bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apoptotic cell-based therapy to treat collagen-induced experimental arthritis (P5191)
Authors: Perruche Sylvain , Clauzon Amandine , Bonnefoy Francis , Saas Philippe 
Published: January 2023

Abstract
Biotherapies are emerging to treat rheumatoid arthritis (RA). Most of them target a cellular or soluble factor involved in the physiopathology of RA. Here we evaluated whether immunomodulatory properties of apoptotic cells can treat RA. Apoptotic cell approach has been successfully assessed to prevent arthritis development in experimental rat model, as well as in other inflammatory experimental settings. Thus we investigated apoptotic cell injection to treat RA in a mouse model of collagen-induced arthritis (CIA). Four to 8 days after CIA development in susceptible DBA/1, mice presenting arthritic symptoms were treated with apoptotic cells (5.10e6 cell/mouse). As control, methotrexate was used (MTX, 15 mg/kg, twice) alone or with apoptotic cells. Regulatory T cells (Treg) were assessed by FACS at time of sacrifice (day 40/45). Apoptotic cell injection demonstrated a significant decrease of arthritis score (p&gt;0.01; 4 independent experiments), associated with an increased percentage of Treg in the spleen at time of sacrifice. MTX was sufficient to decrease arthritis as well and apoptotic cell injection did not influence MTX efficiency and vice-et-versa. Whereas MTX did not affect the percentage of Treg, MTX + apoptotic cell treatment induced a strong increase of Treg in the spleen and draining lymph nodes. Apoptotic cell injection is an effective treatment to reduce RA severity and should be consider in clinic as an alternative method for biotherapy refractory patients.
Laquinimod suppression of lupus nephritis in BWF1 mice associates in renal tissue with increase of myeloid suppressor cells and switch of macrophages to anti-inflammatory type II (P5193)
Authors: Lourenco Elaine , Wong Maida , Skaggs Brian , Matsuura Isao , Hahn Bevra 
Published: January 2023

Abstract
Background: Laquinimod (LAQ) is a novel drug that has been in clinical trial in systemic lupus erythematosus (SLE), an autoimmune disease characterized by nephritis mediated in part by autoantibodies. Aim: We investigated the immunomodulatory properties of LAQ on lupus nephritis in NZB x NZW F1 (BWF1) mice, a murine model for SLE. Methods: Six-month old BWF1 female mice were treated orally 3 times a week with LAQ 25 mg/kg or water. Results: All LAQ-treated animals survived up to 10 weeks after treatment vs 0% survival in controls. No LAQ-treated mouse had proteinuria by week 10 while it was significantly high (3 g/L) in 100% of controls by week 7 after treatment. Examination of kidney specimens showed significantly decreased histologic inflammation, damage, immunoglobulin and C3 deposition in LAQ-treated vs controls. LAQ significantly reduced macrophages (CD11b+) and their expression of MHC, and these cells produced higher levels of IL-10 and lower TNF-alfa vs controls, a phenotype characteristic of anti-inflammatory type II macrophages. In addition, increased frequency of CD11b+Ly6C+Ly6G+ and CD11b+Ly6C+Ly6G- cells was found in LAQ-treated vs controls and these cells suppressed CD4+ T cell proliferation, what characterizes them as myeloid suppressor cells. Conclusion: LAQ suppressed lupus nephritis, improved animals’ survival and increased both anti-inflammatory macrophages and myeloid suppressor cells. Thus, LAQ is a promising therapeutic for human lupus nephritis.
Therapeutic efficacy of suppressing the JAK/STAT pathway in models of neuroinflammation (P5199)
Authors: Benveniste Etty (Tika) , Qin Hongwei , Liu Yudong 
Published: January 2023

Abstract
T helper cells and myeloid cells are involved in the pathogenesis of Multiple Sclerosis (MS) and Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. The JAK/STAT pathway is used by cytokines for signaling, and is critical for development and regulation of immune responses. Many cytokines involved in MS and EAE, including IL-6, IL-12, IL-23, IFN-γ and GM-CSF, use the JAK/STAT pathway to induce biological responses. As such, targeting JAKs has implications for treating autoimmune inflammation of the brain. We used a JAK1/2 inhibitor, AZD1480, to test the potential of inhibiting the JAK/STAT pathway in EAE. AZD1480 treatment effectively inhibits disease severity in classical, atypical and relapsing-remitting EAE models by preventing entry of immune cells into the brain, suppressing differentiation of Th1 and Th17 cells, deactivating macrophages and dendritic cells, inhibiting STAT activation in the brain, and reducing expression of pro-inflammatory cytokines/chemokines. Suppression of the JAK/STAT pathway was also effective in reducing paralysis induced by transfer of pathogenic Th1 or Th17 cells. In vivo AZD1480 treatment impairs both the priming and expansion of T-cells and attenuates antigen-presentation function of myeloid cells. These results suggest the feasibility of the JAK/STAT pathway as a target for immunomodulatory therapy in MS.
Combinations of inhibitory receptors are expressed on CD8+ T cells in pediatric subjects following bone marrow or umbilical cord blood transplantation. (P2162)
Authors: Soudeyns Hugo , Gravel Catherine , Caty Martine , Mezziani Samira , Le Campion Armelle , Duval Michel , Salem Fourati Insaf 
Published: January 2023

