bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD103 blockade reduces CD8 T cell accumulation during GVHD, but does not attenuate GVL effects. (169.35)
Authors: Anthony Bryan , Hamadani Mehdi , Wang Jiao-Jing , Gaughan Alice , Hadley Gregg 
Published: January 2023

Abstract
Graft versus host disease (GVHD) remains the salient barrier to broader use of hematopoietic stem cell transplantation (SCT) as a curative therapy for hematological malignancy. Although multiple means exist to neutralize donor-reactive T cells, such strategies have the potential to inhibit graft-vs-leukemia (GVL) effects, leaving the host vulnerable to relapse. The goals of the present study were: 1) to define the role of CD103 in promoting accumulation of donor CD8 T cells in the host gut following SCT, 2) assess the role of CD103 in promoting GVL effects. Following CD4 depletion, donor specific CD8 T cells selectively accumulated in the host gut epithelium in either MHC-matched or MHC-mismatched SCT models. Moreover, CD103 expression by CD8 T cells increased dramatically over time in both models. BLI studies revealed that CD103 expression is required for efficient accumulation of donor CD8 T cells in the host gut. BLI studies using TCR transgenic CD8 T cells co-expressing luciferase revealed that host-specific CD8 T cells preferentially accumulate in the host gut (as compared to the host spleen) during GVHD. Using a model of human chronic lymphocytic leukemia (CLL), we found that CD103 was not required for effective clearance of malignant B cells. These data indicate CD103 deficiency selectively attenuates GVHD pathology without compromising GVT effects, identifying CD103 as a potential target for GVHD prophylaxis.
Latent membrane protein 1 of Epstein Barr Virus alters cellular microRNAs in B cell lymphomas (169.37)
Authors: Harris Aleishia , Lambert Stacie , Krams Sheri , Martinez Olivia 
Published: January 2023

Abstract
Epstein-Barr Virus (EBV) infection is usually benign but immunodeficiency can lead to B cell lymphomas such as Post-Transplant Lymphoproliferative Disease (PTLD). PTLD is associated the expression of the EBV oncogene latent membrane protein 1 (LMP1). MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression. We hypothesized that LMP1 signaling in EBV+ B cell lymphomas can modulate cellular miRNA expression as a mechanism to promote viral persistence and/or host cell survival. Using an inducible, chimeric LMP1 signaling system we analyzed miR expression in a B cell lymphoma cell line after activation of LMP1 variants isolated from PTLD patients and from the B95.8 form obtained from a mononucleosis patient. The expression of 747 miRs was assayed by qPCR array and 323 miRs were detected. B95.8 LMP1 activation modulated 50 total miRs including miR503, linked to inhibition of proliferation in epithelial cells. The PTLD-derived LMP1 variants modulated 59 distinct miRs. These included pro-apoptotic miR29b which was down-regulated by PTLD-derived LMP1 variants but not by B95.8 LMP1. These data indicate that PTLD-derived forms of LMP1 uniquely alter cellular miR as compared to B95.8 LMP1. Thus, study of the functional properties of LMP1 variants may provide insight into mechanisms of lymphomagenesis.
Human and mouse natural killer cell cytotoxicity towards embryonic stem cells (169.41)
Authors: Peter Anna , Ames Erik , Zhou Ping , Nolta Jan , Murphy William 
Published: January 2023

