bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequence Polymorphisms in the Chemokines Scya1 (TCA-3), Scya2 (Monocyte Chemoattractant Protein (MCP)-1), and Scya12 (MCP-5) Are Candidates for eae7, a Locus Controlling Susceptibility to Monophasic Remitting/Nonrelapsing Experimental Allergic Encephalomyelitis
Authors: Teuscher Cory , Butterfield Russell J. , Ma Runlin Z. , Zachary James F. , Doerge R. W. , Blankenhorn Elizabeth P. 
Published: January 2023

Abstract
Experimental allergic encephalomyelitis (EAE), the principal animal model of multiple sclerosis, is genetically controlled. To date, 13 disease-modifying loci have been identified in the mouse by whole genome scanning using an F2 intercross between EAE-susceptible SJL/J and EAE-resistant B10.S/DvTe mice. Two quantitative trait loci (QTL), eae6 and eae7, on chromosome 11 were identified by classical marker-specific linkage analysis and interval mapping. Both QTL were reported to be associated with severity and duration of clinical signs. eae7 was subsequently shown to be a unique locus controlling the development of monophasic remitting/nonrelapsing EAE. In this study, composite interval mapping resolved eae6 into two linked QTL: eae6a at 0–13 cM is associated with disease severity, and eae6b at 19–28 cM associated with the duration of clinical signs. Additionally, composite interval mapping significantly refined the locations of eae6a, eae6b, and eae7, thereby facilitating systematic candidate gene screening by cDNA sequencing of SJL/J and B10.S/DvTe alleles. Sequence polymorphisms were not seen in Lif and IL12β, candidate genes for eae6a and eae6b, respectively. Similarly, cDNA sequence polymorphisms in Nos2, Scya3, Scya4, Scya5, Scya6, Scya7, Scya9, Scya10, and Scya11 were excluded as candidates for eae7. However, multiple sequence polymorphisms resulting in significant amino acid substitutions were identified in Scya1 (TCA-3), Scya2 (monocyte chemoattractant protein (MCP)-1), and Scya12 (MCP-5). Given the role of chemokines in EAE, these sequence polymorphisms are promising candidates for eae7, a locus associated with severity of clinical signs and susceptibility to the shorter, less severe monophasic remitting/nonrelapsing form of disease.
Generation of Anti-p53 Fab Fragments from Individuals with Colorectal Cancer Using Phage Display
Authors: Coomber David W. J. , Hawkins Nicholas J. , Clark Michelle A. , Ward Robyn L. 
Published: January 2023

Abstract
Although many individuals with malignancy develop Abs against p53, little is currently known of the structural features, V gene usage, and degree of somatic mutation of these Abs. Such information is critical to any meaningful understanding of the nature and significance of this humoral immune response to p53. We have constructed phage display libraries from six individuals with colorectal cancer and a demonstrable serum immune response against p53. Following panning with recombinant p53, a total of 43 binding Fab were identified. Four of these Abs bound with high affinity to wild-type denatured p53 (1.19 × 10−8 − 1.57 × 10−8), as determined by BIAcore analysis, and were highly specific for both recombinant and cell line-derived p53, as determined by ELISA and immunoprecipitation. Epitope mapping showed they were reactive with the N terminus of human p53 between residues 27 and 44. Sequence analysis showed that the heavy chains were derived from the VH1 gene family, and the light chains from VL4. The pattern of replacement and silent mutations in the Fab sequence indicated that negative selection had occurred in the framework regions of all the VH genes. We show that lymphocytes from individuals with cancer represent a valuable source of high affinity human Abs against p53. This approach provides an opportunity to examine the genetic structure of these naturally occurring Abs, and to draw inferences regarding the nature of the immune response that produced them. Abs identified in this way have a number of potential therapeutic applications.
Isolation and Characterization of Human Monoclonal Antibodies to Digoxin
Authors: Ball William J. , Kasturi Rama , Dey Purabi , Tabet Michael , O’Donnell Susan , Hudson Debra , Fishwild Dianne 
Published: January 2023

Abstract
Fab preparations of sheep polyclonal anti-digoxin Abs have proven useful for reversal of the toxic effects of digoxin overdoses in patients. Unfortunately, the use of foreign species proteins in humans is limited because of the potential for immunological responses that include hypersensitivity reactions and acute anaphylaxis. Immunization of recently developed transgenic mice, whose endogenous μ heavy and κ light chain Ig genes are inactivated and which carry human Ig gene segments, with a digoxin-protein conjugate has enabled us to generate and isolate eight hybridoma cell lines secreting human sequence anti-digoxin mAbs. Six of the mAbs have been partially characterized and shown to have high specificity and low nanomolar affinities for digoxin. In addition, detailed competition binding studies performed with three of these mAbs have shown them to have distinct differences in their digoxin binding, and that all three structural moieties of the drug, the primary digitoxose sugar, steroid, and five-member unsaturated lactone ring, contribute to Ab recognition.
High T Cell Epitope Sharing Between Two HLA-B27 Subtypes (B*2705 and B*2709) Differentially Associated to Ankylosing Spondylitis
Authors: García-Peydró Marina , Martí Mercè , López de Castro José A. 
Published: January 2023

