bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transplantation Tolerance and Autoimmunity After Xenogeneic Thymus Transplantation
Authors: Xia Guliang , Goebels Jozef , Rutgeerts Omer , Vandeputte Michel , Waer Mark 
Published: April 2014

Abstract
Successful grafting of vascularized xenografts (Xgs) depends on the ability to reliably induce both T cell-independent and -dependent immune tolerance. After temporary NK cell depletion, B cell suppression, and pretransplant infusion of donor Ags, athymic rats simultaneously transplanted with hamster heart and thymus Xgs developed immunocompetent rat-derived T cells that tolerated the hamster Xgs but provoked multiple-organ autoimmunity. The autoimmune syndrome was probably due to an insufficient development of tolerance for some rat organs; for example, it led to thyroiditis in the recipient rat thyroid, but not in simultaneously transplanted donor hamster thyroid. Moreover, grafting a mixed hamster/rat thymic epithelial cell graft could prevent the autoimmune syndrome. These experiments indicate that host-type thymic epithelial cells may be essential for the establishment of complete self-tolerance and that mixed host/donor thymus grafts may induce T cell xenotolerance while maintaining self-tolerance in the recipient.
The Binding Subunit of Pertussis Toxin Inhibits HIV Replication in Human Macrophages and Virus Expression in Chronically Infected Promonocytic U1 Cells
Authors: Alfano Massimo , Vallanti Giuliana , Biswas Priscilla , Bovolenta Chiara , Vicenzi Elisa , Mantelli Barbara , Pushkarsky Tatyana , Rappuoli Rino , Lazzarin Adriano , Bukrinsky Michael , Poli Guido 
Published: April 2014

AbstractWe have recently shown that the binding subunit of pertussis toxin (PTX-B) inhibits the entry and replication of macrophage-tropic (R5) HIV-1 strains in activated primary T lymphocytes. Furthermore, PTX-B suppressed the replication of T cell-tropic (X4) viruses at a postentry level in the same cells. In this study we demonstrate that PTX-B profoundly impairs entry and replication of the HIV-1ADA (R5), as well as of HIV pseudotyped with either murine leukemia virus or vesicular stomatitis virus envelopes, in primary monocyte-derived macrophages. In addition, PTX-B strongly inhibited X4 HIV-1 replication in U937 promonocytic cells and virus expression in the U937-derived chronically infected U1 cell line stimulated with cytokines such as TNF-α and IL-6. Of interest, TNF-α-mediated activation of the cellular transcription factor NF-κB was unaffected by PTX-B. Therefore, PTX-B may represent a novel and potent inhibitor of HIV-1 replication to be tested for efficacy in infected individuals. In support of this proposition, a genetically modified mutant of PTX (PT-9K/129G), which is safely administered for prevention of Bordetella pertussis infection, showed an in vitro anti-HIV profile superimposable to that of PTX-B.
Conventional αβ T Cells Are Sufficient for Innate and Adaptive Immunity Against Enteric Listeria monocytogenes
Authors: Bregenholt Søren , Berche Patrick , Brombacher Frank , Di Santo James P. 
Published: April 2014

Abstract
We have begun to dissect the cellular requirements for generation of immunity against enteric infection by Listeria monocytogenes using a novel T− B− NK− mouse strain (mice double deficient for the common cytokine receptor γ-chain (γc) and the recombinase-activating gene-2 (RAG2/γc mice). Initial experiments showed that C57BL/6 mice and alymphoid RAG2/γc mice had similar kinetics of bacterial accumulation in the spleen, liver, and brain early after intragastric L. monocytogenes infection (up to day 3), calling into question the physiologic role of gut-associated lymphoid cells during the passage of this enterobacterium into the host. However, in contrast to C57BL/6 mice, RAG2/γc mice rapidly succumbed to disseminated infection by day 7. Polyclonal lymph node CD4+ and CD8+ αβ T cells were able to confer RAG2/γc mice with long-lasting protection against enteric L. monocytogenes infection in the absence of γδ T, NK, and NK-T cells. Moreover, these αβ T-reconstituted RAG2/γc mice produced IFN-γ at levels comparable to C57BL/6 mice in response to L. monocytogenes both in vitro and in vivo. Protection was IFN-γ dependent, as RAG2/γc mice reconstituted with IFN-γ-deficient αβ T cells were unable to control enteric L. monocytogenes infection. Furthermore, αβ T cell-reconstituted RAG2/γc mice were able to mount memory responses when challenged with lethal doses of L. monocytogenes. These data suggest that NK, NK-T, γδ T, and B cells are functionally redundant in the immunity against oral L. monocytogenes infection, and that in their absence αβ T cells are able to mediate the early IFN-γ production required for both innate and adaptive immunity.
The Potent Adjuvant Activity of Archaeosomes Correlates to the Recruitment and Activation of Macrophages and Dendritic Cells In Vivo
Authors: Krishnan Lakshmi , Sad Subash , Patel Girishchandra B. , Sprott G. Dennis 
Published: April 2014