Abstract
Umbilical cord blood transplantation (UCBT) is commonly used to treat a variety of hematologic or neoplastic disorders in children. Compared to bone marrow transplantation (BMT), UCBT is associated with slow engraftment and a higher incidence of graft failure and opportunistic infections. The aim of the present study was to identify immunologic biomarkers expressed by CD8+ T cells during the post-transplant period that predispose patients to develop complications following UCBT or BMT. Pediatric patients who underwent UCBT (n=16) or BMT (n=7) were enrolled at CHU Sainte-Justine. Samples were obtained from graft inoculums and from transplanted subjects during 24 months of follow-up. Expression of inhibitory receptors associated with CD8+ T cell exhaustion (PD-1, CTLA-4, 2B4, TIM-3, BTLA-4, LAG-3) was studied ex vivo using multiparameter flow cytometry. Results showed that inhibitory receptors were expressed at very low levels in UCB graft inoculums. However, in the first 100 days after UCBT or BMT, a notable increase in the frequency PD-1+ CD8+ T cells and 2B4+ CD8+ T cells was observed, and frequencies of PD-1+ and 2B4+ T cells were inversely correlated with absolute CD8+ T cell counts. A low number of CD8+ T cells also co-expressed two or more inhibitory receptors. These results suggest that expression of exhaustion markers by CD8+ T cells in graft recipients during the early post-transplant period may modulate their activity and lead to functional impairment.
Molecular analysis of human HLA-G+ trophoblasts reveals their strong immune regulatory potential (P2172)
Authors: Tilburgs Tamara , Strominger Jack 
Published: January 2023

Abstract
INTRODUCTION: During pregnancy HLA-G+ extravillous trophoblasts (EVTs) play a key role in the prevention of a maternal immune attack to allogeneic fetal tissue. Human EVTs are extremely difficult to study due to their low frequency and lack of proliferative capacity. In this study we obtained robust villous trophoblast (VT) and EVT preparations and performed microarray analysis on RNA isolates. RESULTS: Comparison of the expression profiles revealed &gt;4000 differentially expressed genes based on a 2-fold difference. To identify functional differences a Gene Set Enrichment Analysis (GSEA) was performed. In EVTs, 14 functional gene sets out of the 20 most significantly enriched gene sets were associated with direct immune activation. The core genes of these immune pathways include cytokines (e.g. EBi3, TGFβ and IL8) and cell surface molecules (e.g. B7-H3 and CRTAM) which can all directly influence lymphocyte binding and activation. To evaluate the implications of this immune activating profile, co-cultures of EVT with decidual NK (dNK) cells and decidual T (dT) cells were established. Low percentages of dNK and dT cells form immune synapses with HLA-G+ EVTs. Preliminary analysis of dNK-EVT and dT-EVT co-cultures demonstrates that EVTs influence the expression of activation markers on decidual lymphocytes. CONCLUSION: Our data supports the hypothesis that proper immune activation, rather than general immune suppression, facilitates the establishment of fetal-maternal tolerance.
Skin-specific protection of bortezomib and anti-IL-6 therapy in an acute GVHD model. (P2182)
Authors: Pai Chien-Chun , Tellez Joseph , Hui-Hua Hui-Hua , Sun Kai , Chen Mingyi , Abedi Mehrdad , Murphy William 
Published: January 2023