Abstract
Embryonic stem cells (ESC) have tremendous potential for the treatment of numerous diseases but little is known regarding the immune response towards them. Human ESC (hESC) express very low levels of MHC class I, rendering them resistant to T cell-mediated rejection but making them likely targets of natural killer (NK) cells. As clinical use of MHC-matched ESC is unlikely, we examined the susceptibility of ESC to NK cell mediated killing. We tested the ability of activated human NK cells from several different donors to lyse the H9 hES cell line in vitro. Activated peripheral blood NK cells achieved significant H9 killing in a 4 hour chromium release assay. Similar experiments using mouse ES cell lines (JM8A3.N1, B6 background) with syngeneic (B6) or allogeneic (BALB/c) activated NK effector cells showed significant mouse ESC killing, regardless of NK cell source. This could be explained by very low MHC class I expression on the ESC targets leading to NK cell-mediated lysis due to lack of MHC class I, rather than allogeneic recognition. Experiments determining mouse ESC in vivo clearance by NK cells are under way. Together these data underscore the susceptibility of human and mouse ESC to NK cell-mediated lysis. This suggests that therapeutic applications of ESC are susceptible to host NK-cell mediated resistance.
Dendritic cells facilitate thymic recovery and hasten immune reconstitution after hematopoietic stem cell transplantation (169.44)
Authors: Langfitt Deanna , Busby Ken , Parish Colleen , Dallas Mari 
Published: January 2023

Abstract
The well-established role of dendritic cells in antigen presentation demonstrates their important role in development of T cells. In hematopoietic stem cell transplantation (HSCT) donor T cells are essential for engraftment, immune reconstitution, and graft vs. leukemia effect. Surprisingly, the role of Dendritic cells (DCs) in facilitating donor engraftment of hematopoietic stem cells has not been studied. Previously, we have demonstrated the importance of ex vivo expanded regulatory T cells (Tregs) in facilitating thymic engraftment after HSCT. Here we show the addition of dendritic cells given simultaneously with murine stem cells significantly improves engraftment after HSCT. Histological analysis demonstrated that thymic recovery was faster and more robust when dendritic cells were administered along with hematopoietic stem cells (HSC). Cell recovery and immune reconstitution was observed to occur more quickly in the thymus, spleen, bone marrow, and peripheral blood in experimental samples given additional DCs in HSCT. FACS analysis also confirmed immune reconstitution and donor cell engraftment was faster and increased survival was observed in experimental animals given DCs as well as stem cells. We hypothesize that the additional DCs establish themselves in the recipient thymus and assist in educating donor T cells, hastening immune reconstitution and improving cell engraftment.
Applying systems biology to develop T cell tolerance: Jurkat cell responses to knockdown hub genes using siRNA in-vitro transfection (169.47)
Authors: Lwin Wint , Park Ken , Wauson Matt , Gao Qin , Perkins David , Khanna Ajai 
Published: January 2023

Abstract
Introduction: Systems biology is increasingly gaining importance in studying complex genome wise associations and will, in future, integrate into personalized medicine. Aim: To study the effect of T cell lipotransfection by certain hub genes and evaluate their role in inducing T cell anergy. Methods: Using publically available gene-gene interactions, we constructed a network using an open bioinformatics software platform for visualizing molecular interaction networks to identify the following upregulated hub genes: ATP5C1, IL6ST, PRKCZ, MYC, FOS, JUN and MAPK1. We hypothesized that suppression of hub genes in the gene network would result in significant phenotypic effects on T cells resulting in T cell hyporesponsiveness and examined this in-vitro. Jurkat and HeLa cells were transfected with siRNA for the selected hub genes. Cell proliferation was measured using ATP luminescence and BRDU labeling. Results: We found a significant decrease in ATP production by Jurkat cells (P&lt;0.05) when the hub genes ATP5C1 and PRKCZ were knocked down using siRNA transfection. No difference in ATP production was observed in siRNA transfected HELA cells. However, these cells showed a significant (P&lt;0.05) decrease in cell proliferation when the genes MAPK1, IL6ST, ATP5C1, JUN and FOS were knocked down using siRNA. This experiment provides proof of principle of applying a systems biology approach in identifying hub genes for targeted therapeutics in transplant immunology.
CD200+ graft-infiltrating APCs are sufficient for induction of tolerance to skin allografts (169.8)
Authors: Gorczynski Reginald , Yu Kai , Chen Zhiqi , Khatri Ismat 
Published: January 2023