Abstract
The unique glycerolipids of Archaea can be formulated into vesicles (archaeosomes) with potent adjuvant activity. We studied the effect of archaeosomes on APCs to elucidate the mechanism(s) of adjuvant action. Exposure of J774A.1 macrophages to archaeosomes in vitro resulted in up-regulation of B7.1, B7.2, and MHC class II molecules to an extent comparable to that achieved with LPS. Similarly, incubation of bone marrow-derived DCs with archaeosomes resulted in enhanced expression of MHC class II and B7.2 molecules. In contrast, conventional liposomes made from ester phospholipids failed to modulate the expression of these activation markers. APCs treated with archaeosomes exhibited increased TNF production and functional ability to stimulate allogenic T cell proliferation. More interestingly, archaeosomes enhanced APC recruitment and activation in vivo. Intraperitoneal injection of archaeosomes into mice led to recruitment of Mac1α+, F4/80+ and CD11c+ cells. The expression of MHC class II on the surface of peritoneal cells was also enhanced. Furthermore, peritoneal cells from archaeosome-injected mice strongly enhanced allo-T cell proliferation and cytokine production. The ability of archaeosome-treated APCs to stimulate T cells was restricted to Mac1αhigh, B220− cells in the peritoneum. These Mac1αhigh cells in the presence of GM-CSF gave rise to both F4/80+ (macrophage) and CD11c+ (dendritic) populations. Overall, the activation of APCs correlated to the ability of archaeosomes to induce strong humoral, T helper, and CTL responses to entrapped Ag. Thus, the recruitment and activation of professional APCs by archaeosomes constitutes an efficient self-adjuvanting process for induction of Ag-specific responses to encapsulated Ags.
IL-4 Plays a Crucial Role in Regulating Oxidative Damage in the Liver During Schistosomiasis
Authors: La Flamme Anne Camille , Patton Elisabeth A. , Bauman Beverley , Pearce Edward J. 
Published: April 2014

AbstractLiver enlargement and hepatocyte proliferation, normal responses in wild-type (WT) mice infected with the parasitic helminth Schistosoma mansoni, were found to be severely impaired in infected IL-4−/− mice. Compared with WT mice, increased levels of O2−, NO, and the more highly reactive ONOO− were detected in the liver and produced by lesional cells isolated from liver granulomas of infected IL-4−/− mice. Concurrently, antioxidant defenses in the liver, specifically catalase levels, diminished dramatically during the course of infection in these animals. This contrasted to the situation in infected WT mice, where catalase levels remained as high as those in normal mice. Actual levels of reactive oxygen and nitrogen intermediates in the livers of infected IL-4−/− animals are thus likely to be considerably higher than those in the livers of infected WT mice. To determine whether these changes contributed to the development of the more severe disease that characterizes infection in the IL-4−/− animals, we treated infected IL-4−/− mice with uric acid, a potent scavenger of ONOO−. This resulted in significantly increased hepatocyte proliferation, decreased morbidity, and prolonged survival. Taken together, these data indicate that IL-4 is playing a protective role during schistosomiasis by controlling the tight regulation of the generation of reactive oxygen and nitrogen intermediates in the liver.
Mice Lacking the Chemokine Receptor CCR1 Show Increased Susceptibility toToxoplasma gondiiInfection
Authors: Khan Imtiaz A. , Murphy Philip M. , Casciotti Lori , Schwartzman Joseph D. , Collins Jane , Gao Ji-Liang , Yeaman Grant R. 
Published: April 2014

