bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of systemic anti-154 (CD40L) antibody on clinical outcomes of full-thickness porcine corneal graft in pig-to-rhesus corneal transplantation model (TRAN3P.872)
Authors: Kim Dong Hyun , Choi Hyuk Jin , Kim Mee Kum , Lee Hyun Ju , Jeong Hyun Jeong , Ryu Jin Suk , Kang Hee Jung , Park Chung-Gyu , Wee Won Ryang 
Published: January 2023

Abstract
Purpose: To investigate the effect of systemically administered anti-CD154 antibody(Ab) on the survival of full-thickness porcine corneal grafts. Methods: Seven rhesus macaques were assigned to control (n=3) or immunosuppression (n=4) group and underwent full-thickness corneal transplantation. Systemic steroid was applied to control group while anti-CD154 Ab were administered to immunosuppression group. Rejection sign, central corneal thickness (CCT), and recipients’ immunologic profile including memory T cell, anti-α-Gal and donor-specific Abs, mixed lymphocyte-like reaction and aqueous complement concentration were evaluated. Cellular infiltration into the xenografts was evaluated by immunohistochemical staining. Results: Anti-CD154 Ab-based immunosuppression significantly prolonged the survival of full-thickness xenocorneal grafts. In control group, CCTs, memory T cells, anti-α-Gal IgG and donor pig-specific IgG Abs continuously increased in correspond with the progression of graft rejection in contrast to immunosuppression group. Reactivities to donor-specific stimulators and concentrations of the aqueous complement were also significantly higher in control group than in immunosuppression group. Rejected grafts showed extensive cellular infiltration. Conclusions: Anti-CD154 antibody-based immunosuppression is effective for prolonging the survival of full-thickness xenocorneal grafts and controlling immunologic responses in pig-to-rhesus corneal transplantation model.
Pregnancy primes anti-fetal T cell memory capable of allograft destruction (TRAN3P.874)
Authors: Porrett Paige , Barton Brendan , Klahr Rebecca , Wherry John 
Published: January 2023

Abstract
Pregnancy-induced anti-fetal antibody can destroy allografts and excludes many women from transplantation, but anti-fetal T cell responses are poorly understood and are not currently evaluated in potential organ recipients. To test whether pregnancy (PG) primes graft-reactive T cell memory, we compared Ova skin graft survival (GS) between naive B6 mice (N), mice mated to Ova transgenic (tg) males (Ova PG-sensitized; OP), or mice sensitized by a previous Ova skin graft (OS). Skin grafts were placed 30 days after either Ova pup delivery (OP group) or after rejection of an Ova skin graft (OS group). OP females rapidly rejected Ova skin grafts with second set kinetics identical to OS females [GS (days): 11.3±1.5(OP) vs. 10.3±0.6(OS) vs. 15±0.7(N); p&lt;.01]. To test the effects on antigen-specific T cells, mice were injected with Ova-specific TCR tg T cells. Flow cytometric analysis 30 days after pup delivery revealed memory T cell differentiation in response to fetal antigen [%anti-Ova CD8+CD44+CD62L-: 85%(Ova-mated) vs. 38%(Balb/c-mated)]. OP mice also produced enhanced effector T cells upon secondary challenge with an Ova skin graft [%anti-Ova CD8+IFNγ+: 60%(OP) vs. 43%(Balb-mated) vs. 35%(N)]. These results indicate that PG can prime T cell memory that gives rise to secondary effector T cells that mediate rapid graft destruction. Stimulation of PG-induced anti-fetal T cell memory may contribute to the inferior GS observed in women who receive a transplant from a child or spouse.
Sera miR-338-5p differentially expressed in renal transplant recipients and negatively related with soluble BAFF (TRAN3P.877)
Authors: Xu Haiyan , He Xiaozhou , Ma Xuyi , Xue Dong , Dong Panpan , Zhang Yanyun , Zhang Xueguang 
Published: January 2023

