bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leukocyte Entry into Sites of Inflammation Requires Overlapping Interactions Between the L-Selectin and ICAM-1 Pathways
Authors: Steeber Douglas A. , Tang Mimi L. K. , Green Nathan E. , Zhang Xiu-Qin , Sloane Jennifer E. , Tedder Thomas F. 
Published: January 2023

AbstractLeukocyte interactions with vascular endothelium during inflammation depend on cascades of adhesion molecule engagement, particularly during selectin-mediated leukocyte rolling. Leukocyte rolling is also facilitated by members of the integrin and Ig families. Specifically, leukocyte rolling velocities during inflammation are significantly increased in ICAM-1-deficient mice, with ICAM-1 expression required for optimal P- and L-selectin-mediated rolling. Elimination of ICAM-1 expression in L-selectin-deficient mice significantly reduces leukocyte rolling. Whether disrupted leukocyte rolling in L-selectin and ICAM-1 double-deficient (L-selectin/ICAM-1−/−) mice affects leukocyte entry into sites of inflammation in vivo was assessed in the current study by using experimental models of inflammation; thioglycollate-induced peritonitis, chemokine-induced neutrophil migration to the skin, delayed-type hypersensitivity responses, rejection of allogeneic skin grafts, and septic shock. In many cases, the loss of both L-selectin and ICAM-1 expression dramatically reduced leukocyte migration into sites of inflammation beyond what was observed with loss of either receptor alone. In fact, the effects from loss of both L-selectin and ICAM-1 effectively eliminated multiple chronic inflammatory responses in L-selectin/ICAM-1−/− mice. By contrast, the combined loss of L-selectin and ICAM-1 expression had minimal effects on the generation of Ag-specific T cell responses or humoral immunity. Thus, members of the selectin and Ig families function synergistically to mediate optimal leukocyte rolling and entry into tissues, which is essential for the generation of effective inflammatory responses in vivo.
Soluble Fas Ligand Induces Epithelial Cell Apoptosis in Humans with Acute Lung Injury (ARDS)
Authors: Matute-Bello Gustavo , Liles W. Conrad , Steinberg Kenneth P. , Kiener Peter A. , Mongovin Stephen , Chi Emil Y. , Jonas Mechthild , Martin Thomas R. 
Published: January 2023

Abstract
The goals of this study were to determine whether the Fas-dependent apoptosis pathway is active in the lungs of patients with the acute respiratory distress syndrome (ARDS), and whether this pathway can contribute to lung epithelial injury. We found that soluble Fas ligand (sFasL) is present in bronchoalveolar lavage (BAL) fluid of patients before and after the onset of ARDS. The BAL concentration of sFasL at the onset of ARDS was significantly higher in patients who died. BAL from patients with ARDS induced apoptosis of distal lung epithelial cells, which express Fas, and this effect was inhibited by blocking the Fas/FasL system using three different strategies: anti-FasL mAb, anti-Fas mAb, and a Fas-Ig fusion protein. In contrast, BAL from patients at risk for ARDS had no effect on distal lung epithelial cell apoptosis. These data indicate that sFasL is released in the airspaces of patients with acute lung injury and suggest that activation of the Fas/FasL system contributes to the severe epithelial damage that occurs in ARDS. These data provide the first evidence that FasL can be released as a biologically active, death-inducing mediator capable of inducing apoptosis of cells of the distal pulmonary epithelium during acute lung injury
In Vivo Kinetics of Transduced Cells in Peripheral T Cell-Directed Gene Therapy: Role of CD8+ Cells in Improved Immunological Function in an Adenosine Deaminase (ADA)−SCID Patient
Authors: Kawamura Nobuaki , Ariga Tadashi , Ohtsu Makoto , Kobayashi Ichiro , Yamada Masafumi , Tame Atsushi , Furuta Hirofumi , Okano Motohiko , Egashira Masayuki , Niikawa Norio , Kobayashi Kunihiko , Sakiyama Yukio 
Published: January 2023

