bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific Inhibition of the Classical Complement Pathway by C1q-Binding Peptides
Authors: Roos Anja , Nauta Alma J. , Broers Daniël , Faber-Krol Maria C. , Trouw Leendert A. , Drijfhout Jan Wouter , Daha Mohamed R. 
Published: April 2014

AbstractUndesired activation of the complement system is a major pathogenic factor contributing to various immune complex diseases and conditions such as hyperacute xenograft rejection. We aim for prevention of complement-mediated damage by specific inhibition of the classical complement pathway, thus not affecting the antimicrobial functions of the complement system via the alternative pathway and the lectin pathway. Therefore, 42 peptides previously selected from phage-displayed peptide libraries on basis of C1q binding were synthesized and examined for their ability to inhibit the function of C1q. From seven peptides that showed inhibition of C1q hemolytic activity but no inhibition of the alternative complement pathway, one peptide (2J) was selected and further studied. Peptide 2J inhibited the hemolytic activity of C1q from human, chimpanzee, rhesus monkey, rat, and mouse origin, all with a similar dose-response relationship (IC50 2–6 μM). Binding of C1q to peptide 2J involved the globular head domain of C1q. In line with this interaction, peptide 2J dose-dependently inhibited the binding of C1q to IgG and blocked activation of C4 and C3 and formation of C5b-9 induced via classical pathway activation, as assessed by ELISA. Furthermore, the peptide strongly inhibited the deposition of C4 and C3 on pig cells following their exposure to human xenoreactive Abs and complement. We conclude that peptide 2J is a promising reagent for the development of a therapeutic inhibitor of the earliest step of the classical complement pathway, i.e., the binding of C1q to its target.
Role of IL-18 in Acute Lung Inflammation
Authors: Jordan Jacqueline A. , Guo Ren-Feng , Yun Edward C. , Sarma Vidya , Warner Roscoe L. , Crouch Larry D. , Senaldi Giorgio , Ulich Thomas R. , Ward Peter A. 
Published: April 2014

AbstractWe have examined the role of IL-18 after acute lung inflammation in rats caused by intrapulmonary deposition of IgG immune complexes. Constitutive IL-18 mRNA and protein expression (precursor form, 26 kDa) were found in normal rat lung, whereas in inflamed lungs, IL-18 mRNA was up-regulated; in bronchoalveolar (BAL) fluids, the 26-kDa protein form of IL-18 was increased at 2–4 h in inflamed lungs and remained elevated at 24 h, and the “mature” protein form of IL-18 (18 kDa) appeared in BAL fluids 1–8 h after onset of inflammation. ELISA studies confirmed induction of IL-18 in inflamed lungs (in lung homogenates and in BAL fluids). Prominent immunostaining for IL-18 was found in alveolar macrophages from inflamed lungs. When rat lung macrophages, fibroblasts, type II cells, and endothelial cells were cultured in vitro with LPS, only the first two produced IL-18. Intratracheal administration of rat recombinant IL-18 in the lung model caused significant increases in lung vascular permeability and in BAL content of neutrophils and in BAL content of TNF-α, IL-1β, and cytokine-induced neutrophil chemoattractant, whereas intratracheal instillation of anti-IL-18 greatly reduced these changes and prevented increases in BAL content of IFN-γ. Intratracheal administration of the natural antagonist of IL-18, IL-18 binding protein, resulted in suppressed lung vascular permeability and decreased BAL content of neutrophils, cytokines, and chemokines. These findings suggest that endogenous IL-18 functions as a proinflammatory cytokine in this model of acute lung inflammation, serving as an autocrine activator to bring about expression of other inflammatory mediators.
Administration of Dehydroepiandrosterone Suppresses Experimental Allergic Encephalomyelitis in SJL/J Mice
Authors: Du Caigan , Khalil M. Wahid , Sriram Subramaniam 
Published: April 2014