Abstract
To investigate the expression characteristic of sera miR-338-5p in renal transplant (RTx) recipients, and further analyse its potential significance. Serum of RTx recipients (49 cases) were collected. miR-338-5p were extracted and detected by qPCR, soluble B cell activating factor (sBAFF) was determined by ELISA (R&D), and the presence of circulating anti-HLA&MICA was determined by single-antigen flow bead assays (One Lambda) on a Luminex platform. Healthy volunteers (20 cases) were controls. SPSS17.0 software was applied, two-side t-test was to analyse the means of two-independent samples, Spearman method was to analyse the correlation of miR-338-5p and sBAFF, anti-HLA&MICA. P&lt;0.05 was considered to be significant. Compared with healthy controls, miR-338-5p in RTx recipients significantly decreased and sBAFF significantly increased (P&lt;0.05). miR-338-5p significantly down-regulated in RTx recipients within 1-year post-operation, compared with those over 1-year post-operation (P&lt;0.05); miR-338-5p also signficantly down-regulated in recipients within 3-year post-operation, comapred with those over 3-year post-operation (P&lt;0.05). sBAFF level in different period after operation was not significant. For all subjects, miR-338-5p was negatively correlated with sBAFF (r=-0.51, P&lt;0.001), and sBAFF was positively correlated with anti-MICA antibody (r=0.86, P&lt;0.05). miR-338-5p may involve in the procedure of immune response after RTx by indirectly or directly targeting BAFF signal.
miRNA-181a is critical for the tolerogenic properties of plasmacytoid dendritic cells (TRAN3P.886)
Authors: Lau Audrey , Schaffert Steven , Qu Xiumei , Krams Sheri 
Published: January 2023

Abstract
Liver allografts are well tolerated and other solid organ allografts, when transplanted concurrently with livers, show improved graft outcomes. However, the mechanisms underlying “hepatic tolerance” have yet to be elucidated. Previous data show that hepatic dendritic cells (HDC) have diminished antigen presenting and immune stimulatory function compared with DC in lymphoid tissue. It has been hypothesized that immature plasmacytoid (p)DC are inherently tolerogenic with studies supporting this hypothesis. Our work confirms that HpDC prolong cardiac allograft survival (p&lt;0.01) in a murine model compared to bulk and myeloid (m)DC. Micro-ribonucleic acid (miR) are short (15-22 nucleotides) RNA molecules which can post-transcriptionally regulate messenger RNA transcripts, resulting in translational repression or upregulation. We hypothesize that miR-181a, which we found is highly expressed in HpDC, plays a critical role in the tolerogenic properties of pDC. TLR 9 stimulation of pDC from miR-181a-/- mice exhibited higher levels of maturation markers and differential cytokine production as compared to wild-type C57BL/6 mice. More, there is altered phosphorylation of key members of signal transduction pathways, such as ERK1/2. Finally, in the same murine model of cardiac allograft transplantation, use of pDC from miR-181a-/- mice abrograted the tolerogenic properties seen with HpDC. Together, our data shows a critical role for miR-181a in the tolerance-inducing properties of pDC.
Recipient’s monocyte-derived dendritic cells and macrophages play key roles in acute cardiac allograft rejection (TRAN3P.864)
Authors: Divito Sherrie , Liu Qi , Shufesky William , Nakao Atsunori , Rojas-Canales Darling , Wang Zhiliang , Ochoa Juan , Larregina Adriana , Morelli Adrian 
Published: January 2023

