studieshave shown that progressionof MS and EAE involves apredictable cascade ofnewly acquired selfrecognitionevents called“epitope spreading,” and ourrecent studies show thattransfer of regulatory Tcells targeting the “epitopespreading cascade” causesabrogation of diseaseprogression. Theseregulatory T cells areproduced by geneticmodification such that,upon engagement with selfantigens,they release anti-inflammatory factorsinstead of disease-inducing inflammatory factors.Thus, another focus of our laboratory involves reprogrammingthe autoimmune response by geneticmodification so that an inflammatory diseaseinducingresponse may be shifted to an antiinflammatorydisease-inhibiting response.Vincent K. Tuohy, Ph.D.Although autoimmune diseases are characteristicallymore prevalent in females, the severity ofautoimmune disease is typically worse in males. Thebasis for this perplexing yet consistently observedmale bias in disease severity is unclear and serves as arecent new focus for investigation inour laboratory. To this end, we havedeveloped a mouse model forexperimental autoimmune myocarditis,in which male mice show farmore pronounced inflammation,fibrosis, and dilated cardiomyopathy(DCM) than females, therebymimicking the skewed male biasobserved in human idiopathic DCM,a disease that accounts for about 25%of all cases of congestive heartfailure in the United States and killsmen at a 2- to 3-fold greaterfrequency than women.Finally, we have recentlyinvestigated the role of inflammatoryT cells in autoimmune sensorineuralhearing loss (ASNHL), a disease thattypically produces a sudden bilateralrapidly progressive loss of hearing.Although autoantibodies andautoreactive T cells have beenimplicated in the etiopathogenesis ofASNHL, several central issuesremain unresolved, including the relative prominenceof B-cell or T-cell autoimmunity in the initiation andprogression of ASNHL, the identity of the putativeinner ear self-antigen(s) that target ASNHL, and thedevelopment and application of contemporaryimmunosuppressive therapies to prevent progressivehearing loss.POSTDOCTORAL FELLOWSAndrea E. Edling, Ph.D.Riitika Jaini, Ph.D.Seiko Kataoko, M.D., Ph.D.C. Arturo Solares, M.D.TECHNICAL ASSOCIATESJustin M. Johnson, B.S.GRADUATE STUDENTSCengiz Zubeyir Altuntas, B.S.Bakhautdin Bakytzhan, B.S.Debasmita Chandra, M.S.Daniel Jane-wit, B.SPavani Kesaraju, B.S.Cara A. McCracken, B.A.COLLABORATORSRobert Fox, M.D. 1Keiko Hirose, M.D. 2Gordon Hughes, M.D. 2Wendy B. Macklin, Ph.D. 3Christine S. Moravec, Ph.D. 4Richard M. Ransohoff, M.D. 31Dept. of Neurology, CCF2Dept.of Otolaryngology andCommunicative Disorders, CCF3Dept. of Neurosciences, CCF4Dept. of CardiovascularMedicine, CCFYu, M., Johnson, J.M., and V.K. Tuohy (1996) A predictable sequential determinant spreading cascadeinvariably accompanies progression of experimental autoimmune encephalomyelitis: A basis for peptidespecifictherapy after onset of clinical disease. J. Exp. Med. 183:1777-1788.Mathisen, P.M, Yu, M., Johnson, J.M., Drazba, J.A., and V.K. Tuohy (1997) Treatment of experimental autoimmuneencephalomyelitis with genetically modified memory T cells. J. Exp. Med. 186:159-164.Tuohy, V.K., Yu, M., Yin, L., Kawczak, J.A., Johnson, J.M., Mathisen, P.M., Weinstock-Guttman, B., and R.P. Kinkel(1998) The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis andmultiple sclerosis. Immunol. Rev. 164:93-100.Tuohy, V.K., Yu, M., Yin, L., Kawczak, J.A., and R.P. Kinkel (1999) Spontaneous regression of primary autoreactivityduring chronic progression of experimental autoimmune encephalomyelitis and multiple sclerosis. J. Exp. Med.189:1033-1042.Klein, L., Klugmann, M., Nave, K.-A., Tuohy, V.K., and B. Kyewski (2000) Shaping of the autoreactive T-cellrepertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6:56-61.Huang, D., Tani, M., Wang, J., Han, Y., He, T.T., Weaver, J., Charo, I.F., Tuohy, V.K., Rollins, B.J., and R.M.Ransohoff (2002) Pertussis toxin-induced reversible encephalopathy dependent on monocyte chemoattractantprotein-1 overexpression in mice. J. Neurosci. 22:10633-10642.Jane-wit, D., Yu, M., Edling, A.E., Kataoka, S., Johnson, J.M., Stull, L.B., Moravec, C.S., and V.K. Tuohy (2002) Anovel class II-binding motif selects peptides that mediate organ-specific autoimmune disease in SWXJ, SJL/J, andSWR/J mice. J. Immunol. 169:6507-6514.99