F.119. FTY720+Sirolimus Increase Skin Allograft Survival via Cell Phenotype Changes

F.119. FTY720+Sirolimus Increase Skin Allograft Survival via Cell Phenotype Changes
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  in all or a particular subset of SSc patients. In contrast, IL-17itself was not detected in the majority of SSc patients.Discussion: The combination of IL-17, IFN γ  and TGF β  levels inCD45Ro and CD45Ra cells from SSc patients is useful todistinguish between lSSc, ldSSc or edSSc. Blocking Th17inducing cytokines such as IL-6 and IL-23 may provide a usefultool to intervene in the progression of SSc. doi:10.1016/j.clim.2009.03.368 F.117. Are HLA-E Restricted CD8 + T CellsFunctionally Altered in Multiple Sclerosis? Kim Pannemans  1 , An Goris  2 , Rita Dobosi 2 , BenedicteDubois  2 , Bart Van Wijmeersch 1 , P. Stinissen 1 , Niels Hellings  1 .  1 Hasselt University and TransnationaleUniversiteit Limburg, Diepenbeek, Belgium; 2 University Hospital Gasthuisberg, Leuven, Belgium Qa-1 restricted CD8 + regulatory Tcells suppress autoreac-tiveCD4 + Tcellsintheanimalmodelformultiplesclerosis(MS).This study aims at elucidating the involvement of CD8 + Tcellsrestricted by HLA-E, the human variant of Qa-1, in immunor-egulatory alterations in MS. In a first part, an MS associationstudyofHLA-Epolymorphismswasperformed.TheHLA-Egeneharbors two polymorphic sites, codon 107 (HLA-E ⁎ 0101 versusHLA-E ⁎ 0103) and codon 77 (HLA-E ⁎ 010301 versus HLA-E ⁎ 010302). These polymorphisms were studied in 1078 HCand 832 MS patients. Plink option analysis showed a significanthigher presence of HLA-E ⁎ 010301 and lower frequency of HLA-E ⁎ 0101 in MS patients (p = 0.04). Conditioning on DRB1 ⁎ 1501revealed that this HLA-E association actually reflected theeffect of DRB1 ⁎ 1501 on the development of MS. Although nogenetic association was found, functional alterations in HLA-ErestrictedCD8 + Tcellscouldstillbeinvolvedinthedysbalancedautoimmune responses observed in MS patients. Therefore,HLA-E restricted CD8 + Tcells are characterised at the level of theirphenotypeandregulatorypotential.First,thephenotypeof bothNKG2C + andNKG2A + CD8 + Tcellswas studiedusing flowcytometry. The frequency of NKG2A + CD8 + T cells was notsignificantly different between HC (n=10, 6.9± 3.2 %) and MSpatients (n=10, 8.7±3.2 %). The same could be concluded forNKG2C + CD8 + Tcells (HC: 3.82±2.1 %, MS: 3.32± 1.0 %). Thepercentage of CD28 + T cells within both the NKG2C + andNKG2A + CD8 + TcellfractionisdeclinedinMSpatientscomparedto HC. The functional consequence of this observation iscurrently investigated in coculture experiments with auto-reactive T cells and these CD8 + subsets. Samples will besubdividedaccordingtotheirHLA-Egenotype.Thisstudycouldlead to new insights in the pathogenesis of MS. doi:10.1016/j.clim.2009.03.369 F.118. Association of Impaired NK Cell Activity withImbalance in CD3-CD16+ Bright and Dim SubsetDistribution and Receptor Expression in MetastaticMelanoma Patients Gordana Konjevic 2 , Katarina Mirja č  i ć  Martinovi ć 1 , AnaVuletic 1 , Nada Babovic 1 .  