Abstract
Donor-derived dendritic cells (DCs) migrating out of allografts into recipient lymphoid organs, and recipient lymphoid-resident DCs within draining lymphoid organs are classically considered the instigators of acute rejection in heart transplants. However, the role of the more recently described CD11cint CD11b+ Ly6C+ monocyte-derived (mo) DCs in acute allograft rejection is unknown. We demonstrate in a mouse model that cardiac allografts are infiltrated by recipient mo-DCs and mo-macrophages, each originating from different subsets of blood monocytes, within one week of transplantation. Graft-infiltrating mo-DCs are the main producers of IL-12p70 and exhibit potent T cell allo-stimulation and Th1 bias. Ablation of DCs after allo-sensitization correlates with reduced T cell proliferation and increased T cell death inside the graft, and prolonged transplant survival. Comparatively, graft-infiltrating mo-macrophages are far less efficient Ag-presenting cells, but release TNF-α and nitric oxide, the latter of which impairs T cell survival and promotes allograft survival. Our results indicate that both recipient mo-DCs and mo-macrophages play key roles during acute rejection within heart allografts, and that these cell subtypes, or potentially their blood monocyte precursors, could serve as therapeutic targets to prevent or treat acute rejection.
Effector T cells adopt fatty acid metabolism in response to environmental factors present at the time of activation (TRAN3P.898)
Authors: Byersdorfer Craig , Tkachev Victor , Goodell Stefanie , Swanson Jacob , Ferrara James 
Published: January 2023

Abstract
Lymphocyte metabolism following in vivo activation remains poorly understood. Compared to naïve cells, allogeneic T cells activated during graft-versus-host disease (GVHD) increased fatty acid (FA) transport (44.3 ±6.9% vs. 0.7 ±0.1%, p=0.003), up-regulated FA oxidation enzymes (e.g. carnitine palmitoyltransferase 1a (CPT1a)), oxidized 3-fold more fat ex vivo (p=0.0001), and increased levels of PGC-1α, an oxidation co-activator (0.9 ±0.2 vs. 0.03 ±0.01, p=0.005). We next examined whether environmental factors influenced a T cell’s metabolic adaptation. OT-I T cells were transferred into irradiated CAG.OVA mice, to recapitulate GVHD, or into naïve C57Bl/6 mice challenged one day later with CAG.OVA dendritic cells (i.e. cellular immunization). Cells proliferated robustly in both models (&gt;10 times by day 7), but only during GVHD did OT-I cells escalate FA transport (40.0 ±6.5% vs. 9.0 ±3.0%, p=0.0002) and up-regulate levels of PGC-1α (1.0 vs 0.09 (p = 0.0004)). Furthermore, inhibiting FA oxidation during GVHD decreased allogeneic T cells by 35% (5.3 ±1.5x10^6 vs.3.4 ±1.2 x10^6, (p=0.01)) and improved GVHD clinical scores, without affecting syngeneic reconstitution. In total, these data demonstrate that effector T cells adopt FA metabolism in response to environmental cues present at the time of activation (e.g. ubiquity of antigen) and we conclude that inhibiting FA oxidation may be a selective means to eliminate pathogenic T cells while preserving homeostatic immune responses.
Targeting sirtuin-1 improves murine renal allograft survival and function (TRAN3P.901)
Authors: Beier Ulf , Wang Zhonglin , Xiao Haiyan , Bhatti Tricia , Hancock Wayne , Levine Matthew 
Published: January 2023