AbstractChemokines are critical for the recruitment of effector immune cells to sites of infection. Mice lacking the chemokine receptor CCR1 have defects in neutrophil trafficking and proliferation. In the present study, we tested the susceptibility of CCR1 knockout mice to infection with the obligate intracellular protozoan parasite Toxoplasma gondii. In comparison with parental wild-type mice, CCR1−/− mice exhibited dramatically increased mortality to T. gondii in association with an increased tissue parasite load. No differences were observed in Ag-specific T cell proliferation or in cytokine responses between mutant and wild-type mice. However, the influx of PMNs to the peripheral blood and to the liver were reduced in CCR1−/− mice during early infection. Our results suggest that CCR1-dependent migration of neutrophils to the blood and tissues may have a significant impact in controlling parasite replication.
MD-2 Enables Toll-Like Receptor 2 (TLR2)-Mediated Responses to Lipopolysaccharide and Enhances TLR2-Mediated Responses to Gram-Positive and Gram-Negative Bacteria and Their Cell Wall Components
Authors: Dziarski Roman , Wang Qiuling , Miyake Kensuke , Kirschning Carsten J. , Gupta Dipika 
Published: April 2014

Abstract
MD-2 is associated with Toll-like receptor 4 (TLR4) on the cell surface and enables TLR4 to respond to LPS. We tested whether MD-2 enhances or enables the responses of both TLR2 and TLR4 to Gram-negative and Gram-positive bacteria and their components. TLR2 without MD-2 did not efficiently respond to highly purified LPS and LPS partial structures. MD-2 enabled TLR2 to respond to nonactivating protein-free LPS, LPS mutants, or lipid A and enhanced TLR2-mediated responses to both Gram-negative and Gram-positive bacteria and their LPS, peptidoglycan, and lipoteichoic acid components. MD-2 enabled TLR4 to respond to a wide variety of LPS partial structures, Gram-negative bacteria, and Gram-positive lipoteichoic acid, but not to Gram-positive bacteria, peptidoglycan, and lipopeptide. MD-2 physically associated with TLR2, but this association was weaker than with TLR4. MD-2 enhanced expression of both TLR2 and TLR4, and TLR2 and TLR4 enhanced expression of MD-2. Thus, MD-2 enables both TLR4 and TLR2 to respond with high sensitivity to a broad range of LPS structures and to lipoteichoic acid, and, moreover, MD-2 enhances the responses of TLR2 to Gram-positive bacteria and peptidoglycan, to which the TLR4-MD-2 complex is unresponsive.
Host Responses toPlasmodium yoeliiHepatic Stages: A Paradigm in Host-Parasite Interaction
Authors: Lau Audrey O. T. , Sacci John B. , Azad Abdu F. 
Published: April 2014

AbstractThe liver stage of malaria, caused by the genus Plasmodium, is clinically silent, but immunologically significant. Ample evidence exists for an effective CD8+ T cell response to this stage as well as the involvement of γδT cells and NK1.1int cells in immunized animal models. In contrast, there is little information concerning responses in a naive host. Here we report that several host gene expressions in the liver, spleen, and kidney of BALB/c mice are altered during the liver stage of Plasmodium yoelii infection. Really interesting new gene 3 (Ring3), semaphorin subclass 4 member G, glutamylcysteine synthetase, and p45 NF erythroid 2 were all up-regulated 24 h after infection with P. yoelii. Semaphorin subclass 4 member G expression was elevated in the kidney, whereas Ring3 was elevated in both spleen and kidney. The expression of TNF-α (TNF-α and IFN-γ) were down-regulated in all three tissues tested except in infected spleen where IFN-γ was elevated. P. yoelii-related host gene changes were compared with those in Toxoplasma gondii-infected livers. Ring3 expression increased 5-fold over control values, whereas expression of the other transcripts remained unchanged. TNF-α and IFN-γ expressions were increased in the Toxoplasma-infected livers. The uniform increase of Ring3 expression in both Plasmodium- and Toxoplasma-infected livers suggests an innate immune response against parasitic infections, whereas the other gene expression changes are consistent with Plasmodium parasite-specific responses. Taken together, these changes suggest the immune responses to P. yoelii infection are both parasite and organ specific.
A Model to Predict Cell-Mediated Immune Regulatory Mechanisms During Human Infection withMycobacterium tuberculosis
Authors: Wigginton Janis E. , Kirschner Denise 
Published: April 2014