Abstract
CD200, a molecule of the immunoglobulin supergene family, increases graft survival and suppresses inflammation/acquired immunity after binding to its receptors (CD200Rs). Skin and cardiac allograft survival is increased in transgenic mice over-expressing CD200 under control of a doxycycline-inducible promoter, (CD200tg), along with increased intra-graft expression of mRNAs for genes which alter T cell subset differentiation. We found a decreased ability of CD11c+ or CD11b+ APCs from CD200tg recipients at days 7/14 to induce CTL from control lymph node cells in vitro, and increased induction of Foxp3+Treg by the same APCs. Focused gene array and real-time PCR measurements confirmed that with increased graft survival in CD200tg mice altered chemokines/cytokines expression occurred, in particular of IL-9, a mast cell growth factor. Mast cells infiltrated grafts of control animals also, but in these mice evidence of degranulation was apparent, and fewer Foxp3+Treg were present than in the case of CD200tg mice, where no degranulation was observed. Infusion of a competitive inhibitor of CD200:CD200R interactions, CD200tr, at high concentrations (50μg/mouse iv) caused rapid rejection of grafts in CD200tg mice, with evidence of mast cell degranulation within graft tissue. We conclude that allergic-type responses can break peripheral tolerance with induction of episodes of acute T-cell-mediated inflammation.
Enhanced cardiac allograft survival by TNFRSF25 expanded natural Treg cells in an allogeneic mouse model (169.9)
Authors: Wolf Dietlinde , Li Sen , Schreiber Taylor , Tryphonopoulos Panagiotis , Tzakis Andreas , Ruiz Phillip , Podack Eckhard 
Published: January 2023

Abstract
Thymic derived Foxp3+CD4+ regulatory T cells (Treg) - also called natural Treg or nTreg - are critical for the induction and maintenance of transplantation tolerance. Using an agonistic TNFRSF25 antibody, clone 4C12, we recently showed that TNFRSF25 is a powerful regulator of Treg proliferation in vivo mediating expansion of natural Treg cells in vivo to 30-35% of the CD4+ cells. In the present study we investigate the role of TNFRSF25 expanded Treg cells on cardiac allograft survival in a fully MHC mismatched heterotopic heart transplant mouse model. A single administration of 20 μg of 4C12 antibody four days prior to cardiac transplantation resulted in a significant prolongation of median graft survival to 18 days. On day 7 after transplant - the timepoint when controls reject the graft - the grafts of 4C12 treated animals beat strongly, which was associated with the infiltration of 40% FoxP3+ cells to the graft compared to only 10% FoxP3+ cells out of all CD4+ cells in rejecting controls. A 4-fold upregulation of Foxp3 mRNA in the graft of 4C12 treated mice compared to controls confirmed the increased presence of regulatory cells. We further detected a 3-fold increase of TNFRSF25 mRNA in grafts of 4C12 treated animals. Finally, the combination of 4C12 with the costimulation blocker CTLA4-Ig has synergistic effects on cardiac graft survival. These data highlight the therapeutic potential of preventing allograft rejection using TNFRSF25 agonists to modulate Treg function.
Low molecular weight forms of chicken IgM (170.6)
Authors: Koppenheffer Thomas 
Published: January 2023

