bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct Adenoviral Gene Transfer of Viral IL-10 to Rabbit Knees with Experimental Arthritis Ameliorates Disease in Both Injected and Contralateral Control Knees
Authors: Lechman Eric R. , Jaffurs Daniel , Ghivizzani Steven C. , Gambotto Andrea , Kovesdi Imre , Mi Zhibao , Evans Christopher H. , Robbins Paul D. 
Published: January 2023

Abstract
IL-10, a cytokine produced primarily by macrophages, B lymphocytes, and Th2 cells, has both immunostimulatory and immunosuppressive properties. A homologue of IL-10 encoded by EBV, known as viral IL-10 (vIL-10), is also able to suppress the immune response, but may lack some of the immunostimulatory properties of IL-10. To evaluate the potential of vIL-10 to block the progression of rheumatoid arthritis, we have utilized a replication-defective adenovirus vector to deliver the gene encoding vIL-10 to the knee joints of rabbits with Ag-induced arthritis. Intraarticular expression of vIL-10 significantly reduced leukocytosis, cartilage matrix degradation, and levels of endogenous rabbit TNF-α, as well as the degree of synovitis, while maintaining high levels of cartilage matrix synthesis. Interestingly, an antiarthritic effect was also observed in opposing contralateral control knee joints that received only a marker gene. An adenoviral vector carrying the enhanced green fluorescent protein marker gene was used to demonstrate that a morphologically similar subset of cells infected in the injected knee joint are able to traffic to the uninjected contralateral knee joint. Our results suggest that direct, local intraarticular delivery of the vIL-10 gene may have polyarticular therapeutic effects.
A Null Mutation in the Inflammation-Associated S100 Protein S100A8 Causes Early Resorption of the Mouse Embryo
Authors: Passey Robert J. , Williams Elizabeth , Lichanska Agnieszka M. , Wells Christine , Hu Shengping , Geczy Carolyn L. , Little Melissa H. , Hume David A. 
Published: January 2023

Abstract
S100A8 (also known as CP10 or MRP8) was the first member of the S100 family of calcium-binding proteins shown to be chemotactic for myeloid cells. The gene is expressed together with its dimerization partner S100A9 during myelopoiesis in the fetal liver and in adult bone marrow as well as in mature granulocytes. In this paper we show that S100A8 mRNA is expressed without S100A9 mRNA between 6.5 and 8.5 days postcoitum within fetal cells infiltrating the deciduum in the vicinity of the ectoplacental cone. Targeted disruption of the S100A8 gene caused rapid and synchronous embryo resorption by day 9.5 of development in 100% of homozygous null embryos. Until this point there was no evidence of developmental delay in S100A8−/− embryos and decidualization was normal. The results of PCR genotyping around 7.5–8.5 days postcoitum suggest that the null embryos are infiltrated with maternal cells before overt signs of resorption. This work is the first evidence for nonredundant function of a member of the S100 gene family and implies a role in prevention of maternal rejection of the implanting embryo. The S100A8 null provides a new model for studying fetal-maternal interactions during implantation.
Preferential Localization of CD8+ αEβ7+ T Cells Around Acinar Epithelial Cells with Apoptosis in Patients with Sjögren’s Syndrome
Authors: Fujihara Tsutomu , Fujita Hiromi , Tsubota Kazuo , Saito Keiko , Tsuzaka Kensei , Abe Tohru , Takeuchi Tsutomu 
Published: January 2023