Abstract
We previously reported successful peripheral T cell-directed gene therapy in a boy with adenosine deaminase (ADA)−SCID. In the present study, to better understand the reconstitutive effect of this gene therapy on his immunological system, we investigated the in vivo kinetics and functional subsets of T cells in PBL. Apparent immunological improvements were obtained after infusion of transduced cells at more than 4 × 108 cells/kg/therapy/3 mo. Frequency of ADAcDNA-integrated cells in PBL, ADA activity in PBL and clinical improvement showed good correlation, even though CD8+ cells gradually became predominant in PBL. On the basis that polyethylene glycol (PEG)-ADA was maintained at the same dosage as before gene therapy, we consider that his immunological improvement resulted from the gene therapy itself. Most CD3+ cells in PBL after gene therapy expressed TCRαβ. Analysis of TCR repertoire based on TCR V region usage revealed no expansion of limited clones in his PBL. The T cell subset cells CD8+CDw60+ and CD8+CD27+CD45RA−, which are reported to provide substantial help to B cells, were maintained throughout the gene therapy. Furthermore, his reconstituted peripheral T cells helped normal B cells to produce substantial IgG in vitro. Expression of both Th1- and Th2-type cytokine genes was induced in his reconstituted T cells at the same comparably high level as in normal subjects. Collectively, these results provide evidence of persistent and distinct functions of transduced cells in this patient’s PBL after gene therapy.
Phosphorylated Peptides Can Be Transported by TAP Molecules, Presented by Class I MHC Molecules, and Recognized by Phosphopeptide-Specific CTL
Authors: Andersen Mads Hald , Bonfill Jordi Espuny , Neisig Anne , Arsequell Gemma , Søndergaard Ib , Neefjes Jacques , Zeuthen Jesper , Elliott Tim , Haurum John S. 
Published: January 2023

Abstract
CTL recognize short peptide fragments presented by class I MHC molecules. In this study, we examined the effect of phosphorylation on TAP transport, binding to class I MHC molecules, and recognition by CTL of peptide fragments from known phosphorylated oncogene proteins or virus phosphoproteins. We show that phosphopeptides can be efficiently transported from the cytosol to the endoplasmic reticulum by the TAP. Furthermore, we show that phosphorylation can have a neutral, negative, or even a positive effect on peptide binding to class I MHC. Finally, we have generated phosphopeptide-specific CTL that discriminate between the phosphorylated and the nonphosphorylated versions of the peptide. We conclude that phosphopeptide-specific CTL responses are likely to constitute a subset of the class I MHC-restricted CTL repertoire in vivo.
Two Ancient Allelic Lineages at the Single Classical Class I Locus in theXenopusMHC
Authors: Flajnik Martin F. , Ohta Yuko , Greenberg Andrew S. , Salter-Cid Luisa , Carrizosa Ana , Du Pasquier Louis , Kasahara Masanori 
Published: January 2023

AbstractUnlike all other vertebrates examined to date, there is only one detectable class I locus in the Xenopus MHC. On the bases of a nearly ubiquitous and high tissue expression, extensive polymorphism, and MHC linkage, this gene is of the classical or class Ia type. Sequencing analysis of class Ia cDNAs encoded by eight defined MHC haplotypes reveals two very old allelic lineages that perhaps emerged when humans and mice diverged from a common ancestor up to 100 million years ago. The unprecedented age of these lineages suggests that different class Ia genes from ancestors of the laboratory model Xenopus laevis are now expressed as alleles in this species. The lineages are best defined by their cytoplasmic and α2 peptide-binding domains, and there are highly diverse alleles (defined by the α1 peptide-binding domain) in each lineage. Surprisingly, the α3 domains are homogenized in both lineages, suggesting that interallelic gene conversion/recombination maintains the high sequence similarity.
Intracellular IL-1 Receptor Antagonist Is Elevated in Human Dermal Fibroblasts That Overexpress Intracellular Precursor IL-1α
Authors: Higgins Gloria C. , Wu Yong , Postlethwaite Arnold E. 
Published: January 2023