AbstractExperimental allergic encephalomyelitis (EAE) is a Th1-mediated inflammatory demyelinating disease in the CNS, an animal model of multiple sclerosis. We have examined the effect of dehydroepiandrosterone (DHEA) on the development of EAE in mice. The addition of DHEA to cultures of myelin basic protein-primed splenocytes resulted in a significant decrease in T cell proliferation and secretion of (pro)inflammatory cytokines (IFN-γ, IL-12 p40, and TNF-α) and NO in response to myelin basic protein. These effects were associated with a decrease in activation and translocation of NF-κB. In vivo administration of DHEA significantly reduced the severity and incidence of acute EAE, along with a decrease in demyelination/inflammation and expressions of (pro)inflammatory cytokines in the CNS. These studies suggest that DHEA has potent anti-inflammatory properties, which at least are in part mediated by its inhibition of NF-κB activation.
Role of TGFβ in Development of Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice
Authors: Braley-Mullen Helen , Chen Kemin , Wei Yongzhong , Yu Shiguang 
Published: April 2014

AbstractNearly 100% of NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) and produce anti-mouse thyroglobulin autoantibodies when they receive 0.05% NaI in their drinking water beginning at 8 wk of age. Our previous studies showed that TGFβ1 mRNA was constitutively expressed in thyroids and spleens of normal NOD.H-2h4 mice but not other strains of mice. To determine whether TGFβ might have a role in SAT, mice were given anti-TGFβ mAb at various times during development of SAT. Anti-TGFβ markedly inhibited development of SAT and production of anti-mouse thyroglobulin IgG1 autoantibodies. Anti-TGFβ was most effective in inhibiting SAT when given during the time thyroid lesions were developing, i.e., starting 4 wk after administration of NaI water. The active form of the TGFβ1 protein was present in thyroids of mice with SAT but not in normal NOD.H-2h4 thyroids. However, thyrocytes of normal NOD.H-2h4 thyroids did express latent TGFβ1. TGFβ1 protein expression in the thyroid correlated with SAT severity scores, and administration of anti-TGFβ inhibited TGFβ1 protein expression in both the thyroid and spleen. TGFβ1 was produced primarily by inflammatory cells and was primarily localized in areas of the thyroid containing clusters of CD4+ T and B cells. Depletion of CD8+ T cells had no effect on TGFβ1 protein expression. Activation of splenic T cells was apparently not inhibited by anti-TGFβ, because up-regulation of mRNA for cytokines and other T cell activation markers was similar for control and anti-TGFβ-treated mice. TGFβ1 may function by promoting migration to, or retention of, inflammatory cells in the thyroid.
Systemic Sclerosis (Scleroderma): Specific Autoantigen Genes Are Selectively Overexpressed in Scleroderma Fibroblasts
Authors: Zhou Xiaodong , Tan Filemon K. , Xiong Momiao , Milewicz Dianna M. , Feghali Carol A. , Fritzler Marvin J. , Reveille John D. , Arnett Frank C. 
Published: April 2014