Abstract
The T lymphocytes that infiltrate the exocrine glands in Sjögren’s syndrome (SS) play a key role in damaging glandular epithelial cells, but the mechanisms of this damage by T lymphocytes are not fully understood. To determine the cellular basis of this phenomenon, we focused our attention on the T lymphocytes around acinar epithelial cells in SS. We showed that CD8+ but not CD4+ T lymphocytes were located around the acinar epithelial cells and that a majority of these CD8+ T lymphocytes possess an unique integrin, αEβ7 (CD103). The acinar epithelial cell adherent with αEβ7 (CD103)+ CD8+ T lymphocytes was apoptotic. Both the perforin/granzyme B and Fas/Fas ligand pathways were implicated in the process of programmed cell death in lacrimal glands. These results suggested that αEβ7 integrin, by interacting with E-cadherin, mediates the adhesion between CD8+ T lymphocytes and acinar epithelial cells in SS and participates in inducing epithelial cell apoptosis, leading to secretory dysfunction of exocrine glands, a hallmark of SS.
Increased Susceptibility to Immunologically Mediated Glomerulonephritis in IFN-γ-Deficient Mice
Authors: Ring Guido H. , Dai Zhenhua , Saleem Sohail , Baddoura Fady K. , Lakkis Fadi G. 
Published: January 2023

Abstract
It is postulated that IFN-γ confers susceptibility to immunologically mediated tissue injury. To test this hypothesis, we compared the intensity of accelerated anti-glomerular basement membrane glomerulonephritis between wild-type (IFN-γ+/+) and IFN-γ gene knockout (IFN-γ−/−) mice. This disease model is initiated by binding of heterologous (sheep) anti-glomerular basement membrane Abs to the glomeruli of mice preimmunized with sheep IgG. The secondary cellular and humoral immune responses to the planted Ag then lead to albuminuria and glomerular pathology. We found that IFN-γ−/− mice or IFN-γ+/+ mice injected with IFN-γ-neutralizing Ab develop worse albuminuria and glomerular pathology than IFN-γ+/+ mice. The humoral response to sheep IgG (serum mouse anti-sheep IgG titers and intraglomerular mouse IgG deposits) was comparable in the IFN-γ+/+ and IFN-γ−/− groups. In contrast, IFN-γ−/− mice mounted a stronger cellular immune response (cutaneous delayed-type hypersensitivity reaction) to sheep IgG than IFN-γ+/+ mice. These findings provide evidence that endogenous IFN-γ has a protective role in immunologically mediated glomerulonephritis initiated by foreign Ags.
Newborns Develop a Th1-Type Immune Response to Mycobacterium bovis Bacillus Calmette-Guérin Vaccination
Authors: Marchant Arnaud , Goetghebuer Tessa , Ota Martin O. , Wolfe Ingrid , Ceesay Serign J. , De Groote Donat , Corrah Tumani , Bennett Steve , Wheeler Jeremy , Huygen Kris , Aaby Peter , McAdam Keith P. W. J. , Newport Melanie J. 
Published: January 2023

Abstract
Data obtained in animals indicate that neonatal immune responses are biased toward Th2. This could reduce the efficacy of vaccines against viral and mycobacterial diseases. The ability of human newborns to develop a Th1 immune response upon immunization has not been studied. Since the vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) triggers a Th1-type response in adults, we investigated whether it induces a similar response in newborns and whether age at vaccination influences immunogenicity. We found that BCG vaccination at birth induces a memory Th1-type response of similar magnitude to that when given later in life. This study demonstrates that human newborns can be immunized against pathogens controlled by a Th1 immune response.
B7 Costimulation in the Development of Lupus: Autoimmunity Arises Either in the Absence of B7.1/B7.2 or in the Presence of Anti-B7.1/B7.2 Blocking Antibodies
Authors: Liang Bailin , Gee Renelle J. , Kashgarian Michael J. , Sharpe Arlene H. , Mamula Mark J. 
Published: January 2023