Abstract
Cultured dermal fibroblasts from systemic sclerosis patients express higher levels of intracellular IL-1α than fibroblasts from healthy controls. In this study, we found that systemic sclerosis dermal fibroblasts also express higher levels of the intracellular isoform of IL-1 receptor antagonist (icIL-1Ra) than normal fibroblasts after stimulation with IL-1β or TNF-α. A possible relationship between elevated precursor IL-1α (preIL-1α) and elevated icIL-1Ra was investigated by transducing normal dermal fibroblasts to overexpress preIL-1α, preIL-1β, or icIL-1Ra. Fibroblasts that overexpressed icIL-1Ra did not have elevated levels of IL-1α. On the other hand, fibroblasts that overexpressed preIL-1α had at least 4-fold higher basal levels of icIL-1Ra than control fibroblasts and 4-fold higher levels of icIL-1Ra after induction with IL-1β or TNF-α. Fibroblasts overexpressing preIL-1β did not exhibit elevated icIL-1Ra. The differences in icIL-1Ra protein levels were reflected in differences in mRNA. In contrast, IL-1-stimulated levels of MCP-1 and IL-6 were not different in control and preIL-1α-transduced fibroblasts. Addition of neutralizing anti-IL-1α Abs to fibroblast cultures did not diminish basal or stimulated levels of icIL-1Ra in the preIL-1α-transduced cells, supporting an intracellular site of action of preIL-1α. This is the first report of an association between intracellular levels of these IL-1 family members. We hypothesize that intracellular preIL-1α participates in the regulation of icIL-1Ra.
Identifying the long-term role of iNOS in contusive spinal cord injury (SCI) using a transgenic mouse model (100.14)
Authors: SINGH AMANPREET , Lopez Michael M , Lovera Lillie C , Maggio Dominic M , Flora Govinder , Dietrich Dalton W , Pearse Damien D 
Published: January 2023

Abstract
The inflammatory mediator iNOS is thought to play an important role in the pathophysiology of SCI. Specific inhibition of iNOS is beneficial after acute SCI, but little is known about its role over longer post-injury periods. The current study was carried out to assess the role of iNOS after contusive SCI through the use of chronic iNOS inhibition by a knockout mouse approach. Wild type (WT) and iNOS(−/−) mice were injured and then subjected to behavioral testing (BMS) and histological evaluation of healthy white and gray matter tissue volumes. Behaviorally, iNOS(−/−) mice displayed a significantly faster recovery of function compared to WT in open-field locomotion during the first 4 wk (WT 2.2±0.2, iNOS(−/−) 3.38±0.43; p &lt; 0.05).At the endpoint of the experiment (8wk) however, iNOS(−/−) mice showed a trend towards worsened functional outcome. Histological analysis revealed that i-NOS(−/−) mice had a significant decrease in the volumes of both healthy gray (53%) and healthy white matter (15%) as compared to WT. The present study shows that acute inhibition of iNOS could be behaviorally beneficial after SCI, however, chronic inhibition likely hampers important wound healing functions of NO, leading to a lack of efficacy at later stages.
FUNDING: The Miami Project to Cure Paralysis, The Buoniconti Fund, The US Army Medical Research and Material Command
Adoptive therapy with allogeneic CD4+CD25+ Foxp3+ Treg cells induces transplantation tolerance (102.10)
Authors: Adeegbe Dennis O , Levy Robert B , Malek Thomas R 
Published: January 2023