Abstract
Pharmacologic inhibition of sirtuin-1 (Sirt1) augments suppressive functions of Foxp3+ regulatory T cells (Treg) and prolongs murine cardiac allograft survival. We investigated if Sirt1 targeting produced longer allograft function and allograft-dependent survival in a MHC-mismatched renal transplant model. After transplantation of BALB/c kindey allografts into C57Bl/6 wild type or fl-Sirt1/CD4cre recipients, native kidneys were removed three days post-operatively. We followed the mice for survival, and allograft function by weekly serum electrolyte and renal function (BUN, creatinine), as well as hematocrit. We observed, that loss of Sirt1 in T cells led to prolonged median renal allograft-dependent survival from 14 days (IQR: 11-91.25) to 143 days (IQR: 27-147) in wild type controls vs. fl-Sirt1/CD4cre recipients (Mantel-Cox, p&lt;0.0004). In addition, by comparing mice that survived until 13 weeks, loss of Sirt1 in the recipient’s T cells led to improved renal allograft function, with 34.2 ±20 vs. 90.8 ±37.6 mg/dL BUN (p&lt;0.001), and lower creatinine 0.33 ±0.14 vs. 0.61 ±0.3 mg/dL (p&lt;0.001) in fl-Sirt1/CD4cre vs. wild type control mice, respectively. Long-term surviving fl-Sirt1/CD4cre renal transplant recipients (&gt;100 days) became tolerant to antigen re-challenge with a BALB/c, but rejected third-party C3H cardiac allografts. In conclusion, deletion of Sirt1 in T cells is effective at prolonging allograft function and allograft-dependent survival.
Intrathymic innate lymphoid cells: long-lived mediators of immune regeneration (TRAN3P.905)
Authors: Dudakov Jarrod , Yim Nury , Cole Denzel , Mertelsmann Anna , O'Connor Margaret , Jenq Robert , Velardi Enrico , Young Lauren , Hanash Alan , van den Brink Marcel 
Published: January 2023

Abstract
Innate lymphoid cells (ILC) are a newly described population of immune cells implicated in the maintenance and function of tissues as diverse as liver, gut, lung and lymph nodes. We have recently described a key role for ILC, and their production of IL-22, in endogenous thymic regeneration: a crucial process that allows for renewal of immune competence following immune depletion. Unlike other lymphoid cells, ILC were extremely radio-resistant with little depletion of cells after even lethal doses of total body irradiation. Consistent with these findings, a considerable proportion of ILC were non-cycling in steady-state conditions and expressed high levels of the anti-apoptotic protein Bcl-2. Perhaps unsurprising given their resistance to proliferation-targeted damage, a residual population of host ILC could be identified for up to 12 months after hematopoietic stem cell transplantation and these host ILC were almost exclusively non-proliferating. Intriguingly, although IL-22 appears to play a considerable role in their regenerative capacity, depletion of ILC from IL-22 deficient mice led to significantly worse recovery compared to Il22-/- mice replete with ILC. These pre-clinical studies not only help to identify the mechanisms that allow this nascent cell population to mediate its regenerative effects, but also offer a novel clinical approach to enhance T cell immunity in individuals with deficiencies due to aging, infectious disease, chemotherapy or radiation injury
Human IL-10 exacerbates graft versus host disease in NOD-scid IL2rγcnull mice transplanted with human PBMCs (TRAN3P.910)
Authors: Abraham Sojan , Choi Jang Gi , Manjunath N. , Shankar Premlata 
Published: January 2023

Abstract
Dysregulated cytokine production plays an important role in the clinical manifestation of acute graft-versus-host disease (aGVHD) following allogeneic bone marrow transplantation (BMT). The role of IL-10, anti-inflammatory cytokine in GVHD pathogenesis remains ambiguous. There are reports showing both beneficial and adverse effects of this cytokine in GVHD progression. Hence to determine the role of IL-10 in GVHD progression, we expressed hIL-10 in NOD-scid IL2rγcnull mice (NSG) by hydrodynamic gene delivery and evaluated its effect on xeogenic GVHD manifestations. We demonstrate that hIL-10 is capable of accelerating the hPBMC induced xeno-GVHD in NSG mice. The marked human T cell infiltration and tissue destruction observed in presence of IL-10 suggest that human IL-10 potently activates and expands pathogenic human T cells with the capacity to induce xeno GVHD. The significant reduction in the number of human cells at the initial phase and robust expansion at later stage suggests that those escapes IL-10 mediated suppression is responsible for the development of xeno-GVHD. Taken together, our results demonstrate for the first time that xenografted human T cells expand in response to IL-10 and mediate tissue damage in xeno GVHD mouse model. These finding provide caution against using rhIL-10 as an immunosuppressive cytokine after allogenic BMT.
Asymptomatic ocular herpes infections precipitate rapid rejection of corneal allografts (TRAN3P.917)
Authors: Rowe Alexander , Yun Hongmin , Hendricks Robert 
Published: January 2023