1 Institute for Oncology and Radiology of Serbia, Belgrade, Serbia;  2 School of Medicine,University of Belgrade, Beograde, Serbia As we show that NK cell activity in metastatic melanoma(MM)patientspriortotherapyisimpairedtheaim ofthisstudywas to investigate the expression of a set of NK cell receptorsand activation markers on the two functionally distinct,regulatory CD16dim and cytotoxic CD16bright NK subsets.PBL of MM and controls were analyzed for NK cell activity,percentage of CD3-CD16 dim and bright subsets, expression of CD107a, NKG2D, CD161, CD158a and CD158b on NK cell andintracellular production of IFN- γ , as well as the expression,after  in vitro  4 h co-culture of PBL with tumor cell lines, of CD161 and CD158a on these subsets by Flow cytometry. WeshowthatMMpatientsnotonlyhavesignificantlydecreasedNKcell activity, NK cell CD107a expression and IFN- γ  production,but also a significantly larger CD16dim and smaller cytotoxicCD16bright NK subset. Furthermore, after co-culture withtargettumorcelllines,K562andFemX,thepercentageofCD3-CD16bright, contrary to CD3-CD16dim NK cells significantlydecreased,aswellasCD161andCD158aonCD3-CD16brightNKsubset. Also, in support of suppressed NK cells is our novelfinding of decreased NK cell IFN- γ  production in MM patients,that can affect their cytotoxicity, as reflected in CD107adecrease. The novel results for NK subsets showing howsecondaryNK cell contact with tumor cells changes CD161 andCD158a expression supports the tumor-related nature of thisphenomenon. Therefore, we report an unfavorable tip of thebalance towards the less mature, CD16bright158alow NK cellphenotype in MM patients. doi:10.1016/j.clim.2009.03.370 F.119. FTY720+Sirolimus Increase Skin AllograftSurvival via Cell Phenotype Changes Camila Lopes  1 , Flavia Rosin 1 , José Cordeiro 2 , ValquiriaBueno 1 .  1 UNIFESP Federal University of São Paulo, SãoPaulo, Brazil;  2 FAMERP São José do Rio Preto MedicalSchool, São José do Rio Preto, Brazil FTY720(FTY) prevents lymphocyte(Ly) egress from lymphnodes(LN) and thymus whereas Sirolimus(SRL) prevents Tcellactivation. Skin allograft recipient mice were either non-treated(Tx) or treated with SRL or FTYor FTY+SRL(1 mg/Kg/day).FTY+SRL had no rejection vs Tx:9.8±0.8/SRL:15.0±0.5/FTY:14.8±0.9 days,p b 0.0005. On day +5, FTY+SRL hadlower counts of splenocytes vs Tx and SRL[Tx:62.0(18.5)/SRL:34.4(10.2)/FTY:30.0(8.7)/FTY+SRL:24.6(6.8)x106,p b 0.05];thymocytes (THY) vs Tx and FTY[Tx:43.2(7.8)/SRL:26.3(40.3)/FTY:40.0(6.9)/FTY+SRL:25.2(6.5)x106,p b 0.005];CD4+ cells in spleen (SPL) vs Tx and SRL[Tx:15.9(5.2)/SRL:9.0(2.6)/FTY:5.5(3.4)/FTY+SRL:4.3(1.1)x106,p b 0.005],in LN vs Tx [Tx:0.6(0.2)/SRL:0.6(0.1)/FTY:0.3(0.2)/FTY+SRL:0.1(0.1)x106,p b 0.05], in peripheral blood(PB) vs others[Tx:22.4(13.9)/SRL:25.1(4.4)/FTY:2.2(1.6)/FTY+SRL:1.1(0.4)%,p b 0.05;CD8+ cells in SPL vs Tx[Tx:13.0(3.7)/SRL:5.9(1.5)/FTY:4.8(3.6)/FTY+SRL:5.4(1.0)x106,p b 0.005],in LN vs others[Tx:0.6(0.5)/SRL:04(0.5)/FTY:0.5(0.2)/FTY+SRL:0.3(0.2)x106,p