AbstractThe pathogenesis of systemic sclerosis (SSc) involves complex interactions between activated fibroblasts eventually leading to fibrosis, and impaired immune tolerance characterized by a variety of circulating SSc-specific autoantibodies. The expression of autoantigens in fibroblasts, a key target tissue in SSc, may play an important role in this process. To obtain a global view of this process, we examined gene expression profiles of SSc dermal fibroblasts using cDNA microarrays. The results show that dermal fibroblasts from SSc patients obtained from either affected or unaffected skin displayed a characteristic pattern of increased SSc autoantigen gene expression compared with that from normal controls. In particular, fibrillarin (p = 0.028), centromeric protein B (p = 0.01), centromeric autoantigen P27 (p = 0.042), and RNA polymerase II (220 kDa; p = 0.02) were significantly overexpressed in SSc fibroblasts. Quantitative RT-PCR confirmed overexpression of these autoantigens and also revealed increased levels of DNA topoisomerase I transcripts in SSc fibroblasts compared with normal control fibroblasts (p = 0.0318). The polymyositis/scleroderma autoantigen gene was overexpressed in some SSc patients (p = 0.09). To examine the specificity of these overexpressed autoantigen genes for SSc and its tissue specificity for fibroblasts, cDNA microarrays of dermal fibroblasts from patients with eosinophilic fasciitis and scleromyxedema were studied as well as PBMC and muscle biopsies from SSc patients. None of these tissues showed significant alterations in gene expression of SSc-specific autoantigens. Therefore, SSc-associated autoantigen genes are selectively overexpressed in SSc dermal fibroblasts, a major tissue involved in disease pathogenesis.
Infrequent Detection of HIV-1-Specific, But Not Cytomegalovirus-Specific, CD8+ T Cell Responses in Young HIV-1-Infected Infants
Authors: Scott Zachary A. , Chadwick Ellen G. , Gibson Laura L. , Catalina Michelle D. , McManus Margaret M. , Yogev Ram , Palumbo Paul , Sullivan John L. , Britto Paula , Gay Hannah , Luzuriaga Katherine ,   PACTG 345 Investigators
Published: April 2014

AbstractEarly potent combination antiretroviral therapies (ART) for HIV-1 infection can preserve or restore immune function, but control of viral replication early in infection may interfere with the development of HIV-1-specific immune responses. Using an IFN-γ ELISPOT assay, we evaluated the breadth and intensity of HIV-1-specific CD8+ T cell responses in 17 vertically infected infants who began ART at 1–23 mo of age. CMV-specific responses were also characterized in three infants coinfected with HIV-1 and CMV. Before ART, HIV-1-specific CD8+ T cell responses were detected in two of 13 (15%) infants &lt;6 mo of age. HIV-1-specific CD8+ T cells became undetectable in these two infants after the control of viral replication. Intermittent HIV-1-specific responses were noted in six infants who did not experience durable control of viral replication. In contrast, HIV-1-specific responses were detected before ART in four of four infants &gt;6 mo of age and became persistently undetectable in only one child. CMV-specific CD8+ T cell responses were persistently detected in all HIV-1 and CMV coinfected infants. In conclusion, HIV-1-specific CD8+ T cell responses were less commonly detected before therapy in young infants than in older infants. Suppression of viral replication appeared to interfere with the development and maintenance of HIV-1-specific CD8+ T cell responses. The detection of CMV-specific responses in HIV-1 and CMV coinfected infants suggests a selective defect in the generation or maintenance of HIV-1-specific CD8+ T cell responses. Therapeutic HIV-1 vaccine strategies in young infants may prolong the clinical benefit of ART by expanding the HIV-1-specific CD8+ T cell pool.
Dendritic Cell-Based Xenoantigen Vaccination for Prostate Cancer Immunotherapy
Authors: Fong Lawrence , Brockstedt Dirk , Benike Claudia , Breen Jami K. , Strang George , Ruegg Curtis L. , Engleman Edgar G. 
Published: April 2014