AbstractA key issue for the study of tuberculosis infection (TB) is to understand why individuals infected with Mycobacterium tuberculosis experience different clinical outcomes. Elaborating the immune mechanisms that determine whether an infected individual will suffer active TB or latent infection can aid in developing treatment and prevention strategies. To better understand the dynamics of M. tuberculosis infection and immunity, we have developed a virtual human model that qualitatively and quantitatively characterizes the cellular and cytokine control network operational during TB infection. Using this model, we identify key regulatory elements in the host response. In particular, factors affecting cell functions, such as macrophage activation and bactericidal capabilities, and effector T cell functions such as cytotoxicity and cytokine production can each be determinative. The model indicates, however, that even if latency is achieved, it may come at the expense of tissue damage if the response is not properly regulated. A balance in Th1 and Th2 immune responses governed by IFN-γ, IL-10, and IL-4 facilitate this down-regulation. These results are further explored through virtual deletion and depletion experiments.
Perforin Is Required for Primary Immunity toHistoplasma capsulatum
Authors: Zhou Ping , Freidag Brenda L. , Caldwell Charles C. , Seder Robert A. 
Published: April 2014

AbstractProtective immunity against primary and secondary infection by the fungus Histoplasma capsulatum (HC) is multifactorial, requiring cells of the innate and adaptive immune response. Effector mechanisms that could mediate intracellular killing of HC include cytokines such as IFN-γ and TNF-α and/or direct cytolytic activity by T and NK cells. In this regard, although previous work has clearly demonstrated a critical role for IFN-γ and TNF-α in limiting fungal growth in primary HC infection, less is known regarding the role of cytolytic mechanisms. The studies reported here first address the role of perforin in mediating immunity to HC. Remarkably, perforin-deficient knockout (PfKO) mice were shown to have accelerated mortality and increased fungal burden following a lethal or sublethal primary challenge. These data established an essential role for perforin in primary immunity systemic HC infection. Interestingly, depletion of CD8+ T cells in PfKO mice caused a further increase in fungal burden and accelerated mortality, suggesting a perforin-independent role for CD8+ T cells. Moreover, adoptive transfer of CD8+ T cells from PfKO mice into IFN-γ−/− mice caused a reduction in fungal burden following infectious challenge compared with control IFN-γ−/− mice. Together, these data suggest that CD8+ T cells can mediate immunity to HC through both perforin-dependent and -independent mechanisms.
Therapeutic Benefit of a Dissociated Glucocorticoid and the Relevance of In Vitro Separation of Transrepression from Transactivation Activity
Authors: Belvisi Maria G. , Wicks Sharon L. , Battram Clifford H. , Bottoms Stephen E. W. , Redford Jane E. , Woodman Paul , Brown Thomas J. , Webber Stephen E. , Foster Martyn L. 
Published: April 2014

Abstract
Glucocorticoids (GCs) are the mainstay of asthma therapy; however, major side effects limit their therapeutic use. GCs influence the expression of genes either by transactivation or transrepression. The antiinflammatory effects of steroids are thought to be due to transrepression and the side effects, transactivation. Recently, a compound, RU 24858, has been identified that demonstrated dissociation between transactivation and transrepression in vitro. RU 24858 exerts strong AP-1 inhibition (transrepression), but little or no transactivation. We investigated whether this improved in vitro profile results in the maintenance of antiinflammatory activity (evaluated in the Sephadex model of lung edema) with reduced systemic toxicity (evaluated by loss in body weight, thymus involution, and bone turnover) compared with standard GCs. RU 24858 exhibits comparable antiinflammatory activity to the standard steroid, budesonide. However, the systemic changes observed indicate that transactivation events do occur with this GC with similar potency to the standard steroids. In addition, the GCs profiled showed no differentiation on quantitative osteopenia of the femur. These results suggest that in vitro separation of transrepression from transactivation activity does not translate to an increased therapeutic ratio for GCs in vivo or that adverse effects are a consequence of transrepression.
Bacterial Lipopolysaccharide and IFN-γ Induce Toll-Like Receptor 2 and Toll-Like Receptor 4 Expression in Human Endothelial Cells: Role of NF-κB Activation
Authors: Faure Emmanuelle , Thomas Lisa , Xu Helen , Medvedev Andrei E. , Equils Ozlem , Arditi Moshe 
Published: April 2014

