Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/10635
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dc.contributor.authorMulley, William Ren
dc.contributor.authorLi, Yu Qinen
dc.contributor.authorWee, Janet Len
dc.contributor.authorDodge, Natalieen
dc.contributor.authorChristiansen, Daleen
dc.contributor.authorSimeonovic, Charmaineen
dc.contributor.authorIerino, Francesco Len
dc.contributor.authorSandrin, Mauro Sen
dc.date.accessioned2015-05-16T00:09:15Z
dc.date.available2015-05-16T00:09:15Z
dc.date.issued2008-05-06en
dc.identifier.citationXenotransplantation; 15(3): 174-83en
dc.identifier.govdoc18611225en
dc.identifier.otherPUBMEDen
dc.identifier.urihttp://ahro.austin.org.au/austinjspui/handle/1/10635en
dc.description.abstractTo overcome cell-mediated xenorejection by transgenic expression of immunomodulatory molecules by a graft, it is likely that expression of multiple molecules will be required. Previous studies support the use of the immunomodulatory agents indoleamine 2,3-dioxygenase (IDO), CD40Ig, interleukin 10 (IL10), and CTLA4Ig for suppression of rejection responses. We examined the effects of local expression of these molecules by a porcine cell line (PIEC) on indirect murine xenorejection responses in vitro and in vivo.The PIEC stable lines expressing IDO, CD40Ig, and IL10 as single molecules were generated. In addition, PIEC lines expressing IDO with either CD40Ig, IL10 or CTLA4Ig were generated to produce cell lines expressing two molecules. BALB/c mice were primed with wild type PIEC, followed by harvesting splenocytes used as responder cells and PIEC expressing immunomodulatory molecules as stimulators, in proliferation and cytokine assays. In vivo effects of modified PIEC were examined by transplantation of PIEC lines expressing the immunomodulatory molecules under the renal capsule of naïve mice. PIEC grafts were harvested for histological evaluation at days 7 and 14.Proliferation of primed BALB/c splenocytes was inhibited most significantly by IDO compared with control cells (49%, P = 0.02). In addition both Th1 (interferon-gamma) and Th2 (IL4 and IL10) cytokines were markedly inhibited in vitro by IDO expression. IL10 expressing cells did not inhibit proliferation as potently (37%, P = 0.03) whilst CD40Ig lead to an increase in proliferative responses (59%, P = 0.02). Co-expression of CD40Ig, IL10, and CTLA4Ig with IDO resulted in further modest reductions in proliferation compared with IDO expression alone. When transplanted under the renal capsule of BALB/c mice, those grafts expressing IDO demonstrated significantly lower levels of lymphocyte infiltration at days 7 and 14 than control grafts and those expressing CD40Ig, CTLA4Ig or IL10 alone. Grafts co-expressing IDO and a second molecule were no better protected than those expressing IDO alone. Graft cell viability (PIECs) was reduced in some IDO expressing grafts suggesting high levels of IDO expression may inhibit PIEC viability, however, grafts co-expressing IDO-CTLA4Ig and IDO-IL10 were not affected in this way.Indoleamine 2,3-dioxygenase appears to be a potent molecule for protecting xenografts from cell-mediated rejection responses activated via the indirect pathway. Co-expression of IDO with both CTLA4Ig and IL10 warrants further investigation. Overall these findings support pursuing further studies, in larger animal models, to determine whether increased IDO activity within the graft itself can attenuate xenorejection responses.en
dc.language.isoenen
dc.subject.otherAnimalsen
dc.subject.otherAntigens, CD.genetics.immunologyen
dc.subject.otherAntigens, CD40.genetics.immunologyen
dc.subject.otherCTLA-4 Antigenen
dc.subject.otherCell Proliferationen
dc.subject.otherCells, Cultureden
dc.subject.otherEndothelial Cells.cytology.immunology.metabolism.transplantationen
dc.subject.otherGene Expression Regulationen
dc.subject.otherGraft Rejection.genetics.immunology.metabolism.prevention & controlen
dc.subject.otherHumansen
dc.subject.otherImmunoglobulins.immunologyen
dc.subject.otherIndoleamine-Pyrrole 2,3,-Dioxygenase.genetics.metabolismen
dc.subject.otherInterleukin-10.genetics.immunologyen
dc.subject.otherMiceen
dc.subject.otherRecombinant Proteins.genetics.immunologyen
dc.subject.otherSwineen
dc.subject.otherT-Lymphocytes.immunologyen
dc.subject.otherTransplantation, Heterologous.immunologyen
dc.titleLocal expression of IDO, either alone or in combination with CD40Ig, IL10 or CTLA4Ig, inhibits indirect xenorejection responses.en
dc.typeJournal Articleen
dc.identifier.journaltitleXenotransplantationen
dc.identifier.affiliationDepartment of Surgery, Austin Health and University of Melbourne, Melbourne, Vic., Australiaen
dc.identifier.doi10.1111/j.1399-3089.2008.00472.xen
dc.description.pages174-83en
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/18611225en
Appears in Collections:Journal articles

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