b 0.05] and in PB vs SRL[Tx:15.8(4.0)/SRL:17.9(4.1)/FTY:1.8(0.3)/FTY+SRL:6.5S125Abstracts  (3.9)%,p b 0.05];CD4+CD8+ THY vs Tx[Tx:39.9(5.6)/SRL:23.4(36.3)/FTY:33.4(10.2)/FTY+SRL:18.3(4.7)x106,p b 0.005], Lyin PB vs Tx and SRL[Tx:63.0(27.0)/SRL:50.0(14.8)/FTY:15.0(5.0)/FTY+SRL:17.0(4.3)%,p b 0.005];CD11b+ cells in theallografts vs FTY[Tx:8.8(9.2)/SRL:7.2(6.2)/FTY:14.1(22.1)/FTY+SRL:4.6(2.4)%,p b 0.05];higher counts of CD11b+ non-Ly inSPL vs Tx[Tx:42.9(18.2)/SRL:22.6(6.0)/FTY:21.7(5.0)/FTY+SRL:20.7(7.1)x106,p b 0.005]; CD11b+ lymphocytes vs Tx andSRL in PB[Tx:6.0(3.5)/SRL:7.3(7.4)/FTY:50.7(3.3)/FTY+SRL:43.5(10.6)%,p b 0.005];CD11b+ non-Ly vs Tx and SRL in PB[Tx:42.7(28.7)/SRL:56.5(42.4)/FTY:93.5(9.8)/FTY+SRL:93.4(1.5)%,p b 0.005].Increased allograft survival in FTY+SRL wasassociated with decreased peripheral and allograft-infiltratingimmune cells. doi:10.1016/j.clim.2009.03.371 F.120. FTY720 Treatment Impairs Lung TumorDevelopment Due to Decrease of MyeloidSuppressor Cells (CD11b+Gr-1+) and RegulatoryT Cells (CD4+CD25hiFoxp3+) Flavia Rosin 1 , Camila Lopes  1 , Patricia Cury  2 , CelinaOshima 1 , Valquiria Bueno 1 .  1 Federal University of São Paulo - UNIFESP, Sao Paulo, Brazil;  2 Sao Jose do Rio PretoMedical School, Sao Jose do Rio Preto, Brazil Introduction: Tumor growth is associated with the increaseof myeloid suppressor cells (MySC:CD11b+Gr-1+) and regula-tory Tcells (Treg:CD4+CD25highFoxp3+), which inhibit CD8+ Tcell responses to specific tumor-associated antigens. FTY720experimentally reduces tumor growth and metastasis. How-ever,thereisnoreportwhetherFTY720interfereswithTregorMySC expression during tumor development. Aim: To investi-gate the role of FTY720 in urethane-induced lung tumor.Methods: Lung tumor was induced in BALB/c mice by twoinjectionsof urethane(1,5g/Kgeach)witha48-hourinterval.Mice were either non-treated (UR/n=9) or FTY720-treated(5 mg/Kg/day, FTY/n=10) during five consecutive daysstarting 30 days after the last urethane injection. Spleen,thymus and lungs were harvested 120 days later. Using flowcytometryweevaluatedCD3+CD4+,CD3+CD8+andTregcellsinspleenandthymusandMySCinspleen.Noduleandhyperplasiaareas (NHA) were measured in lung sections. Results: FTY720smaller total NHA (UR:2.21 mm2/FTY:2.00 mm2) was asso-ciated with decreased Treg (UR:7.6±2,2%/FTY:6.8±2,3%) andMySC (UR:25.4±8.9%/FTY:23.0±7.%) in spleen and withincreased Treg in thymus (UR:1.0±1.0%/FTY:2.8±3.9%). Also,FTY720 decreased CD3+CD4+ and CD3+CD8+ T lymphocyte inspleen (CD3+CD4+:UR:33.2±10.7%/FTY:29.5±8.2%; CD3+CD8+:UR:16.2±4.2%/FTY: 15.0±4.6%) and thymus (CD3+CD4+:UR:13.3±4.0%/FTY:11.8±3.8%; CD3+CD8+:UR:7.2±3.4%/FTY:6.2±3.1%). Conclusion: In urethane-induced lungtumor FTY720 administration was able to limit tumor devel-opmentandtherelatedmechanismswerethedecreaseofTregand MySC in spleen, which could lead to the non-inhibition of the immune response against tumor. Key-words: Lung Cancer,Treg Cell, Suppressor Cell, Flow Cytometry. doi:10.1016/j.clim.2009.03.372 F.121. B Cell-mediated Autoimmunity inHypomorphic rag1 and lig4 Mouse Mutants asModels for Human Leaky SCID  Jolan Walter  1 , Francesca Rucci 1 , Laura Patrizi 1 , Emma-Maria Andersson 1 ,MartonKeszei 2 ,CatherineYan 2 ,IrinaGavanescu 3 ,Pietro Poliani 5 , JoAnn Sekiguchi 4 , Frederick Alt 3 ,Luigi Notarangelo 1 .  