Abstract
Alloantigen primed Treg cells offer the potential for non-toxic suppression of transplant rejection reactions. If they are not rejected by the recipient, MHC-mismatched Treg cells might also establish transplant tolerance to the MHC molecules that the Treg cells were selected on during their development. In this regard, we have shown that the adoptive transfer of allogeneic Treg cells into neonatal IL-2Rβ−/−mice, which lack Treg cells and develop rapid lethal autoimmunity, lead to long-term engraftment by the donor Treg cells, effective prevention of this autoimmunity, and simultaneous long-term tolerance to the skin grafts expressing alloantigens shared by the Treg cells. This tolerance depended upon active suppression by Treg cells, not deletion or anergy. Mice tolerant to allogeneic C57BL/6 skin grafts were also tolerant to MHC class II-deficient C567BL/6 skin grafts, but rejected bm3 and bm12 skin grafts. These latter findings demonstrate that Treg cells are not required to directly recognize alloantigens within the skin grafts and that a single neo-antigen was sufficient to break tolerance. Collectively, these data demonstrate induction of dominant donor-specific transplantation tolerance by allogeneic Treg cells provided that the MHC antigens of both the Treg cells and transplant are matched.
(Supported by the NIH)
Mutations to Bid cleavage sites protect hepatocytes from apoptosis following ischemia/reperfusion injury (102.23)
Authors: Krams Sheri M , Nagasaki Kazuhito , Esquivel Carlos O , Martinez Olivia M , Riddle Erica 
Published: January 2023

Abstract
Apoptosis of hepatocytes occurs during graft rejection, and ischemia/reperfusion injury (IRI). Hepatocytes require mitochondrial disruption to execute apoptosis, a process that is controlled by proteins of the Bcl-2 family. Bid is a proapoptotic Bcl-2 family member that is cleaved to its active form, tBid, by caspase 8 and granzyme B.
We demonstrate that FaO hepatoma cells, transduced with recombinant adenoviruses expressing Bid with mutations to the caspase 8 (D60E) and granzyme B (D76E) cleavage sites (AdBidEE), are significantly protected from both TNF-induced and cell-mediated apoptosis. Furthermore, rats expressing cleavage-resistant Bid in the liver display significantly less hepatocyte apoptosis and improved liver function as compared to control (AdLacZ) rat livers following warm IRI. All untreated and LacZ-expressing animals died within the first 24 hours post-IRI. In marked contrast, rats expressing AdBidEE (n=8) had significantly improved survival following IRI compared with AdLacZ-expressing rats (p = 0.0079, n=6), and have normal liver function at seven days.
We demonstrate that administration of AdBidEE protects hepatocytes from apoptosis and preserves liver function. Moreover, we propose that administration of AdBidEE may be useful in preventing apoptosis associated with warm ischemia in donors after cardiac death and thus increase the pool of deceased donors for transplantation.
Fas mediated cell death promotes cardiac allograft acceptance in T cell-NF-κB impaired mice (102.24)
Authors: Molinero Luciana Lorena , Wang Ying , Zhou Ping , Yagita Hideo , Alegre Maria-Luisa 
Published: January 2023

Abstract
The transcription factor NF-κB is critical for T cell activation and survival. We have shown that mice expressing a T cell-restricted NF-κB superrepressor (IκBαΔN-Tg) permanently accept heart but not skin allografts. Overexpression of the prosurvival factor Bclx-L in T cells restored heart rejection, suggesting that graft acceptance in IκBαΔN-Tg mice was due to deletion of alloreactive T cells. Accordingly, transplantation of OVA-expressing skin grafts resulted in division of adoptively transferred DO11.10/IκBαΔN-Tg T cells, whereas heart grafts induced T cell death. In vitro, Fas was responsible for the increased death of IκBαΔN-Tg T cells upon TCR stimulation compared to WT T cells. Similarly, Fas played a key role in cardiac allograft acceptance by IκBαΔN-Tg mice as both genetic and antibody-mediated inhibition of Fas signaling restored cardiac allograft rejection. Rejection correlated with graft infiltration by T cells and splenic production of IFN-γ upon allostimulation. These results indicate that T cell inhibition of NF-κB results in cardiac allograft acceptance because of increased susceptibility to Fas-mediated cell death.
Research support: NIH AI52352-03.
Synergistic control of T cell activation, regulatory T cell function, and autoimmunity by Diacylglycerol Kinases alpha and zeta (128.26)
Authors: Zhong Xiao-Ping , Guo Rishu , Carpenter Jeffery H 
Published: January 2023