Abstract
Low MW Igs with truncated heavy chains have been described in a small number of reptilian species and anseriform birds. While these shortened Abs can bind Ag, their immunological significance is not understood since they are unable to mediate effector functions performed by full-length Ig. We isolated a low MW form of IgM from chicken serum by gel filtration chromatography. The low MW IgM was present in both adult heparinized plasma and EDTA-plasma containing protease inhibitors, but was not detected in sera of 2-3 week old birds. Thus it is unlikely that low MW IgM was derived from the native pentamer/tetramer by proteolytic fragmentation. Low MW IgM retained biologic activity as a partially purified isolate prepared from anti-DNP antisera exhibited hapten binding as determined by ELISA. SDS-PAGE of serum under non-reducing conditions followed by Western Blotting using a polyclonal goat anti-mu chain Ab revealed two low MWspecies of about 260 and 160KD. Both low MW forms were detected by Western Blotting with a monoclonal anti-mu chain and anti-L chain Abs, but only the larger form was detected with a second anti-mu chain Ab. These observations suggest the possibility that at least the smaller of the low MW IgM species contains a truncated heavy chain.
pDCs and IL-4+ T-cells in scleroderma as novel targets of imatinib mesylate (44.18)
Authors: Divekar Anagha , Khanna Dinesh , Abtin Fereidoun , Maranian Paul , Saggar Rajeev , Saggar Rajan , Furst Daniel , Singh Ram 
Published: January 2023

Abstract
Fibrosis is the end-result of many inflammatory conditions. Using scleroderma-associated interstitial lung disease (SLD) as a model fibrotic disease, we investigated cellular mediators of fibrosis in an open-label trial of imatinib mesylate (imatinib), a tyrosine kinase inhibitor. At baseline, high-resolution computer tomography (HRCT) findings of SLD strongly correlated with plasmacytoid dendritic cells (pDC) and IL-4-producing (IL-4+) T-cells in bronchoalveolar lavage (BAL) from individual lung lobes. pDC and IL-4+ and CD4+ T-cells in BAL correlated with each other, and with molecules CCL24, Nampt, PAI1-active, and PDGF-AB, which can recruit/activate leukocytes, smooth muscle cells and collagen-producing cells. pDCs also correlated with IL-3 and M-CSF. One-year post-imatinib, lung pDC and IL-4+ T-cells were significantly reduced. Interestingly, CD4+ T-cells increased along with soluble ICAM-3 and PECAM-1, except in one patient who showed worsened SLD. Thus we envision a role for pDCs in SLD, and propose that IL-3/M-CSF induce differentiation and maturation of pDCs that mediate local T-cell infiltration and differentiation into IL-4+ T-cells and promote fibrosis. Further elucidation of this axis and how drugs such as imatinib intercept it may identify targets to counter fibrosis that invariably leads to end-organ failure.
Exosome-like microparticles can stimulate both innate and adaptive autoimmunity in non-obese diabetes mice (44.20)
Authors: Dai Yang , Sheng Huiming , Hassanali Saleema , Nugent Courtney , Wen Li , Hamilton-Williams Emma , Dias Peter 
Published: January 2023

Abstract
Exosomes (EXO) are secreted intracellular microparticles that can trigger inflammation and induce antigen-specific immune responses. To test possible roles of EXO in autoimmunity, we isolated EXO from mouse insulinoma and examined their activities to stimulate the autoimmune responses in NOD mice, a model for human type 1 diabetes. We demonstrate that the EXO contains strong innate stimuli and expresses candidate diabetes autoantigens; it can activate splenocytes or purified APC through MyD88-dependent pathways, and result in T cell proliferation. To address whether exosomal antigens could be targets of the islet-specific autoimmunity, we monitored the spontaneously developed memory response in NOD mice for its reactivity to the EXO and compared the response with resistant strains. We found that older NOD females, which have advanced islet destruction, accumulated more EXO-reactive, IFN-gamma-producing lymphocytes than younger females or age-matched males, and that pancreatic lymph nodes of NOD but not resistant strains were enriched with EXO-reactive Th1 cells. Importantly, high titer of EXO-binding antibodies was also detected in serum of the NOD females but absent in resistant strains. Thus, certain exosomal antigens can be recognized by the autoreactive T cells and autoantibodies that are spontaneously developed in prediabetic NOD mice, supporting that EXO might be a possible autoimmune target in this diabetes-susceptible strain.
Anti-U1 autoantibody interferes with the U1RNP-mediated splicing of Angiopoietin-1 gene and induces functionally defective Ang-1/ins variant in the patients with MCTD (44.3)
Authors: Komai Koichiro , Hashiramoto Akira , Shiozawa Kazuko , Shiozawa Shunichi 
Published: January 2023