Abstract
HLA-B*2705 is strongly associated with ankylosing spondylitis (AS) and reactive arthritis. In contrast, B*2709 has been reported to be more weakly or not associated to AS. These two molecules differ by a single amino acid change: aspartic acid in B*2705 or histidine in B*2709 at position 116. In this study, we analyzed the degree of T cell epitope sharing between the two subtypes. Ten allospecific T cell clones raised against B*2705, 10 clones raised against B*2703 but cross-reactive with B*2705, and 10 clones raised against B*2709 were examined for their capacity to lyse B*2705 and B*2709 target cells. The anti-B*2705 and anti-B*2703 CTL were peptide dependent as demonstrated by their failure to lyse TAP-deficient B*2705-T2 transfectant cells. Eight of the anti-B*2705 and five of the anti-B*2703 CTL clones lysed B*2709 targets. The degree of cross-reaction between B*2705 and B*2709 was donor dependent. In addition, the effect of the B*2709 mutation (D116H) on allorecognition was smaller than the effect of the other naturally occurring subtype change at this position, D116Y. These results demonstrate that B*2705 and B*2709 are the antigenically closest HLA-B27 subtypes. Because allospecific T cell recognition is peptide dependent, our results imply that the B*2705- and B*2709-bound peptide repertoires are largely overlapping. Thus, to the extent to which linkage of HLA-B27 with AS is related to the peptide-presenting properties of this molecule, our results would imply that peptides within a relatively small fraction of the HLA-B27-bound peptide repertoire influence susceptibility to this disease.
Immune Responses in Asymptomatic HIV-1-Infected Patients After HIV-DNA Immunization Followed by Highly Active Antiretroviral Treatment
Authors: Calarota Sandra A. , Leandersson Ann-Charlotte , Bratt Göran , Hinkula Jorma , Klinman Dennis M. , Weinhold Kent J. , Sandström Eric , Wahren Britta 
Published: January 2023

Abstract
Intensive chemotherapy is capable of reducing the viral load in HIV-1-infected individuals while infected cells are still present. A special property of DNA immunization is to induce both new CTL and Ab responses. We evaluated the possibility of inducing new immune responses in already infected individuals by means of DNA constructs encoding the nef, rev, or tat regulatory HIV-1 genes. Significant changes in viral loads and CD4+ counts were observed in four patients who started highly active antiretroviral treatment (HAART) during the immunization study. The DNA immunization induced Ag-specific T cell proliferation, which persisted up to 9 mo after the last DNA injection, and cytolytic activities but did not, by itself, reduce viral load. Increased levels of CTL precursor cells were induced in all nine DNA-immunized patients. The profile of IFN-γ secretion observed when human PBMC were transfected with the nef, rev, and tat DNA resembled that found in the CTL activity (nef &gt; tat &gt; rev). Ab responses that occurred after immunizations were of a low magnitude. In accordance with the high IL-6 production induced by the nef DNA plasmid, IgG titers were highest in patients immunized with nef DNA. The initiation of HAART appears to contribute to the induction of new HIV-specific CTL responses, but by itself did not cause obvious re-induction of these activities.
Cutting Edge: Mouse IgG1 Antibodies Comprise Two Functionally Distinct Types That Are Differentially Regulated by IL-4 and IL-12
Authors: Faquim-Mauro Eliana L. , Coffman Robert L. , Abrahamsohn Ises A. , Macedo Mahasti S. 
Published: January 2023

Abstract
IL-4-dependent and -independent IgG1 Abs differ in their ability to induce mast cell degranulation as measured by passive cutaneous anaphylaxis (PCA). Mice immunized with OVA or PIII (fraction of Ascaris suum) produced high titers of IgG1 as shown by ELISA and PCA. In contrast, another A. suum fraction, PI, elicited IgG1 Abs with no PCA activity. IgG1 with anaphylactic activity required IL-4, as IgG1 responses to OVA and PIII in IL-4−/− mice gave no PCA. PI-specific IgG1 was IL-4-independent, because no difference was found between the responses of IL-4−/− and IL-4+/+ mice. Significant PCA reactions were elicited, however, with PI-specific IgG1 from IL-12−/− or anti-IFN-γ Ab-treated mice, although less Ab was measured by ELISA. These results indicate that one type of IgG1 has anaphylactic activity and its synthesis is IL-4-dependent, being inhibited by IL-12 or IFN-γ; the other lacks this activity and its synthesis is stimulated by IL-12 or IFN-γ.
Cutting Edge: Thymic Selection and Autoreactivity Are Regulated by Multiple Coreceptors Involved in T Cell Activation
Authors: Page Dawne M. 
Published: January 2023