AbstractMany tumor-associated Ags represent tissue differentiation Ags that are poorly immunogenic. Their weak immunogenicity may be due to immune tolerance to self-Ags. Prostatic acid phosphatase (PAP) is just such an Ag that is expressed by both normal and malignant prostate tissue. We have previously demonstrated that PAP can be immunogenic in a rodent model. However, generation of prostate-specific autoimmunity was seen only when a xenogeneic homolog of PAP was used as the immunogen. To explore the potential role of xenoantigen immunization in cancer patients, we performed a phase I clinical trial using dendritic cells pulsed with recombinant mouse PAP as a tumor vaccine. Twenty-one patients with metastatic prostate cancer received two monthly vaccinations of xenoantigen-loaded dendritic cells with minimal treatment-associated side effects. All patients developed T cell immunity to mouse PAP following immunization. Eleven of the 21 patients also developed T cell proliferative responses to the homologous self-Ag. These responses were associated with Ag-specific IFN-γ and/or TNF-α secretion, but not IL-4, consistent with induction of Th1 immunity. Finally, 6 of 21 patients had clinical stabilization of their previously progressing prostate cancer. All six of these patients developed T cell immunity to human PAP following vaccination. These results demonstrate that xenoantigen immunization can break tolerance to a self-Ag in humans, resulting in a clinically significant antitumor effect.
Identification of Anti-Thrombin Antibodies in the Antiphospholipid Syndrome That Interfere with the Inactivation of Thrombin by Antithrombin
Authors: Hwang Kwan-Ki , Grossman Jennifer M. , Visvanathan Sudha , Chukwuocha Reginald U. , Woods Virgil L. , Le Dzung T. , Hahn Bevra H. , Chen Pojen P. 
Published: April 2014

AbstractThe combined presence of anti-phospholipid (PL) Ab, including lupus anticoagulants (LAC) and/or anticardiolipin Ab (aCL), and thrombosis is recognized as the antiphospholipid syndrome (APS). LAC are detected as an inhibitory effect on PL-restricted in vitro blood coagulation tests, and are comprised mainly of Ab against β2 glycoprotein I and prothrombin (PT). Recently, anti-PT Ab (aPT) were found to be associated with thrombosis by some investigators, although this is not confirmed by others. Considering that aPT are heterogeneous in patients and that PT is converted into thrombin, we hypothesize that certain aPT in patients may bind to thrombin, and that some of such anti-thrombin Ab may interfere with thrombin-antithrombin (AT) interaction and thus reduce the AT inactivation of thrombin. To test this hypothesis, we searched for anti-thrombin Ab in APS patients and then studied those found for their effects on the AT inactivation of thrombin. The results revealed that most, but not all, aPT-positive patient plasma samples contained anti-thrombin Ab. To study the functional significance of these Ab, we identified six patient-derived mAb that bound to both PT and thrombin. Of these mAb, three could reduce the AT inactivation of thrombin, whereas others had minimal effect. These findings indicate that some aPT in patients react with thrombin, and that some of such anti-thrombin Ab could inhibit feedback regulation of thrombin. Because the latter anti-thrombin Ab are likely to promote clotting, it will be important to develop specific assays for such Ab and study their roles in thrombosis in APS patients.
Loss of Direct and Maintenance of Indirect Alloresponses in Renal Allograft Recipients: Implications for the Pathogenesis of Chronic Allograft Nephropathy
Authors: Baker Richard J. , Hernandez-Fuentes Maria P. , Brookes Paul A. , Chaudhry Afzal N. , Cook H. Terry , Lechler Robert I. 
Published: April 2014

AbstractChronic allograft nephropathy (CAN) is the principal cause of late renal allograft failure. This complex process is multifactorial in origin, and there is good evidence for immune-mediated effects. The immune contribution to this process is directed by CD4+ T cells, which can be activated by either direct or indirect pathways of allorecognition. For the first time, these pathways have been simultaneously compared in a cohort of 22 longstanding renal allograft recipients (13 with good function and nine with CAN). CD4+ T cells from all patients reveal donor-specific hyporesponsiveness by the direct pathway according to proliferation or the secretion of the cytokines IL-2, IL-5, and IFN-γ. Donor-specific cytotoxic T cell responses were also attenuated. In contrast, the frequencies of indirectly alloreactive cells were maintained, patients with CAN having significantly higher frequencies of CD4+ T cells indirectly activated by allogeneic peptides when compared with controls with good allograft function. An extensive search for alloantibodies has revealed significant titers in only a minority of patients, both with and without CAN. In summary, this study demonstrates widespread donor-specific hyporesponsiveness in directly activated CD4+ T cells derived from longstanding recipients of renal allografts, whether they have CAN or not. However, patients with CAN have significantly higher frequencies of CD4+ T cells activated by donor Ags in an indirect manner, a phenomenon resembling split tolerance. These findings provide an insight into the pathogenesis of CAN and also have implications for the development of a clinical tolerance assay.
Cutting Edge: CCR4 Mediates Antigen-Primed T Cell Binding to Activated Dendritic Cells
Authors: Wu Meng-tse , Fang Hui , Hwang Sam T. 
Published: April 2014