Abstract
Purpose: Angiopoietin-1 (Ang1) is the ligand of endothelial tyrosine kinase receptor Tie2. We showed that the frequency of the splicing variant of Ang1 with nt805GGT insertion (Ang1/ins) was significantly increased in the Japanese MCTD and those with PH (Arth. Rheum. 52: S283, ‘05). We also found that Ang1/ins proliferate pulmonary endothelial cells and potentially induce hyperplasia of smooth muscle cell in relation to the pathogenesis of PH as compared with Ang1/del (Arth. Rheum. 60: S8, ‘09). We have now studied the contribution of subclass of Abs against each U1 compoments to the induction of Ang1/ins. Methods: Anti-U1A, C and 70K Abs were introduced into human pulmonary artery smooth muscle cells using PULS-in (Polyplus) with IL6 and TNFα (20ng/ml each). Ang1 mRNA was obtained by RT-PCR. Anti-U1RNP Ab titer in sera of Japanese MCTD was determined by ELISA. Results: Anti-U1C and 70K Abs significantly induced Ang1/ins (P&lt;0.05). Frequency of the patients having anti-U1RNP Ab titer exceeding 200 was 81.3% (39/48) and 50.0% (6/12) (P&lt;0.05) among those with Ang1/ins dominant and Ang1/del dominant. The titer of each subclass of anti-U1RNP Ab in the sera of patients among those with Ang1/hetero (n=13) and Ang1/ins dominant (n=18) was: 11.8±23.6 and 47±58.9 (P&lt;0.05) for anti-U1A, 13.6±25.7 and 122.1±124.5 (P&lt;0.005); for anti-U1C, 406.2±599.5 and 5512.9±12484.7 (n.s.); for anti-U1-70K. Conclusions: It is suggested that anti-U1C Ab specifically affect the splicing of Ang1.
Antigen-independent recruitment of CTL to pancreatic islets expressing an NKG2D ligand (44.38)
Authors: Markiewicz Mary , Wise Erica , Buchwald Zachary , Pinto Amelia , Shaw Andrey 
Published: January 2023

Abstract
The mechanisms by which CTLs enter and are retained in non-lymphoid tissue are not well-characterized. Using a novel transgenic mouse expressing the NKG2D ligand RAE1ϵ in β-islet cells of the pancreas, we found RAE1 expression was sufficient to induce the recruitment of adoptively transferred CTLs to islets. This was dependent on NKG2D expression by the CTLs and independent of antigen recognition. While transgenic mice did not develop diabetes, RAE1 expression was sufficient to induce insulitis in older, unmanipulated transgenic mice that was enhanced by viral infection and pancreatic inflammation. Surprisingly, the recruitment of CTLs resulted in the subsequent recruitment of a large number of endogenous lymphocytes. These results demonstrate that the expression of NKG2D ligands in islets is sufficient to recruit CTLs and induce a significant insulitis.
IFNα causes systemic lupus erythematosus and possibly mediates self-organized criticality theory of autoimmunity (44.47)
Authors: Shiozawa Shunichi , Akiyama Chieri , Honda Eriko , Miyazaki Yumi , Tsumiyama Ken 
Published: January 2023