Abstract
T cell receptor (TCR) signaling plays a critical role in T cell development, activation of conventional T cells, and induction of suppressive function of regulatory T cells (Treg). Abnormal TCR signaling can skew the T cell repertoire, induce dysregulated T cell activation, and lead to autoimmune diseases. How TCR signals control intrathymic T cell development, T cell activation, and Treg function is still not fully understood. Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that catalyze the conversion of DAG to phosphatidic acid (PA) through phosphorylation. Both DAG and PA are second messengers involved in signaling from many receptors and both are generated following TCR stimulation. DAG and PA exert their activities by associating with and modulating the activities and subcellular localizations of numerous effector molecules. In T cells, both alpha and zeta isoforms of the DGK family are expressed. We have recently demonstrated that DGKalpha and zeta negatively regulate T cell activation, and that deficiency of either DGKalpha or zeta results in T cells that are hyper-responsive to TCR stimulation and resistant to anergy induction. Our current studies using DGKalpha and zeta doubly deficient mice have further demonstrated that these two DGK isoforms synergistically regulate thymic selection, T cell homeostasis, and Treg function to prevent autoimmune disease.
The defect in CD4+CD25− cell conversion into CD4+CD25+ regulatory cells in NOD mice can be rescued by treatment with "normal" antigen presenting cells (128.3)
Authors: Zhao Yuan , Alard Pascale , Parnell Sarah , Gross Eleanore , Kosiewicz Michele M 
Published: January 2023

Abstract
NOD mice are unable to convert CD4+CD25− cells into functional CD4+CD25+ regulatory cells in vivo. To analyze this defect, we reciprocally transferred CD4+CD25− cells into NOD and B6.g7 (B6 mice expressing NOD I-Ag7) mice. In NOD recipients, transferred B6.g7 CD4+CD25− cells were unable to convert, while in B6.g7 mice, transferred NOD CD4+CD25− cells converted as effectively as controls, suggesting that it may be the NOD APC that are defective in the conversion process. To test this, we co-transferred B6.g7 DC (APC) along with NOD CD4+CD25− T cells into NOD mice. Providing NOD mice with non-defective APC rescued their ability to convert. Interestingly, although Foxp3 expression did not, granzyme B expression did correlate with regulatory ability in converted CD4+CD25+ cells: NOD CD4+CD25− cells that upregulated CD25 after transfer into NOD mice expressed comparable Foxp3, but lower levels of granzyme B and were unable to regulate, whereas converted CD4+CD25+ cells from B6 controls or NOD mice treated with B6.g7 DC expressed high levels of granzyme B and were able to regulate. Taken together, these data suggest that the failure of NOD CD4+CD25− cells to convert into functional CD4+CD25+ regulatory cells in NOD mice may be due to a defect in the ability of NOD APC to induce granyme B expression in the converted cells.
Supported by NIH grant AI064421 and the KY Challenge for Excellence Fund.
A model to study the role of MHC-II dependent events in the suppression mediated by antigen specific CD4+ CD25+ FoxP3+ regulatory T cells (128.5)
Authors: Mmanywa Faith , Koni Pandelakis 
Published: January 2023