AbstractToll-like receptor (TLR) 4 has been identified as the primary receptor for enteric LPS, whereas TLR2 has been implicated as the receptor for Gram-positive and fungal cell wall components and for bacterial, mycobacterial, and spirochetal lipoproteins. Vascular endothelial cell (EC) activation or injury by microbial cell wall components such as LPS is of critical importance in the development of sepsis and septic shock. We have previously shown that EC express predominantly TLR4, and have very little TLR2. These cells respond vigorously to LPS via TLR4, but are unresponsive to lipoproteins and other TLR2 ligands. Here we show that LPS, TNF-α, or IFN-γ induce TLR2 expression in both human dermal microvessel EC and HUVEC. Furthermore, LPS and IFN-γ act synergistically to induce TLR2 expression in EC, and LPS-induced TLR2 expression is NF-κB dependent. LPS and IFN-γ also up-regulate TLR4 mRNA expression in EC. These data indicate that TLR2 and TLR4 expression in ECs is regulated by inflammatory molecules such as LPS, TNF-α, or IFN-γ. TLR2 and TLR4 molecules may render EC responsive to TLR2 ligands and may help to explain the synergy between LPS and lipoproteins, and between LPS and IFN-γ, in inducing shock associated with Gram-negative sepsis.
Blockade of Secondary Lymphoid Tissue Chemokine Exacerbates Propionibacterium acnes-Induced Acute Lung Inflammation
Authors: Itakura Meiji , Tokuda Atsuko , Kimura Hiroshi , Nagai Shigenori , Yoneyama Hiroyuki , Onai Nobuyuki , Ishikawa Sho , Kuriyama Takayuki , Matsushima Kouji 
Published: April 2014

Abstract
Chemokine-chemokine receptor interaction plays an essential role in leukocyte/dendritic cell (DC) trafficking in inflammation and immune responses. We investigated the pathophysiological roles of secondary lymphoid tissue chemokine (SLC; CCL21) and macrophage inflammatory protein-2 (MIP-2) in the development of acute pulmonary inflammation induced by an intratracheal injection of Propionibacterium acnes in mice. Immunohistochemical studies revealed that SLC was constitutively expressed in the peribronchial areas and perivascular lymphatics in normal mice. MIP-2-positive cells were observed in alveolar spaces in mice challenged with P. acnes. Both neutralization Abs against MIP-2 and CXC chemokine receptor 2 alleviated the P. acnes-induced pulmonary inflammation when injected before P. acnes Ag challenge. On the other hand, polyclonal anti-SLC Abs (pAbs) exacerbated the pulmonary inflammation. The numbers of mature DCs (MHC class II +, CD11c+, and CD86+) as well as macrophages and neutrophils in the P. acnes Ag-challenged lungs were increased, whereas the number of CD4+ T cells, including memory T cells, was decreased. The numbers of mature and proliferating CD4+ T cells (bromodeoxyuridine+CD4+) in regional lymph nodes were decreased in mice injected with anti-SLC pAbs compared with those in mice treated with control Abs. An in vitro proliferation assay confirmed the impairment of the Ag-specific T cell response in regional lymph nodes of mice treated with anti-SLC pAbs. These results indicate for the first time a regulatory role for SLC-recruited mature DCs in bridging an acute inflammatory response (innate immunity) and acquired immunity in the lung.
Local Transgenic Expression of Granulocyte Macrophage-Colony Stimulating Factor Initiates Autoimmunity
Authors: Biondo Mark , Nasa Zeyad , Marshall Aiden , Hock Toh Ban , Alderuccio Frank 
Published: April 2014

Abstract
Mechanisms leading to breakdown of immunological tolerance and initiation of autoimmunity are poorly understood. Experimental autoimmune gastritis is a paradigm of organ-specific autoimmunity arising from a pathogenic autoimmune response to gastric H/K ATPase. The gastritis is accompanied by autoantibodies to the gastric H/K ATPase. The best characterized model of experimental autoimmune gastritis requires neonatal thymectomy. This procedure disrupts the immune repertoire, limiting its usefulness in understanding how autoimmunity arises in animals with intact immune systems. Here we tested whether local production of GM-CSF, a pro-inflammatory cytokine, is sufficient to break tolerance and initiate autoimmunity. We generated transgenic mice expressing GM-CSF in the stomach. These transgenic mice spontaneously developed gastritis with an incidence of about 80% after six backcrosses to gastritis-susceptible BALBc/CrSlc mice. The gastritis is accompanied by mucosal hypertrophy, enlargement of draining lymph nodes and autoantibodies to gastric H/K ATPase. An infiltrate of dendritic cells and macrophages preceded CD4 T cells into the gastric mucosa. T cells from draining lymph nodes specifically proliferated to the gastric H/K ATPase. CD4 but not CD8 T cells transferred gastritis to nude mouse recipients. CD4+ CD25+ T cells from the spleen retained anergic suppressive properties that were reversed by IL-2. We conclude that local expression of GM-CSF is sufficient to break tolerance and initiate autoimmunity mediated by CD4 T cells. This new mouse model should be useful for studies of organ-specific autoimmunity.