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Hediul Research Society A model will be proposed explaining h o w t h ~ ssingle genetic defect could, by dysregulating a number of cell types, result in an amplification of autoimmunity and inflammation. 43 MHC AND a GAL EXPRESSION IN PORCINE FETAL NEURAL TISSUE .I HARROWER’,G CRUZ’*, LCOPEMAN,”.A RICHARDS’. S OIJNNEll”, I 3~ stimulation with TGFpl (432+46% basal levels), transgenic cells showed no induction (104+20% non-TGFp control), despite higher basal secretion. Westem blot analysis of Smad protein levels in cell extracts was used to investigate TGFp signal transduction. Interestingly. basal Smad7 levels were up to 4-fold greater for transgenic than wildtype dermal fibroblasts, suggesting that increased constitutive expression of this inhibitory Smad may underlie the altered TGFp responses. Thus, expression of this mutant human TPRll in fibroblasts in vivo leads to a fibroproliferative phenotype with increased constitutive activity of downstream signal transduction pathways. R BARKER‘ ‘Cambridge Centre for Brain Repair, Forvie Site, Cambridge, CB22PY lmutran Ltd (A Novartis Pharma AG Co),PO Box 399, Cambridge, CB22AH ’ Porcine neural fetal tissue has been investigated as an alternative to human fetal tissue for transplantation however such tissue will be immunologically rejected and in an attempt to understand the initiation of this rejection we have undertaken characterization of immunologically relevant surface epitopes. Major Histocompatibility Complex (MHC) proteins and gal a-I-3-gal (aGal) have been shown to be involved in solid xenorejection and therefore may play a role in neural xenograft rejection. Cell suspensions of ventral mesencephalic (VM),striatal and corhcal tissue were prepared from E26-28 porcine fetal brains and analyzed by fluorescent activated flow cytometry and inununocytochemisfxyfor the expression of MHC I and I1 and a gal. The tissue was either analyzed freshly prepared or incubated at 37 with human TNF a and human IFN y. Cortically derived fetal tissue was expanded under condihons allowing the formation of neural precursors, which were passaged once then, analysed similarly. Freshly prepared porcine neural tissue un-perturbed by the presence of inflammatory cytokines from the ventral mesencephalon and the striaturn does not express MHC I. Low expression of MHC I on cortically derived tissue was detected (Me? Fluorescent Intensity (MFI) 9,2 +/- 0.572, n=9.) Activation by INF y can lead to expression of MHC I (MFI 55.3 t/- 13.2, n=3.) This expression is evident on no more than 25 % of the cells. MHC I1 expression is evident in the un-stimulated state on I2 % of cells in freshly prepared cells from the V M (MFI 22.5+/- 4,91, n=ll) and Striaturn (MFI 21,4 +/- 1.29, n-7) and 25 % n the cortex (MFI = 30 +/- 3.96, n=9.) LFN y induces more expression of MHC 11 (MFI 48.3 +I- 10.73, n=3.) However in cells prepared from neurospheres there was no detection of MHC II expression at all. a Gal expression (Vm MFI 280 +/- 34 n=6, striaturn MFI 24411- 44,n=7 and cortex 428 +/- 1 I I , n=9) is evident on 97 +/-3 %, n=19 of all cells but is only expressed at one fifth of the expression of aomc endothelial cells (MFI 2266+/-625, n=5). The a gal expression is not changed by exposure to inflammatory cytokines. a Gal expression is found on 97 +/- 3 %, n=12 of cells prepared from neurospheres. These fndings suggest MHC I is inducible in conditions, which could exist after the trauma of transplantation and may therefore play a significant role in antigen presentation. MHC I1 expression is present in freshly prepared tissue and is inducible by human cytokines but is absent in expanded neural precursors, which could convey a immunological benefit for graft survival using these cells. a Gal is present on all neural cells and therefore potentially could be responsible for initiating the xenograft rejection of neural cell transplants. 