Abstract
Costimulatory molecules, termed B7.1 and B7.2, are present on the surfaces of APC and are important for the activation of T lymphocytes specific for both foreign Ags and autoantigens. We have examined the role of B7 costimulation in the MRL-lpr/lpr murine model of human systemic lupus erythematosus. MRL-lpr/lpr mice receiving both anti-B7.1 and anti-B7.2 Abs expressed significantly lower anti-small nuclear ribonucleoprotein particles (snRNP) and anti-dsDNA autoantibodies than did untreated mice. Anti-B7.2 Ab treatment alone inhibited anti-dsDNA autoantibody expression while having no effect on anti-snRNP autoantibody expression. Anti-B7.1 Ab treatment alone did not change the expression of either anti-snRNP or anti-dsDNA autoantibodies. Parallel studies performed in MRL-lpr/lpr mice genetically deficient in either B7.1 or B7.2 expressed autoantibody profiles comparable to those found in wild-type MRL-lpr/lpr mice. However, B7.1-deficient MRL-lpr/lpr mice exhibited distinct and more severe glomerulonephritis while B7.2-deficient MRL-lpr/lpr mice had significantly milder or absent kidney pathology as compared with age-matched wild-type mice. These studies indicate that each B7 costimulatory signal may control unique pathological events in murine systemic lupus erythematosus that may not always be apparent in autoantibody titers alone.
Cutting Edge: A Single, Essential Hydrogen Bond Controls the Stability of Peptide-MHC Class II Complexes
Authors: McFarland Benjamin J. , Beeson Craig , Sant Andrea J. 
Published: January 2023

Abstract
The binding of peptides to MHC class II molecules is mediated in part by a conserved array of intermolecular hydrogen bonds. We have evaluated the consequences of disrupting the hydrogen bond between β-His-81 of the class II molecule and bound peptide. These studies revealed that peptide dissociation rates were accelerated by factors ranging to 200-fold. The sensitivity of a peptide to loss of the hydrogen bond is inversely correlated with the inherent kinetic stability of the peptide-MHC complex. The same relationship has been observed between inherent kinetic stability and the susceptibility to DM. Given that the rate enhancement observed for MHC class II I-Ad protein mutated at position 81 in the β-chain is comparable with DM-catalyzed rates for other class II molecules, we suggest that DM could function by stabilizing a peptide-MHC intermediate in which one or more hydrogen bonds between the peptide and MHC, such as that contributed by the β-His-81 hydrogen bond, are disrupted.
Fibroblast-Secreted Macrophage Colony-Stimulating Factor Is Responsible for Generation of Biphenotypic B/Macrophage Cells from a Subset of Mouse B Lymphocytes
Authors: Borrello Melinda A. , Phipps Richard P. 
Published: January 2023

Abstract
Normal and malignant CD5+ B lymphocytes can develop macrophage-like characteristics. One stimulus of this phenotypic shift is culture of normal mouse splenic B lymphocytes with splenic fibroblasts or their conditioned media. These biphenotypic B/macrophage (B/Mφ) cells simultaneously display macrophage characteristics, such as phagocytosis and F4/80 expression, while retaining B cell features, including expression of surface Ig, CD5, B220, and rearranged Ig genes. The present study investigated the fibroblast-secreted factor that promotes this phenotypic change from B cell to B/Mφ cell. RT-PCR analysis demonstrated that mRNA for M-CSF is produced by splenic fibroblasts. Recombinant M-CSF (CSF-1) could replace fibroblast-conditioned medium to elicit the development and survival of B/Mφ cells from splenic B lymphocytes. In addition, neutralization of fibroblast-secreted M-CSF with specific mAbs abrogated the ability of conditioned supernatants to promote outgrowth of B/Mφ cells. The transition from B lymphocyte to B/Mφ cell was marked by the kinetic appearance of mRNA for the M-CSF receptor, c-fms, at day 3 following culture initiation. These results demonstrate that M-CSF is important in the development and physiology of mouse B/Mφ cells and potentially in the growth of human biphenotypic hematological malignancies. Interestingly, the presence of IFN-γ in splenic B lymphocyte cultures abrogated the effect of fibroblast-conditioned medium or M-CSF on outgrowth of B/Mφ cells. Furthermore, these findings suggest that a Th1 microenvironment favored by typical macrophages is detrimental to the outgrowth of B/Mφ cells.
Kinetic Analysis of Oral Tolerance: Memory Lymphocytes Are Refractory to Oral Tolerance
Authors: Chung Yeonseok , Chang Sun-Young , Kang Chang-Yuil 
Published: January 2023