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is currently viewed as a standard treatment for highly aggressive hematologic malignancies. However, graft versus host disease (GvHD) is a major complication that limits its therapeutic application. Although current therapies suppress GvHD symptoms, they also hinder graft versus tumor effects (GvT). Therefore, there is an urgent need to develop a novel therapy that can dissociate graft versus host disease from graft versus tumor effects. Bortezomib, a proteasome inhibitor, specifically depletes alloreactive T-cells and decreases GvHD symptoms while preserving GvT responses. However, the paradoxical treatment responses, ranging from beneficial in early administration to detrimental in late administration, hinder its clinical application. We hypothesize that serum IL-6 could be a potential biomarker to monitor the treatment response of bortezomib and as an indicator of GvHD pathology. We demonstrated serum IL-6 levels specifically correlated with skin GvHD responses but not liver or gut GvHD. By applying bortezomib or anti-IL-6 therapy, we observed skin specific protection in our GvHD model. This study demonstrated the importance of IL-6 regulation by bortezomib as well as its role in tissue specific GvHD pathology. These findings have clinical implications in selecting the appropriate patient population for bortezomib and/or anti-IL6 clinical trials for skin GvHD patients.
T cell responses to Epstein Barr Virus infections in pediatric organ transplant recipients (P2196)
Authors: Lin Dongxia , Piard-Ruster Karine , Esquivel Carlos , Martinez Olivia , Maecker Holden 
Published: January 2023

Abstract
Pediatric organ transplant recipients are at highest risk of developing morbidity and mortality from EBV infection. There is broad consensus that T cell immunity is important in controlling viral replication and expansion of infected B cells. In this study, we simultaneously analyze virus-specific T cells’ phenotypes, functions, and epitope specificity using 37-parameter mass cytometry in the setting of pediatric organ transplant recipients, followed over the first two years post-transplant. We compared T cell responses to peptide pools derived from lytic and latent EBV antigens in both healthy EBV+ donors and pediatric transplant patients. The results suggest that healthy EBV+ donors can mount CD8+ T cell responses to both lytic and latent EBV antigens, with production of multiple cytokines. In contrast, pediatric patients have much weaker T cell responses, especially to lytic antigens. Based on current data, we hypothesize a polyfunctional T cell response to lytic antigens may preferentially protect against EBV viremia. We also use the SPADE algorithm for unsupervised clustering to compare the distribution of different T cell subsets in cytokine-producing cells. In addition, we analyze these T cells’ functional capacity for cytokine production by visualization in a heatmap. By employing highly multi-parameter mass cytometry and longitudinal sampling, we have created a more detailed picture of the T cell responses to EBV in the setting of pediatric transplant recipients.
miR-338-5p indirectly regulate BAFF signal by targeting TRAF3 during renal allograft antibody-mediated rejection (P2200)
Authors: Xu Haiyan , He Xizhou , Xu Renfang , Xu Xianlin , Jiang Jingting , Wu Cangping , Zhang Yanyun , Zhang Xueguang 
Published: January 2023

Abstract
Objective: To investigate the regulation mechanism of B cell activating factor (BAFF) signal during antibody-mediated renal allograft rejection (ABMR), microRNAs chip assay and further studies were carried out. Methods: The renal allograft tissues were diagnosed according to Banff'2005 criteria. MicroRNA chip assay was done (tested group: 4 ABMR tissues with high expression of BAFF and C4d; controlled group: 4 IF-TA tissues with no expression of BAFF and C4d). 20 other renal allograft tissues were chosen for differentially expression microRNAs testification, and TRAF3, BAFF and BAFF-R detection by IHC. Dual-lucifirase assay and further functional experiments were taken. Results: microRNA chip assay indicated that miR-200c, miR-30c, let-7b, miR-30b, and 7 other microRNAs were differentially up-regulated and only miR-338-5p was significantly down-regulated. Combing with research background, bioinformatics analysis suggested that TRAF3 was the target gene of miR-338-5p and only regulated by miR-338-5p, which was testified by luciferase assay. The real-time PCR data indicated that miR-338-5p was significantly down-regulated in ABMR tissues, and inversely correlated with BAFF, BAFF-R and TRAF3 (these three molecules high expressed in ABMR tissues). And miR-338-5p mimics and inhibitors can seperately stimulate and inhibit IgG secretion by tonsil B cells in vitro. Conclusions: miR-338-5p participate in ABMR by indirectly regulating BAFF signal via targeting TRAF3.
Ex-vivo expansion and characterization of naturally occurring CD4+CD25+Tregs in rhesus monkey (P2204)
Authors: Kim Jung-Sik , Lim Hyun Ju , Nam Hae Young , Kong Na Rae , Park Chung Gyu 
Published: January 2023