Abstract
Most herpes simplex virus type 1 (HSV-1) infected individuals are asymptomatic despite harboring latent virus in their trigeminal ganglia (TG). To determine if these ‘quiet’ infections influence corneal transplant survival we infected the corneas of C57Bl/6 mice with an HSV-1 strain that causes a latent TG infection but no overt corneal pathology. Infected mice received a corneal transplant from syngeneic mice that express ovalbumin (OVA) as a surrogate alloantigen. Graft survival was 9% in infected mice as compared to 58% in non-infected mice. Transcripts for chemokines including CXCL10, CXCL9, CCL5, and CCL2 were significantly elevated, and were significantly reduced by CD4 T cell depletion prior to infection. To assess CD4 T cell antigen specificity irradiated wild type C57BL/6 mice were reconstituted with mixed BM from CD4 KO mice and RAG-/- OT-II transgenic mice so all CD4 T cells were OVA-specific. The chimeras were not infected or received a quiet HSV-1 infection with or without transfer of polyclonal CD4 T cells prior to transplantation of OVA expressing grafts. Graft survival in chimeras was: 100% (non-infected), 60% (quiet infection, no T cell transfer), and 20% (quiet infection with CD4 T cell transfer). We conclude that quiet HSV-1 corneal infections can augment CD4 T cell mediated corneal allograft rejection by increasing chemokine expression in the graft bed and possibly recruiting HSV-specific CD4 T cells into the rejection response.
Autoimmunity as an endogenous source of heterologous alloimmunity (TRAN3P.868)
Authors: Burrack Adam , Nakayama Maki , Landry Laurie , Coulombe Marilyne , Gill Ronald 
Published: January 2023

Abstract
Curiously, although autoimmunity is restricted to self MHC molecules, spontaneously diabetic NOD mice reject MHC-unrelated islet allografts more rapidly than syngeneic (NOD) grafts. We hypothesized that the autoimmune (islet-reactive) T cell repertoire harbors a subset of TCRs that also cross-react to allogeneic MHC molecules. To test this concept, we performed high throughput TCR sequencing of T cells infiltrating MHC-mismatched (C3H, H-2k) islet allografts on the day of rejection in diabetic female NOD mice. TCRs expressed in high frequency in the allograft (&gt;1%) were cloned and tested for islet autoreactivity and/or alloreactivity following TCR cDNA transfection into IL-2 producing hybridoma cells. Of note, three TCRs studied that were the most frequent in the graft were also detected in the endogenous pancreas. All three transfectants expressing these TCRs were islet reactive. Importantly, all three of these TCR also were directly alloreactive to C3H spleen cells. Two of the three TCRs were MHC class I reactive (anti-H-2Dk), and the other was MHC class II-reactive (anti-I-Ak). These results suggest that dual auto/allo-reactive T cells are selectively expanded in islet allografts. As such, we propose that autoimmunity is an unusual source of endogenous heterologous alloreactivity that may accelerate allograft rejection by simultaneous auto- and allo-reactivity.
In-vivo testing of PSMA-targeted T-cell immunotherapy for prostate cancer (TUM7P.920)
Authors: Liu Zhe , Papa Sophie , Morris Jonathan , Maher John 
Published: January 2023