Abstract
CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) play an important role in maintaining peripheral tolerance and preventing autoimmunity. In order to exert their suppressive functions, Tregs require TCR stimulation, both in vitro and in vivo. Upon stimulation they are able to suppress both CD4+ and CD8+ T cells in an antigen non-specific manner. The mechanism of suppression by Tregs is still not fully understood. Here we employ conditional MHC class II (MHC-II) deficient mice to test the hypothesis that MHC-II dependent events are involved in the suppressive function of antigen specific Tregs. To this end, we employ Foxp3+ CD4+ cells from ovalbumin-reactive OT-II TCR transgenic mice as Tregs and ovalbumin-reactive CD8+ OT-I TCR transgenic cells as responder cells. We demonstrate that antigen specific Tregs mediate suppression of CD8+ T cell proliferation and effector function in a MHC-II dependent manner. Therefore in this system the suppressive function of Tregs is MHC-II dependent.
Role of Foxp3 in CD8+ T regulatory/inhibitory cells ability to suppression of autoimmunity defined by mircoarray analysis and silencing of target genes after tolerization of BWF1 lupus mice with pConsensus peptide (128.6)
Authors: Singh Ram P , La Cava Antonio , Ebling Fanny M , Tamayo Alejandro M , Elashoff David , Sven De Vos , Patel Divyan , Rooney Robert J 
Published: January 2023

Abstract
NZB/NZW Fl female (BWF1) mice, a model of SLE, after tolerization with an artificial peptide (pCONSENSUS, pCons) that is based on anti-DNA IgG sequences containing MHC Class I and Class II T cell determinants, develop regulatory CD4+CD25+T cells and inhibitory CD8+T cells, both of which suppress anti-DNA Ig production. In the present study, we analyzed 45,000 murine genes in a one- to- one comparison of white blood cells (WBC), CD4, and CD8 cell subsets from tolerized vs. non-tolerized mice. Results showed 448, 174 and 60 genes, respectively, that were differentially expressed by at least twofold. From the CD8+ T cells, we confirmed up regulation of several genes in cells from tolerized mice, including Foxp3, Trp-53, CCR7, IFI202B, bcl2, and IFNar1. Using tranfection of CD8+ T cells with siRNA for Foxp3, Trp-53 and CCR7, silencing of Foxp3 eliminated 60–100% of the suppressive capacities of CD8+ T cells from tolerized mice, as well as their ability to secrete TGFb. There was significant correlation between expression of Foxp3 and ability of CD8+ Ti cells to secrete TGFb. In contrast, silencing of Trp-53 and CCR7 did not abrogate suppressive capacity of these cells. In summary, suppressive capacity of CD8+ Ti in this system of tolerance depend in large part on expression of Foxp3, and there may be a bi-directional Foxp3/TGFb autocrine loop that determines the ability of the CD8+ T cells to control autoimmunity.
Supported by NIH grants AI63515, AI 63515, AR53239 and Tina C. Foundation.
Viral infection enables CD4+CD25+ regulatory T cells to protect from autoimmune diabetes (128.9)
Authors: von Herrath Matthias , Oldham Janine , Christen Urs , Martinic Marianne , Togher Lisa 
Published: January 2023

Abstract
While viral infections may be capable of triggering autoimmune diabetes (T1D) in genetically susceptible individuals, accumulating evidence indicates that viruses can also prevent T1D. However, the underlying mechnisms are only partially understood. Here, we show that activation of CD4+CD25+ Tregs by acute lymphocytic choriomeningitis virus (LCMV) infection provides these cells with the capacity to prevent both spontaneous and virally induced T1D in the mouse. We found that CD4+CD25+ Tregs activated by LCMV in vivo or in vitro produce the regulatory cytokine TGF-b and are capable of protecting NOD and RIP-LCMV mice from spontaneous and LCMV-induced diabetes, respectively. Our results suggest that LCMV-modulated CD4+CD25+ Tregs act in a bystander fashion independent of beta-cell antigens and suppress TNF-a production by autoreactive CD8+ T cells, leading to prevention of T1D. These findings provide a novel mechanistic explanation for the previously reported ability of viral infections to prevent autoimmune diabetes. Furthermore, our results support a model explaining the differential ability of viral infections to modulate diabetes. Activation of Tregs during viral infections may be a general feature accounting for the ability of viruses to prevent T1D as well as other autoimmune disorders.