Abstract
Regulatory T cells (Treg) offer potential for improving long-term outcomes in cell and organ transplantation. The non-human primate (NHP) model has been a valuable resource to bridge Treg therapy to the clinic. Here we address the highly effective Treg expansion protocols and phenotypic and functional characteristics of rhesus monkey. Rhesus monkey CD4+CD25+FoxP3+Treg cells exists 2-5% in CD4+T cells in blood. Around 1-2% of CD4+CD25high population in CD4+T cells were enriched by FACSAria III and cultured, simultaneously stimulated with antiCD3/antiCD28 antibody, in the presence of hIL-2, TGF-beta and irradiated autologous CD4-T cells for 14 days. The CD4+CD25+FoxP3+Treg cells expanded from 400 to 1200 times during two round stimulations. Expansion was far retarded during third round stimulation. Expansion rates were greatly affected by the initial ratio of Treg cell to autologous CD4-T cells. Phenotypically expanded Treg are CD25+CD95+CD27+CD47+FoxP+Treg cells. CCR7, LN-homing receptor, was expressed by 70%. In contrast, inflammatory cytokines including IL-17 and IFN-r were minimally expressed by 0.4% and 1.8%, respectively. Expanded Tregs were able to suppress the monkey CD4+CD25-T cell proliferation at even 1: 32 ratio of T regs to T effector cells. These finding suggests that ex-vivo expanded Treg cells may be promising modalities to overcome cell-mediated graft rejection in preclinical transplantation model.
Apoptotic cell injection-induced tolerance preserved graft versus leukemia effect (P2206)
Authors: Perruche Sylvain , Chauchet Adrien , Vallion Romain , Bonnefoy Francis , Saas Philippe 
Published: January 2023

Abstract
Allogeneic hematopoietic cell transplantation (AHCT) is a curative therapy for hematological malignancies unfortunately limited by graft-versus-host-disease (GvHD) occurrence. We have demonstrated that apoptotic cell injection can favor tolerance due to their immunomodulatory properties and thus increase engraftment and limit GvHD, through TGF-β and regulatory T cell dependent mechanisms. However, since apoptotic cell injection favors tolerance we evaluated whether graft-versus-leukemia (GvL) was preserved. In an experimental mouse model of T cell-depleted bone marrow transplantation (TCD BMT), leukemic A20 luciferase+ cells were injected at d0 and allogeneic donor T cell infusion was given on d6. Apoptotic cells were injected either on d0 or d6. Eradication of leukemic cells was observed in all mice receiving T cells, as attested by tumor growth evaluated by luminescence. Mice not receiving T cells died from leukemia within 27 days. Mice demonstrating GvL also developed GvHD according to Ferrara's score, and only 27% survived at d27. In contrast, 50% of mice receiving apoptotic cells on d0 or d6 survived at d27 and demonstrated long-term GvL with the complete absence of leukemic cell growth. Our data clearly demonstrated that GvHD suppression by apoptotic cell injection does not abrogate GvL activity. Thus, apoptotic cell injection should be considered in clinic to favor engraftment, prevent GvHD, conserving high GvL therapeutic activity.
iPS cells but not their hematopoietic derivatives are immunogenic in the autologous recipient (P2210)
Authors: Zavazava Nicholas , Kim Eun-Mi 
Published: January 2023

Abstract
Induced pluripotent stem (iPS) cells are derived by reprogramming somatic cells, mostly fibroblasts. Since these cells can be generated from patients, the asuumption is that when the cells are transplanted back to the donor, immunological rejection can be ruled out. However, recently a manuscript showed that in fact iPS cells are rejected by "self". This result was unexpected and might significantly impact the use of iPS cells clinically. Here, we hypothesized that iPS cells are immunogenic to "self" because they express carcinogenic/embryonic antigens that are not expressed on somatic cells. Consequently, we argued that iPS cell derivatives lose the ability to express these antigens and should therefore be non-immunogenic to "self". To address this question, 129SvJ iPS cells or 129SvJ ES cells were subcutaneously injected in 129 SvJ mice, respectively. After 4 weeks, teratomas were visible in mice that had been injected with ES cells but not in mice injected with iPS cells, suggesting that iPS cells had been rejected. iPS cells were then used to derive hematopoietic progenitor cells. When these cells were infused intravenously, they easily induced long-term mixed chimerism, suggesting that non-differentiated iPS cells but not their derivatives are immunogenic to"self". Interestingly, ES cells were also rejected in" iPS-sensitized" but not in naive mice. Rejection was mediated by T cells.
Enhanced pro-inflammatory profile and Th17 alloresponse by targeting mTORC2 in DC (P2138)
Authors: Raich-Regue Dalia , Rosborough Brian , Lee Keunwook , Boothby Mark , Turnquist Heth , Thomson Angus 
Published: January 2023