Abstract
Objectives: The pathogenesis of SLE is unclear. Overstimulation of CD4 T cells by antigen led to the development of autoantibody-inducing CD4 T (aiCD4 T) cell capable of inducing autoantibodies and lupus tissue disease. In this novel ‘Self-organized criticality theory of autoimmunity’, we noted that aiCD4 T cell is induced via de novo TCR revision. We now test IFNα as a mediator for the induction of aiCD4 T cell to cause SLE. Methods: Mouse IFNα gene controlled under TetOp promoter was microinjected into eggs of C57BL/6 to generate TetOp-mIFNα Tg mice. They were mated with EμSR-tTA Tg mice, expressing doxycycline-transactivator (tTA) gene under the control of IgH chain enhancer and SRα promoter, to obtain double Tg mice. Results: By increasing IFNα, anti-dsDNA antibody and immune complex (IC) were generated. Pathological lesions consisted of IC-deposited glomerulonephritis, interstitial lung disease, alopecia, liquefaction and positive skin lupus band test, onion skin splenic lesion, and inflammatory infiltrates to salivary gland and bile duct. There was an increase in IFNγ-producing effector CD4+, full-matured CD8+ CTL, and activated CD3+CD4-CD8- double negative (DN) T cells. The DN T cells not only infiltrated to the glomerular lesions of mice, but also induced de novo glomerulonephritis and alopecia when transferred into naïve recipients. Conclusions: IFNα is responsible for the core manifestation of SLE, and may induce lupus tissue injury via DN T cells.
A role for CD8+ T cells in an autoantibody response (44.7)
Authors: Hoyer Katrina , Isakson Sara , Abbas Abul 
Published: January 2023

Abstract
IL-2-deficient mice develop a spontaneous systemic autoimmune disease and on the BALB/c background die at 3-4 weeks due to hypoxia from autoimmune hemolytic anemia (AIHA). These mice develop progressive lymphadenopathy due to the accumulation of CD4+ and CD8+ T cells. It is known that CD4+ T cells are necessary for disease progression and we have previously shown that IL-2-KO CD4+ T cells from sick mice can transfer AIHA and lymphadenopathy to recipient mice. As CD8+ T cells also accumulate during disease, we asked whether these cells play a role in the development of autoimmune disease. To address this, we depleted CD8+ T cells by treating mice twice a week with anti-CD8α (clone 2.43). Elimination of CD8+ T cells for two weeks resulted in an augmentation of survival from 3-4 weeks to 3 months. The number and activation state of the CD4+ T cells and B cells was decreased, and the development of red blood cell (RBC)-specific antibodies delayed. Our results suggest that autoreactive CD8+ T cells contribute to the initiation and/or propagation of lymphoproliferation and pathogenesis of autoimmunity. Both CD4+ and CD8+ T cells from the IL-2-deficient mice produce IFNγ in response to RBC antigens. We are currently addressing the importance of these autoreactive CD8+ T cells relative to that of the self-reactive CD4+ T cells. We are also evaluating the possible mechanisms by which CD8+ T cells influence the disease process.
Human Fc receptor-like 5 promotes B cell proliferation and the development of cells displaying surface IgG and IgA (45.10)
Authors: Tolnay Mate , Dement-Brown Jessica , Newton Christopher , Ise Tomoko , Nagata Satoshi 
Published: January 2023

Abstract
The functional roles of B cell membrane proteins belonging to the Fc receptor-like (FCRL) family are unclear. However, the demonstrated signaling capacities of FCRL suggest co-receptor functions that modulate B cell receptor (BCR) signaling. Nevertheless, the subsequent functional consequences of FCRL engagement are unknown. Using naive B cells obtained from peripheral blood of human subjects, we show that while FCRL5 surface protein is not present on resting cells, it is temporarily induced following BCR stimulation. Co-stimulation of FCRL5 and the BCR on B cells induced to express FCRL5 significantly enhanced proliferation in the presence of toll-like receptor 9 agonists. The same combination of stimuli led to the development of high proporsion of cells expressing the switched isotypes IgG and IgA on their surface. Optimal development of cells expressing downstream isotypes also required T cell help. Unexpectedly, IgG and IgA expression was most prominent on cells that underwent 1-3 cell divisions, suggesting an unusual mechanism. We suggest that FCRL5-dependent enhancement of proliferation and downstream isotype expression could play roles in the physiological expansion and development of antigen-primed B cells. Additionally, FCRL5 may contribute to tumor progression in hairy cell leukemia and other FCRL5 expressing B cell malignancies.