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Publication Export Tuesday, October 2, 2018 2:30 PM - 4:00 PM Scholar Award Abstract Session OR1 INVISIBLE ORGANS MADE BY GENETIC ENGINEERING TO TURN OFF MHC PRIOR TO ALLOGENEIC TRANSPLANTATION PREVENT A PRO-INFLAMMATORY CYTOKINE RESPONSE IN THE RECIPIENT Constanca Figueiredo, Marco Carvalho Oliveira, Chen Chen-Wacker, Klaus Hoeffler, Mark Kuehnel, Katharina Jansson, Axel Haverich, Gregor Warnecke, Rainer Blasczyk, Hannover Medical School, Hannover, GERMANY. Aim: HLA and minor antigen mismatches are the main causes of allograft rejection and graft failure. We have shown in mice and rats that MHC silenced cells and tissues are protected against immune rejection. We also demonstrated in porcine lungs that SLA expression can be turned off in a complex vascularized organ. In this study we evaluated the effect of MHC I silencing prior to allogeneic lung transplantation (Tx) in an established porcine Tx model by monitoring the cytokine response during the first 12 weeks after Tx with immunosuppression given only in the first 4 weeks. Methods: SLA I was permanently silenced during normothermic ex vivo perfusion with lentiviral vectors encoding short hairpin RNAs targeting b2m (n=2). A lentivirally transduced non-specific shRNA was used in the control lung Tx group (n=3). NanoLuc was used as a reporter gene in both groups. In each transplant experiment both donor lungs were genetically engineered with one lung being transplanted and the other lung used for quality control. Levels of b2m mRNA and SLA were quantified by RT-PCR and flow cytometry. SLA downregulation of endothelial cells was advisedly designed to not exceed 70%. Cytokines were monitored every second day after Tx and weekly after the post-operative day (POD) 7 by multiplex technology. Results: Already 1h after Tx the serum levels of IL-1b, IL-6 and IL-8 increased significantly in all animals by up to 0.263, 1.370 and 0.497 pg/ml, respectively. On POD 1, the cytokine secretion in the SLA silenced group decreased to pre-transplant levels whereas those of the control group remained significantly elevated (p<0.01). On POD 14, levels of IL-12 increased significantly by up to 0.286 pg/ml in the control group whereas it remained at pre-transplant levels in the SLA silenced group. In addition, levels of IL-2, IL-10 and TNF-a increased exclusively in animals with SLA expressing lungs while it was undetectable in animals with SLA silenced lungs. Due to severe rejection none of the control group animals reached the end of the monitoring period whereas all recipients of the SLA silenced lungs could be monitored over the entire period. Conclusions: These data strongly indicate that grafts silenced for MHC I are immunologically invisible supporting that MHC I and II silencing may successfully combat the burden of rejection and immunosuppression. OR2 LIGATION OF HLA CLASS II MOLECULES PROMOTES ENDOTHELIAL CELL PERMEABILITY THROUGH ACTIVATED SRC AND ERK SIGNALS Fang Li1, Nicole Valenzuela1, Rebecca Sosa1, Enrique Rozengurt2, Elaine F. Reed1, 1UCLA Immunogenetics Center, Los Angeles, CA, 2UCLA Digestive Diseases Research Center, Los Angeles, CA. Aim: Microvascular inflammation, increased vascular permeability, and accumulation of intravascular mononuclear cells are characteristics of acute (AMR) and chronic (cAMR) antibody-mediated rejection. In solid organ transplantation, donor specific antibodies (DSA) are associated with AMR, and early or late graft loss. However, the mechanisms underlying how DSA against HLA class II (HLA II) activate the endothelium and mediate inflammation and vascular permeability are poorly understood. Methods: We utilized recombinant Class II Transactivator (CIITA) sub-cloned with pAd/PL-DEST vector to achieve expression of HLA II on vascular endothelium, and then evaluated the effects of HLA II antibodies (anti-HLA II) on endothelial cell (EC) permeability. Immunoblotting was used to determine the activation of signaling pathways and confocal microscopy was used to determine vascular endothelial - Cadherin (VE-Cad) phosphorylation and internalization. Results: Ligation of HLA II by anti-HLA II activated Src and ERK, induced stress fiber formation, and increased EC permeability. Anti-HLA II also stimulated VE-Cad phosphorylation at Tyr685 as well as its internalization, thereby disassembling intercellular junctions. Class II mediated stress fiber formation and EC permeability was abrogated by pharmacological inhibition of ERK (U0126), Src (PP2) or MLC2 (ML-7). Both pharmacological and siRNA inhibition of Src, but not ERK, inhibited class II-induced phosphorylation of VE-cCd at Tyr685 and consequent VE- Cad internalization. Conclusions: In conclusion, our data show that HLA class II DSA promotes actin stress fiber formation via a Src/ERK/MLC2 dependent pathway. Further, class II crosslinking with antibodies induces rapid endocytosis of VE-Cad via Src-dependent tyrosine phosphorylation of VE-Cad, thereby disrupting the endothelial barrier function and contributing to vascular permeability. OR3 DEVELOPMENT OF HLA DE