AbstractOral administration of soluble Ag before immunization induces peripheral tolerance and is effective in suppressing animal models of autoimmune diseases. Although tolerance induction in primed animals is more clinically relevant, it is not well studied. Therefore, this study was designed to examine the feeding effects on different phases of the immune response. We observed that feeding a single high dose (250 mg) of OVA to OVA-primed BALB/c mice could induce OVA-specific suppression in the Ab production and T cell proliferation only at the naive and the activation phases of the immune response, whereas multiple high doses (100 mg/feed for 10 days) were effective at the effector phase. OVA-specific IL-4 production in culture supernatant was also suppressed in the tolerized groups. However, when the mice had resting memory lymphocytes, even multiple feeding regimens were not effective in tolerance induction, although multiple low doses (1 mg/feed for 10 days) partially suppressed Ab production. This phenomenon was confirmed by adoptive transfer study. Nevertheless, the reactivated memory response was suppressed partially by multiple high doses. Our findings have an important implication for understanding the mechanism of oral tolerance and for the therapeutic applications of oral tolerance to autoimmune diseases.
Tyrosine Phosphorylation of Crk-Associated Substrate Lymphocyte-Type Is a Critical Element in TCR- and β1 Integrin-Induced T Lymphocyte Migration
Authors: Ohashi Yoshiyuki , Iwata Satoshi , Kamiguchi Kenjiro , Morimoto Chikao 
Published: January 2023

AbstractCrk-associated substrate (Cas) lymphocyte-type (Cas-L) is a 105-kDa cytoplasmic protein consisting of Src homology-3 domain and multiple YXXP motifs (substrate domain). Our previous studies showed that Cas-L is tyrosine-phosphorylated following the ligation of TCR and β1 integrins in T lymphocytes. Here we show that Cas-L is involved in T cell motility following the ligation of TCR and β1 integrin. Peripheral T lymphocytes showed a marked increase of migration on fibronectin (FN) after the ligation of TCR. In contrast, the migrating Jurkat cells, in which Cas-L was marginally expressed, were less than one-tenth in number on the same condition. Transfection of wild-type Cas-L into Jurkat cells resulted in restoring CD3 plus FN-induced cell migration. Furthermore, following the ligation of β1 integrin alone, the Cas-L transfectants significantly migrated better than the vector control. Mutational analysis of Cas-L revealed that the substrate domain is required for both FN- and CD3-induced tyrosine phosphorylation of Cas-L and cell migration caused by FN alone and CD3 plus FN. In contrast, the Src homology-3 domain is required only for the FN-induced tyrosine phosphorylation of Cas-L and cell migration, but not for CD3-induced tyrosine phosphorylation or CD3 plus FN-induced cell migration. These data strongly suggest that Cas-L is a key molecule in T cell migration induced by the ligation of CD3 and β1 integrins and that tyrosine phosphorylation of Cas-L is essential for T cell migration.
Expression of B7 Molecules in Recipient, Not Donor, Mice Determines the Survival of Cardiac Allografts
Authors: Mandelbrot Didier A. , Furukawa Yutaka , McAdam Alexander J. , Alexander Stephen I. , Libby Peter , Mitchell Richard N. , Sharpe Arlene H. 
Published: January 2023