Abstract
The binding of a T cell to an Ag-laden dendritic cell (DC) is a critical step of the acquired immune response. Herein, we address whether a DC-produced chemokine can induce the arrest of T cells on DC under dynamic flow conditions. Ag-primed T cells and a T cell line were observed to rapidly (∼0.5 s) bind to immobilized DC at low shear stress (0.1–0.2 dynes/cm2) in a pertussis toxin-sensitive fashion. Quantitatively, Ag-primed T cells displayed 2- to 3-fold enhanced binding to DC compared with unprimed T cells (p &lt; 0.01). In contrast to naive T cells, primed T cell arrest was largely inhibited by pertussis toxin, neutralization of the CC chemokine, macrophage-derived chemokine (CCL22), or by desensitization of the CCL22 receptor, CCR4. Our results demonstrate that DC-derived CCL22 induces rapid binding of activated T cells under dynamic conditions and that Ag-primed and naive T cells fundamentally differ with respect to chemokine-dependent binding to DC.
Cutting Edge: Membrane Lymphotoxin Regulates CD8+ T Cell-Mediated Intestinal Allograft Rejection
Authors: Guo Zhong , Wang Jun , Meng Lingzhong , Wu Qiang , Kim Oliver , Hart John , He Gang , Zhou Ping , Thistlethwaite J. Richard , Alegre Maria-Luisa , Fu Yang-Xin , Newell Kenneth A. 
Published: April 2014

AbstractBlocking the CD28/B7 and/or CD154/CD40 costimulatory pathways promotes long-term allograft survival in many transplant models where CD4+ T cells are necessary for rejection. When CD8+ T cells are sufficient to mediate rejection, these approaches fail, resulting in costimulation blockade-resistant rejection. To address this problem we examined the role of lymphotoxin-related molecules in CD8+ T cell-mediated rejection of murine intestinal allografts. Targeting membrane lymphotoxin by means of a fusion protein, mAb, or genetic mutation inhibited rejection of intestinal allografts by CD8+ T cells. This effect was associated with decreased monokine induced by IFN-γ (Mig) and secondary lymphoid chemokine (SLC) gene expression within allografts and spleens respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4+ T cells. Combining disruption of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice. These data demonstrate that membrane lymphotoxin is an important regulatory molecule for CD8+ T cells mediating rejection and suggest a strategy to avoid costimulation blockade-resistant rejection.
T Cell Subsets and In Vitro Immune Regulation in “Infectious” Transplantation Tolerance
Authors: Zhai Yuan , Shen Xiu-Da , Lehmann Manfred , Busuttil Ronald , Volk Hans-Dieter , Kupiec-Weglinski Jerzy W. 
Published: April 2014