NOVO DONOR SPECIFIC ANTIBODY IS ASSOCIATED WITH PREFORMED NON-HLA AUTOANTIBODIES AND LUNG TRANSPLANTATION REJECTION Aiwen Zhang1, Rui Pei2, Dawn M. Thomas1, Yuchu Sun3, John McMichael1, Jeffrey Allen1, Elizabeth Winn1, Karen Seifarth1, Marie Budev4, 1Allogen Lab, Cleveland Clinic, Cleveland, OH, 2Thermo Fisher Scientific, Waltham, MA, 3Avalon University School of Medicine, Youngstown, OH, 4Cleveland Clinic, Cleveland, OH. Aim: Autoantibodies have been implicated in the chronic rejection process after Lung Transplantation (LuT), but it is less certain if preformed non-HLA autoantibody (pAuAb) is the pre-LuT determinant for De Novo Donor Specific Antibody (dDSA) development. This study aims to investigate the relationship of pAuAb to dDSA fomation and the clinical impact of dDSA to LuT. Methods: 124 recipients underwent LuT during 10/2012 -2/2014 at our center were retrospectively analyzed for dDSA (Mean Fluorescence Intensity ≥ 1000). pAuAbs were detected among a subgroup of 118 patients using LABScreen™ Autoantibody (Thermofisher, panel coverage is listed in Table 1a). Cut-offs for pAuAbs were set up using 85% reference background values, which were calculated of lower than 85% population from a group of random selected non-transplanted and non-transfused individuals. Acute Cellular Rejection (ACR), Antibody Mediated Rejection (AMR) were recorded to assess LuT outcomes. Results: 71 out of 124 (57%) recipients were identified with dDSA. Among dDSA recipients, Class I only, Class II only, and combined Class I and Class II were 16 (23%), 30 (42%), and 25 (35%), respectively. 53 (75%) of total dDSA was from DQ. pAuAbs to Angiotensinogen and Vimentin were clearly related to the formation of dDSA (p<0.001), while pAuAbs to FLRT2, CD36, and TubulinA1B were also associated with the generation of dDSA (p<0.05) (Table 1a). Total class II and DQ dDSAs were relevant to the occurrence of ACR, while total Class I and total Class II dDSAs, as well as DQ dDSA were significantly related to incidence of AMR (Table 1b). Conclusions: The significant relevance of multiple pAuAbs to the formation of dDSA may provide a new perspective for evaluating the possibility of pAuAbs in eliciting dDSA at pre-LuT, which may help to reduce the risk of ACR and AMR related negative impact to LuT. OR4 HIGH RESOLUTION HAPLOTYPE ANALYSES OF CLASSICAL HLA GENES IN FAMILIES WITH MULTIPLE SCLEROSIS Kazutoyo Osoegawa1, Lisa E. Creary2, Kalyan Mallempati1, Sridevi Gangavarapu1, Stacy Caillier3, Jill Hollenbach4, Jorge Oksenberg3, Marcelo Fernandez-Vina2, 1Stanford Blood Center, Palo Alto, CA, 2Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, 3UCSF School of Medicine, San Francisco, CA, 4Univ. of California San Francisco School of Medicine, San Francisco, CA. Aim: HLA alleles are observed in specific haplotypes because of linkage disequilibrium between particular alleles. Multiple sclerosis (MS) has been associated with HLA genes and haplotypes. Our goal was to identify candidate HLA gene alleles and haplotypes that are susceptible or protective to MS. Methods: We applied a high-throughput, high-resolution NGS method to type 11 HLA loci in 481 trio families comprising of 962 unaffected parental controls and 481 children diagnosed with MS. We developed an in-house computer program named HaplObserve that builds haplotypes by comparing offspring and parents HLA genotypes from nuclear families. HLA haplotypes were built from the trio families using HaplObserve that also allows tracing HLA allele/haplotype transmissions from the parents to the offspring. We dissected the extended haplotypes generated into smaller haplotypes and alleles, then explored associations with MS using standard transmission disequilibrium test (TDT) and multiallelic TDT analyses. Results: We built a pipeline to systematically analyze HLA alleles and various segments of haplotypes using standard TDT and multiallelic TDT tests. Standard TDT and multiple allelic TDT showed that the DRB5*01:01:01~DRB1*15:01:01:01 haplotype was significantly predisposing (standard TDT: p < 2.2e-16). We identified that DRB1*01:01:01~DQB1*05:01:01:03 (standard TDT: p = 8.63e-06), C*04:01:01:01~B*35:01:01:02 (p = 0.001645) and A*02:01:01:01~C*03:04:01:01~B*40:01:02 (p = 0.008318) haplotypes were protective. Our analysis indicated that DRB1*11:01:01:01 (p = 0.001738), B*27:05:02 (p = 0.0004531), B*38:01:01 (p = 0.0031953) and C*07:04:01:01 (p = 0.004126) were protective. Conclusions: We have shown the suitability of the HaplObserve to efficiently build haplotypes from NGS data in a large number of families, as well as the efficacy and power of TDT analysis for MS association studies. By comparing statistical significance of various haplotype segments, we were able to fine-map MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. Tuesday, October 2, 2018 4:30 PM - 6:00 PM Abstract Session I: Solid Organ Pre/Post - Transplant Testing I OR5 DONOR SPECIFIC ANTIBODY (DSA) ASSESSMENTS USING HLA P GROUPS: THE DEVIL IS IN THE DETAILS June Jones1, Annette M. Jackson1, Donna P.
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