Abstract
Blockade of the CD28/CTLA4/B7 costimulatory pathway using CTLA4-Ig has great therapeutic potential, and has been shown to prolong allograft survival in a variety of animal models. To gain further insight into the mechanism by which costimulatory blockade prevents allograft rejection, we studied cardiac allograft survival in the complete absence of B7 costimulation using mice lacking B7-1 and B7-2 (B7-1/B7-2−/− mice). To determine the role of B7 on donor vs recipient cells, we used B7-1/B7-2−/− mice as either donors or recipients of allografts. Wild-type (WT) recipients acutely reject fully allogeneic hearts from both WT and B7-1/B7-2−/− mice. In contrast, B7-1/B7-2−/− recipients allow long-term survival of grafts from both WT and B7-1/B7-2−/− mice, with minimal histologic evidence of either acute or chronic rejection in grafts harvested after 90 days. The B7-1/B7-2−/− mice acutely reject B7-1/B7-2−/− allografts if CD28 stimulation is restored by the administration of Ab to CD28 and can mount an alloresponse in mixed lymphocyte reactions. Therefore, B7-1/B7-2−/− mice are capable of generating alloresponses both in vivo and in vitro. Our results demonstrate that in the alloresponse to mouse heterotopic cardiac transplantation, B7 molecules on recipient cells rather than donor cells provide the critical costimulatory signals. The indefinite survival of allografts into B7-1/B7-2−/− recipients further shows that the absence of B7 costimulation alone is sufficient to prevent rejection.
IL-5 Mediates Eosinophilic Rejection of MHC Class II-Disparate Skin Allografts in Mice
Authors: Le Moine Alain , Surquin Murielle , Demoor François Xavier , Noël Jean Christophe , Nahori Marie-Anne , Pretolani Marina , Flamand Véronique , Braun Michel Y. , Goldman Michel , Abramowicz Daniel 
Published: January 2023

Abstract
CD4 T cells play a crucial role in the acute rejection of MHC class II-disparate skin allografts, mainly by Fas/Fas ligand-mediated cytotoxicity. Because recent observations indicate that eosinophils may be found within allografts rejected by CD4 T cells, we evaluated the role played by IL-5, the main eosinophil growth factor, and by eosinophils in the rejection of MHC class II-disparate skin grafts. C57BL/6 mice rapidly rejected MHC class II-disparate bm12 skin grafts. Rejected skins contained a dense, aggressive eosinophil infiltrate. Lymphocytes isolated from lymph nodes draining rejected bm12 skin were primed for IL-5 secretion, and IL-5 mRNA was present within rejected grafts. The IL-5/eosinophil pathway played an effector role in allograft destruction, because the rejection of bm12 skin was significantly delayed in IL-5-deficient mice as compared with wild-type animals. The role of the IL-5/eosinophil pathway was further investigated in MHC class II-disparate donor-recipient strains unable to establish Fas/Fas ligand interactions. Fas ligand-deficient gld/gld mice rejected bm12 skins, and bm12 mice rejected Fas-deficient lpr/lpr C57BL/6 skins. Neutralization of IL-5 prevented acute rejection in both combinations. We conclude that MHC class II-disparate skin allografts trigger an IL-5-dependent infiltration of eosinophils that is sufficient to result in acute graft destruction.
Elucidation and Role of Critical Residues of Immunodominant Peptide Associated with T Cell-Mediated Parasitic Disease
Authors: Hernandez Hector J. , Stadecker Miguel J. 
Published: January 2023

Abstract
Granulomatous inflammation in schistosomiasis is strictly dependent on CD4+ Th lymphocytes sensitized to egg Ags, but its intensity is genetically regulated. C3H and CBA (H-2k) are strains of mice that develop large granulomas; they also strongly respond to the major egg Ag Sm-p40. We now show that the immunodominant epitope recognized by CD4+ Th cells from infected H-2k mice is confined to 13-mer peptide 234–246 (PKSDNQIKAVPAS), which elicits an I-Ak-restricted Th1-type response. Using a panel of alanine-monosubstituted peptides, we identified Asp237 as the main contact residue with I-Ak. On the other hand, three TCR contact residues were essential to stimulate epitope-specific T cell hybridomas: for two hybridomas these were Asn238, Gln239, and Lys241; and for one, Asn238, Lys241, and Pro244. In one instance, alanine substitution for Gln239 generated an antagonist that blocked subsequent stimulation with wild-type peptide. Most importantly, replacement of Asn238, Gln239, or Lys241 caused a profound loss of polyclonal CD4+ T cell reactivity from schistosome-infected mice. This study identifies the critical residues of immunodominant peptide 234–246 involved in the T cell response against the Sm-p40 egg Ag and suggests that suitable altered peptides may be capable of precipitating its down-regulation.
Dendritic Cell (DC)-Based Anti-Infective Strategies: DCs Engineered to Secrete IL-12 Are a Potent Vaccine in a Murine Model of an Intracellular Infection
Authors: Ahuja Seema S. , Reddick Robert L. , Sato Naoko , Montalbo Elleanor , Kostecki Vannessa , Zhao Weiguo , Dolan Matthew J. , Melby Peter C. , Ahuja Sunil K. 
Published: January 2023