AbstractCD4-targeted mAb therapy results in permanent acceptance of cardiac allografts in rat recipients, in conjunction with features of the infectious tolerance pathway. Although CD4+ T cells play a central role, the actual cellular and molecular tolerogenic mechanisms remain elusive. This study was designed to analyze in vitro alloimmune responses of T lymphocytes from CD4 mAb-treated engrafted hosts. Spleen, but not lymph node, cells lost proliferative response against donor alloantigen in MLR and suppressed test allograft rejection in adoptive transfer studies, suggesting compartmentalization of tolerogenic T cells in transplant recipients. A high dose of exogenous IL-2 restored the allogeneic response of tolerogenic T cells, indicating anergy as a putative mechanism. Vigorous proliferation of the tolerogenic T cells in in vivo MLR supports the existence of alloreactive lymphocytes in tolerogenic T cell repertoire and implies an active operational suppression mechanism. The tolerogenic splenocytes suppressed proliferation of naive splenocytes in vitro, consistent with their in vivo property of dominant immune regulation. Finally, CD45RC+ but not CD45RC− T cells from tolerant hosts were hyporesponsive to alloantigen and suppressed the proliferation of normal T cells in the coculture assay. Thus, nondeletional, anergy-like regulatory mechanisms may operate via CD4+CD45RC+ T cells in the infectious tolerance pathway in transplant recipients.
Bryostatin-1 and IL-2 Synergize to Induce IFN-γ Expression in Human Peripheral Blood T Cells: Implications for Cancer Immunotherapy
Authors: Curiel Rafael E. , Garcia Carmen S. , Farooq Lubna , Aguero Martin F. , Espinoza-Delgado Igor 
Published: April 2014

AbstractBryostatin-1 (Bryo-1), a protein kinase C modulator with antineoplastic activity, may exert some of its antitumor activity through activation of the immune response. Studies in tumor-bearing hosts have indicated that the T cell response, particularly IFN-γ production, is impaired. To evaluate whether Bryo-1 plus IL-2 may affect the activation pattern of T cells, we investigated the expression of IFN-γ mRNA and protein in human primary T cells. Northern blot analysis and ELISAs demonstrated that Bryo-1 and IL-2 synergized to induce both IFN-γ mRNA and protein expression. This synergistic induction was seen within 3 h of treatment and with as little as 10 U/ml IL-2 and 1.0 ng/ml Bryo-1. In vitro transcription assays revealed that Bryo-1 plus IL-2 induced transcriptional activation of the IFN-γ gene. Furthermore, mRNA stability studies indicated that this treatment also enhanced the IFN-γ mRNA half-life. Both CD4+ and CD8+ T cells responded to the treatment with IFN-γ expression. The induction of the IFN-γ expression was decreased by a specific p38 mitogen-activated protein kinase inhibitor, but not by a protein kinase C inhibitor. Our results demonstrate for the first time that Bryo-1 in combination with IL-2 control IFN-γ gene expression at both the transcriptional and post-transcriptional levels through a p38 mitogen-activated protein kinase-dependent process. Given the pivotal role that IFN-γ plays in the orchestration of an effective Th1 type of response, our results suggest that Bryo-1 plus IL-2 may be a valuable combined therapy for cancer treatment.
Viral Infections Induce Abundant Numbers of Senescent CD8 T Cells
Authors: Voehringer David , Blaser Claudine , Brawand Pierre , Raulet David H. , Hanke Thomas , Pircher Hanspeter 
Published: April 2014

Abstract
Viral infections are often accompanied by extensive proliferation of reactive CD8 T cells. After a defined number of divisions, normal somatic cells enter a nonreplicative stage termed senescence. In the present study we have identified the inhibitory killer cell lectin-like receptor G1 (KLRG1) as a unique marker for replicative senescence of murine CD8 T cells. KLRG1 expression was induced in a substantial portion (30–60%) of CD8 T cells in C57BL/6 mice infected with lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus, or vaccinia virus. Similarly, KLRG1 was found on a large fraction of LCMV gp33 peptide-specific TCR-transgenic (tg) effector and memory cells activated in vivo using an adoptive transfer model. Transfer experiments with CFSE-labeled TCR-tg cells into LCMV-infected hosts further indicated that induction of KLRG1 expression required an extensive number of cell divisions. Most importantly, KLRG1+ TCR-tg effector/memory cells could efficiently lyse target cells and secrete cytokines, but were severely impaired in their ability to proliferate after Ag stimulation. Thus, this study demonstrates that senescent CD8 T cells are induced in abundant numbers during viral infections in vivo.