Abstract
Introduction: Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Examining impact of bone metastasis in vivo remains a significant challenge, as animal models that closely mimic the natural history and malignant progression of clinical prostate cancer are not available. Objectives: To develop an animal model of human metastatic prostate cancer. Once a model has been developed and optimized, it was this to test efficacy of immunotherapy using T-cells that have been genetically targeted against prostate-specific membrane antigen (PSMA). Material and methods: PCR, western blot, flow cytometry and ELISA, we performed functional anaylsis of fucosyltransferase 3(FT3) in PC3LN3(PL)and PC3LN3-PSMA (PLP) tumour cell lines. In vivo bioluminescent imaging (BLI) was used to detect metastases. Results: In preliminary studies, we have observed that delivery of a FT3-encoding retroviral vector to PL and PLP enables them to express sialyl Lewis X and to acquire E-selectin binding activity. We also showed that FT3 promotes increased PLP motility and invasiveness in vitro. Bioluminescent animal model of metastasised prostate cancer is established to determine the effect of this upon their pattern of metastatic spread in SCID Beige mice. Conclusion: We have established an in-vivo model of PSMA-expressing prostate cancer. This will serve as a platform to test immunotherapy using P28z+ T-cells.
VCAM-1 enhances immune evasion in a murine model of metastatic cervical cancer (TUM7P.938)
Authors: Huang Alex , Scrimieri Francesca , Tong Alexander , Askew David , Eid Saada , Bobanga Iuliana , Corn David 
Published: January 2023

Abstract
Surface over-expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) was shown to provide a pro-survival advantage in metastatic breast cancer. Similarly, the immune-resistant murine cervical cancer A17 expresses an increased surface VCAM-1 expression compared with the non-metastatic parental tumor, TC1-P0. To test whether VCAM-1 overexpression was responsible for the immune evasive phenotype in A17, we modulated surface VCAM-1 levels on A17 using an shRNA knockdown approach. We inoculated these cells intravenously and subcutaneously into both C57BL/6 and athymic nude mice to interrogate how VCAM-1 affects surrounding immune cell interactions with the tumor, including the use of intravital 2-photon microscopy. VCAM-1lo A17 exhibited reduced growth in C57BL/6 mice but had similar growth kinetics as wild type A17 in nude mice, suggesting an extrinsic T-cell dependent role for tumor-associated VCAM-1 that was responsible for the differences in vivo. Moreover, VCAM-1lo cell lines showed decreased lung metastasis in both immune-competent mice and athymic nude mice, coinciding with changes in M1/M2 polarized macrophages and altered cytokine productions. Together, our results define a functional role for tumor-associated VCAM-1 in helping aggressive tumors circumvent antitumor immune surveillance, and support VCAM-1 as a target for novel immunotherapy against metastatic cervical cancer.
Sensitization of BRAFi- and immune- dual resistant melanomas to immune effector cells through HDACi-mediated regulation of apoptotic machinery (TUM7P.940)
Authors: Jazirehi Ali , Nazarian Ramin , Torres-Collado Antonio , Economou James 
Published: January 2023

Abstract
BRAFV600E-inhibitors (BRAFi; e.g., vemurafenib) and modern immune-based therapies such as PD-1/ PD-L1 and CTLA-4 checkpoints blockade and adoptive cell transfer (ACT) have significantly improved the care of melanoma patients. Having these two effective therapies raises the question whether there is a rational biological basis for using them in combination. We developed an in vitro model to determine whether tumor resistance mechanisms to a small molecule inhibitor of a driver oncogene, and to cytotoxic T lymphocyte (CTL)- and natural killer (NK) cell-delivered death signals were exclusive or intersecting. We generated melanoma sublines resistant to BRAFi vemurafenib and to CTL recognizing MART-1 melanoma antigen. Vemurafenib-resistant (VemR) sublines were cross-resistant to MART CTL and NK cells indicating a common apoptotic pathway governing tumor response to both modalities was disrupted. Pretreatment of VemR melanomas with a histone deacetylase inhibitor restored sensitivity to MART CTL and NK apoptosis by skewing the apoptotic gene programs towards a proapoptotic phenotype. Our findings suggest that during the course of acquisition of BRAFi resistance, melanomas develop cross-resistance to CTL- and NK-killing. Further, aberrant apoptotic pathways, amenable by an FDA-approved chromatin modifier, regulate tumor resistance mechanisms to immune effector cells. These results provide rational molecular basis for further investigations to combine these therapies clinically.