Abstract
Mammalian target of rapamycin (mTOR) is an important integrative kinase that regulates immune cell function. mTOR functions in two independent complexes: mTOR complex (mTORC) 1 and 2. The immunosuppressant Rapamycin inhibits mTORC1 but not mTORC2. Our aim was to study the immune regulatory role and underlying mechanistic properties of mTORC2 in DC. We generated a conditional mTORC2 knockout, targeting Rictor. Bone marrow cells were obtained from KO and WT B6 controls, and DC propagated in the presence of IL-4 and GM-CSF, with or without LPS. The phenotype, cytokine production, STAT3 activation and ability of DC to induce allogeneic T cell proliferation were evaluated, and also the responder T cell phenotype and cytokine production. DC differentiation was not affected, while DC yield was slightly reduced in mTORC2-deficient BM cultures compared with WT controls. DC lacking mTORC2 activity displayed similar levels of MHC and co-stimulatory molecules, but diminished B7-H1 expression, increased levels of IL-12p40, diminished STAT3 activation and higher T cell stimulatory ability following LPS stimulation, compared with WT. Staining of allogeneic T cells stimulated by Rictor-KO DC revealed more CD4+IL-17+ cells than those stimulated with WT DC. These novel data indicate that DC lacking mTORC2 activity exhibit an enhanced pro-inflammatory profile with ability to promote Th17 responses. Thus, targeting mTORC2 provides new insight into molecular regulation of DC function.
T-bet is critical for development of acute graft-versus-host disease through controlling T cell differentiation and function (P2142)
Authors: Yu Xue-Zhong , Fu Jianing 
Published: January 2023

Abstract
T-bet is a master regulator for the differentiation into Th1 cells that produce IFN-γ. We evaluated the roles of T-bet and IFN-γ in acute graft-versus-host disease (GVHD) using murine model of allogeneic bone marrow transplantation (BMT). IFN-γ-/- CD4 T cells caused similar GVHD compared with WT cells, whereas T-bet-/- CD4 T cells induced significantly ameliorated GVHD. Recipients of T-bet-/- donor T cells had markedly reduced T cell infiltration and tissue damage in liver and gut, and they produced significantly lower levels of IFN-γ, TNF-α, and IL-2 but higher IL-10, IL-6 and IL-4 in serum. T-bet-/- CD4 T cells expressed significantly less IFN-γ, CXCR3 and CD122, but more IL-17 and CCR6 compared with WT CD4 T cells, indicating that T-bet-/- T cells impaired in differentiating into Th1 but not Th17 cells. IFN-γ-/- Th17 cells had a comparable ability to cause GVHD compared with WT Th17 cells, while T-bet-/- Th17 cells had a significantly reduced pathogenicity. Microarray analysis identified genes that are regulated by T-bet but independent of IFN-γ, including Cxcr3, Ccr5, Ccl3, Ccl4, Klrc1, Klrd1, Nkg7 and Pdcd1, which may explain the compromised ability of T-bet-/- not IFN-γ-/- T cells in the induction of GVHD. We conclude that T-bet is required for Th1 differentiation and migration, and contributes to optimal function of Th17 cells. Targeting T-bet or regulating its downstream effectors independent of IFN-γ may be a promising strategy to control GVHD in clinic.
JNK2 has distinct roles in CD1d-dependent and CD1d-independent activation of NKT cells (APP3P.112)
Authors: Liu Jianyun , Gallo Richard , Khan Masood , Iyer Abhirami , Kratzke Ian , Brutkiewicz Randy 
Published: January 2023

Abstract
CD1d-mediated activation of NKT cells plays critical roles in auto-immune, anti-tumor and anti-microbial immune responses. Our previous work has shown that activation of the p38 mitogen-activated protein kinase (MAPK) pathway impairs, whereas the ERK MAPK pathway enhances, CD1d-mediated Ag presentation to NKT cells. In the current study, we found that, like p38, the JNK MAPK pathway is a negative regulator of CD1d-mediated Ag presentation. Moreover, activation of the JNK2 (but not JNK1) isoform was responsible for the reduction in CD1d-mediated Ag presentation observed. Unexpectedly, a deficiency in JNK2 (but not JNK1) in mice resulted in fewer NKT cells. We have previously shown that viral infections result in a CD1d-independent loss of NKT cells. When JNK2-deficient (KO) mice were infected with vaccinia virus, the virus-induced loss of NKT cells was substantially lower than that observed in JNK1 KO or WT mice. Furthermore, NKT cells from JNK2 KO mice expressed a slightly lower level of IL-12 receptor (IL-12R) expression on the surface. In vivo administration of IL-12 (which can induce apoptosis of WT NKT cells) to JNK2 KO mice resulted in less NKT cell loss than that observed in IL-12-treated WT littermates. Overall, our work strongly suggests that JNK2 (but not JNK1) plays an important role as a negative regulator of CD1d-mediated Ag presentation and also contributes to the virus-induced loss of NKT cells.