Abstract
Infections with intracellular pathogens such as Leishmania donovani and Mycobacterium tuberculosis pose serious health problems worldwide. Effective vaccines for these pathogens are not available. Furthermore, despite optimal therapy, disease progression is often seen with several intracellular infections. For these reasons, we initiated studies to develop novel anti-infective vaccine and treatment strategies that couple the potent Ag-presenting capacity of dendritic cells (DC) with paracrine delivery of potent anti-infective cytokines such as IL-12 to local immune response sites. We tested this strategy in a murine model of visceral leishmaniasis. Adoptive transfer of DCs pulsed ex vivo with soluble L. donovani Ags (SLDA) to naive mice induced the Ag-specific production of IFN-γ, and increased the percentage of activation markers on spleen lymphocytes. SLDA-pulsed DCs engineered by retroviral gene transfer techniques to secrete high levels of biologically active murine IL-12 augmented this immune response further. In several different vaccination and immunotherapy protocols, compared with sham-treated mice, animals receiving SLDA-pulsed DCs either before or following infection had 1–3 log lower parasite burdens, and this protection was associated with a pronounced enhancement in the parasite-specific IFN-γ response. The augmentation of this protection by IL-12-engineered DCs was striking. First, live parasites were not detected in the liver of mice vaccinated with IL-12-transduced, SLDA-pulsed DCs. Second, this parasitological response was associated with a nearly normal liver histology. In contrast, parasites and granulomas were found in mice vaccinated with SLDA-pulsed, nontransduced DCs. Collectively, these studies provide the rationale for the development of potent DC-based immunotherapies.
Human Toll-Like Receptors Mediate Cellular Activation by Mycobacterium tuberculosis
Authors: Means Terry K. , Wang Shuyan , Lien Egil , Yoshimura Atsutoshi , Golenbock Douglas T. , Fenton Matthew J. 
Published: January 2023

Abstract
Recent studies have implicated a family of mammalian Toll-like receptors (TLR) in the activation of macrophages by Gram-negative and Gram-positive bacterial products. We have previously shown that different TLR proteins mediate cellular activation by the distinct CD14 ligands Gram-negative bacterial LPS and mycobacterial glycolipid lipoarabinomannan (LAM). Here we show that viable Mycobacterium tuberculosis bacilli activated both Chinese hamster ovary cells and murine macrophages that overexpressed either TLR2 or TLR4. This contrasted with Gram-positive bacteria and Mycobacterium avium, which activated cells via TLR2 but not TLR4. Both virulent and attenuated strains of M. tuberculosis could activate the cells in a TLR-dependent manner. Neither membrane-bound nor soluble CD14 was required for bacilli to activate cells in a TLR-dependent manner. We also assessed whether LAM was the mycobacterial cell wall component responsible for TLR-dependent cellular activation by M. tuberculosis. We found that TLR2, but not TLR4, could confer responsiveness to LAM isolated from rapidly growing mycobacteria. In contrast, LAM isolated from M. tuberculosis or Mycobacterium bovis bacillus Calmette-Guérin failed to induce TLR-dependent activation. Lastly, both soluble and cell wall-associated mycobacterial factors were capable of mediating activation via distinct TLR proteins. A soluble heat-stable and protease-resistant factor was found to mediate TLR2-dependent activation, whereas a heat-sensitive cell-associated mycobacterial factor mediated TLR4-dependent activation. Together, our data demonstrate that Toll-like receptors can mediate cellular activation by M. tuberculosis via CD14-independent ligands that are distinct from the mycobacterial cell wall glycolipid LAM.