1 Children's Hospital Boston, Harvard Medical School, Boston, MA;  2 Beth Israel Deaconess MedicalCenter, Harvard Medical School, Boston, MA;  3 Harvard Medical School, Boston, MA;  4 University of Michigan, Ann Arbor, MI;  5 University of Brescia, Spedali Civili of Brescia,Brescia, Italy  T-cell mediated immunopathology is a hallmark of humancombined immunodeficiencies (Omenn syndrome, leaky SCID)due to hypomorphic mutations in genes involved in V(D)Jrecombination. These defects are also expected to result inimpaired receptor editing, and hence in B-cell mediatedautoimmunity. However, the contribution of autoantibodyformationtothepathologyofOmennsyndromeandleakySCIDhasnotbeeninvestigated.Wehave studiedtwo mousemodelswith hypomorphic mutations in rag1 (rag1S723C/S723C) andlig4 (lig4R278H/R278H) that recapitulate leaky SCID. In bothmodels, V(D)J recombination is impaired, but not abrogated.Both mice show a severe, but incomplete, block in B celldevelopment atthe pre toproB cell stage.Bothmouse modelshave detectable IgG, IgM, IgA, with significantly higher levelsincaseoftherag1hypomorphicmodel.ELISPOTassaysindicatethat antibody-secreting cells are present both in the spleenand bone marrow, thus confirming that the hypomorphicmutations are permissive for residual B cell development andfunction. Importantly, autoantibodies to dsDNA and tochromatin were detected by ELISA, Hep2 cell line stainingand immunohistochemistryin a significant proportion of mice,andweremorefrequentlyobservedinrag1mutants.Moreover,the frequency of autoantibody-producing mice increases withage. Overall, these data indicate that B-cell-mediated auto-immunity may be an important component of the immuno-pathology of leaky SCID and Omenn syndrome, presumablybecause of stochastic generation of an autoreactive B cellrepertoire, associated with impaired receptor editing. doi:10.1016/j.clim.2009.03.373 F.122. Toll Like Receptor 2 Promotes Th2/Th17Responses via TLR4 and TLR8 by Human DendriticCells by Abrogating the Type 1 InterferonAmplification Loop Mark Wenink 1 , Kim Santegoets  1 , Lenny van Bon 1 , Jasper Broen 1 , Richard Huijbens  1 , Erik Lubberts  2 , Piet van Riel 1 ,Wim van den Berg 1 , Timothy Radstake 1 .  1 Radboud University Nijmegen Medical Center, Nijmegen, Netherlands;  2 Erasmus Medical Center, Rotterdam, Netherlands  TheprecisefunctionofTLR2intheimmunesystemremainselusive. We delineated the role of TLR2 in the determinationof the fate of human dendritic cells (DCs) and it's interactionwithotherTLRs.Monocyte-derivedDCswereculturedfrom15healthy controls and  in vitro  experiments were performed.Both P3C(TLR2/1ligand)andP2C(TLR2/6)dose-dependentlyS126 Abstracts
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