44 PERTURBATIONOF TGFp SIGNALING IN FIBROBLASTS OF TRANSGENIC MICE INDUCES A FIBROPROLIFERATWE PHENOTYPE CP DENTON. X SHIWEN. B ZHENG. V RAJKUMAR, D ABRAHAM, B DE CROMBRUGGHE and CM BLACK Centre for Rheumatology, Royal Free Campus, University College London, UK; Department of Molecular Genetics, University of Texas MD Anderson Cancer Center, Houston, USA We have expressed, in transgenic mice, a kinasdeficient human type II TGFp receptor (TpRII). regulated by a mouse proa2(l)collagen promoter wnstruct previously shown to induce high-level lineagespecific expression in fibroblasts. Coexpression of a pgalactosidase (LacZ) reporter gene was used to delineate the level of transgene expression. Two transgenic mouse lines were established, each demonstrating sustained LacZ expression in fibroblasts. One line manifested altered lung histology including parenchymal inflammation and increased extracellular matrix deposition in 25% of offspring between 12 and 24 weeks old, and this was lethal in 5% of mice. Skin fibroblasts cultured from neonatal transgenic (n=5) or control non-transgenic littermates ( n 4 ) were compared. Transgenic fibroblasts showed high level LacZ expression up to the fourth passage, and proliferated faster than control strains (meanfsd doubling time was 55f3 hours for transgenic, compared with 72k7 hours for wildtype; p-0.008). Transient transfection of a PAL1 promoter-luciferase(PAl-Luc) construct was used to assess TGFp responsiveness of these cells. In wildlype cells PAl-Luc expression was highly inducible by TGFpI (862325% non-stimulated) whereas transgenic fibroblast strains showed no induction (95*5% non-stimulated). In addition, whereas wild-type cells increased type I procollagen secretion after 45 A NOVEL MECHANISM OF IMMUNE TOLERANCE BREAKDOWN AND AUTOIMMUNE DISEASE INDUCTION DEJ JONES, JM PALMER, AJ ROBE, MH BONE, AD BURT, SJ YEAMAN, JA KIRBY and MF BASSENDINE Centre for Liver Research, University of Newcastle, UK Experimental autoimmune cholangitis (EAC) is a recently described murine model of the autoimmune liver disease primary biliary cirrhosis (PBC), in which S J U J mice demonstrate histological’ and immunological’ features typical of human disease. EAC can be induced by sensitisation with non-self (bovine) pyruvate dehydrogenase complex (bPDC), the autoantigen in PBC. This approach induces breakdown of T-cell selftolerance’ and the development of PBC-like bile duct lesions at 16-20 weeks post-sensitisation’ (but not before). It has previously been demonstrated that breakdown of tolerance to self-antigen (cytochrome c) can be brought about by co-sensitisation with self and foreign cytochrome c, but this was not associated with the induction of autoimmune disease. Here we set out to study whether a similar approach of Selflforeign antigen co-sensitisation approach accelerates the development of autoimmune disease in our model. Female SJUJ mice sensitised with murine PDC (mPDC) or bPDC alone in adjuvant (n=6 each group) demonstrated neither breakdown of T-cell self-tolerance to PDC nor the bile duct lesions of EAC at 5 weeks post-sensitisation. When mice (n=10) were co-sensitised with bPDC and mPDC significant proportions showed breakdown of T c e l l tolerance to mPDC (9/10) and the development of the bile duct lesions of EAC (7/10). Bile duct lesion development was typically associated with a significant increase in the numbers of CD3+ CD8+ T-cells present in the portal tract mononuclear cell infiltrate. A significant proportion of the cells adjacent to the affected biliary epithelium were CD103+ denoting the capability to bind directly to e-cadherin expressing biliary epithelial cells (BEC). Aberrant BEC surface expression of PDC was seen in some affected ducts, a feature typical of PBC in humans. Conclusion: SelWforeign PDC co-sensitisation significantly accelerates the development of EAC. Given the ubiquitous distribution of PDC in the mitochondria of all cells, the PBC-specific aberrant cell-surface expression of self-PDC and the presence of foreign PDC in pathogens (bacterialyeast) this phenomenon may represent an important natural mechanism for tolerance breakdown and disease induction in human PBC. I) Jones DEJ et al Liver zW0:u)In PIEIS.2) Joncs DE!et al H~polology1999.3055-70 46 THYMUS-INDEPENDENT MUCOSAL T CELLS REGULATE THE INCREASE IN PANETH AND INTERMEDIATE CELLS IN THE SMALL INTESTINE OF MICE INFECTED WITH T. s p r m r s D WAKELIN’, M KAMAL”’, PODOLSKY’ and YR MAHIDA’ A SMITH’, A OUELLETTE‘, DK Division of Gastroenterology’ and School of Life & Environmental Science’, University of Nottingham, UK, Institute of Animal Health’, Compton, UK, Department of Pathology’, University of California, Irvine, USA, and Gastrointestinal Unit‘, Massachusetts General Hospital 6 Harvard Medical School, Boston, USA T cells may link systemic adaptive and innate immunity but little is known of this capability in the gastrointestinal tract. Secretory products of Paneth, goblet and intermediate cells have been implicated in innate intestinal host defence. The latter have ultrastructural features of both Paneth & goblet cells but their functions remain to be determined. Small intestinal Paneth and intermediate cell numbers (counted together, per 10 villus crypt units) in T. spiralis-infected athymic (nude) mice