Abstract
Immune responses are shaped by several processes that promote responses to pathogens and hinder responses to self. One mechanism that contributes to this polarization in response is negative selection, in which thymocytes that can respond to self-peptide/MHC complexes are deleted from the T cell repertoire. I found here that several coreceptors known to contribute to mature T cell activation also participate in negative selection. Interestingly, these molecules appeared to act in a cooperative fashion. Blocking the contribution of these molecules in fetal thymus organ culture not only prevented negative selection in the CD4+ lineage, but also induced the appearance of autoreactive thymocytes. This is the first demonstration that blocking coreceptor interactions during thymic development can produce autoreactive T cells. The contribution of negative selection to the mature T cell repertoire and to autoimmunity is discussed in light of these results.
Unexpected Reactivities of T Cells Selected by a Single MHC-Peptide Ligand
Authors: Singh Nagendra , Van Kaer Luc 
Published: January 2023

Abstract
In H2-DM mutant mice, most MHC class II molecules are bound by a single peptide, CLIP, derived from the class II-associated invariant chain. Previous studies showed that H2-DM− cells are defective in presenting synthetic peptides to class II-restricted T cells. In sharp contrast, however, the same peptides elicited strong CD4+ T cell responses in H2-DM− animals. We now provide an explanation for this apparent discrepancy. Peptide-specific CD4+ T cells from wild-type mice were efficiently stimulated by H2-DM+, but not by H2-DM− cells pulsed with the cognate peptide. In sharp contrast, CD4+ T cells from mutant animals specific for the same MHC-peptide combination recognized peptide-pulsed H2-DM+ and H2-DM− cells equally well. In addition, unlike Ag-specific T cells from wild-type animals, the reactivities of peptide-specific T cells from mutant animals could not be efficiently blocked by Abs specific for the cognate MHC class II-peptide combination. We further demonstrated that the distinct reactivities of CD4+ T cells from H2-DM+ and H2-DM− mice are due to differences in thymic selection. Collectively, these findings indicate that the CD4+ T cell repertoires of H2-DM+ and H2-DM− mice are remarkably different.
Dendritic Cells Generated Either from CD34+ Progenitor Cells or from Monocytes Differ in Their Ability to Activate Antigen-Specific CD8+ T Cells
Authors: Ferlazzo Guido , Wesa Amy , Wei Wei-Zen , Galy Anne 
Published: January 2023

Abstract
Dendritic cells (DC) can be generated in vitro from monocytes (M-DC) or from CD34+ hemopoietic progenitor cells (CD34-DC) but their precursors are not equivalent cells, prompting a comparison of the functional capacities of these APC. Both types of DCs established from the same individuals using the same cytokines displayed a comparable phenotype of mature DC (CD1a+, CD83+, CD86+, CD4+, HLA-DR++, CD14−, CD15− ) and were equally potent stimulators of allogeneic T cell proliferation, being both more powerful than immature M-DCs. An autologous panel of APCs produced in HLA-A2+ individuals, including CD34-DC, M-DC, monocytes, and EBV-lymphoid cell line was comparatively evaluated for presentation of the Erb-B2 peptide E75 to a CTL line. After short exposures (5 h) to E75-loaded APCs, similar levels of intracellular IFN-γ were induced in Ag-specific CD8+ T cells regardless of APC type. In sustained cultures (4–14 days), more Ag-specific T cells were obtained when peptide was presented on CD34-DC (p &lt; 0.05) rather than on M-DC, EBV-lymphoid cell lines, or monocytes, and these effects were dose-dependent. Activated T cells expressed 4-1BB, and the presence of 4-1BB-Ig fusion protein partially blocked Ag-specific CD8+ cell activation after CD34-DC or M-DC presentation. Our results show that 34-DC have a preferential capacity to activate CD8+ T cells and that this property is not strictly correlated to their ability to induce allogeneic T cell proliferation but due to mechanisms that remain to be defined.
β1 Integrin- and Proteoglycan-Mediated Stimulation of T Lymphoma Cell Adhesion and Mitogen-Activated Protein Kinase Signaling by Thrombospondin-1 and Thrombospondin-1 Peptides
Authors: Wilson Katherine E. , Li Zhuqing , Kara Murat , Gardner Kevin L. , Roberts David D. 
Published: January 2023

Abstract
Cell-cell and cell-matrix interactions play important regulatory roles in lymphocyte homeostasis. Thrombospondin-1 (TSP1) is a matricellular protein that differentially promotes the adhesion of resting and activated T cells. In this work, we show that adhesion of Jurkat T cells on substrates coated with TSP1 or TSP1-derived peptides is mediated by β1 integrins, CD47, and heparan sulfate proteoglycans. Interactions with TSP1 or TSP1 peptides stimulated CD3-induced Ras activation and tyrosine phosphorylation of several T cell proteins. The signals from TSP1 and its derived peptides differentially synergized with activation of the TCR to induce phosphorylation of linker for activation of T cells (LAT) and extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase, and p38 kinases. The phosphorylation of ERK in the presence of full-length TSP1 was transient and dependent on a β1 integrin receptor. Interestingly, peptides derived from the type 1 repeats of TSP1 and a CD47-binding peptide from the carboxyl-terminal domain of TSP1 also stimulated mitogen-activated protein (MAP) kinase phosphorylation. Moreover, the TSP1 heparin-binding peptide synergized with Ab-ligated TCR to transduce signals to the nucleus, detected by activation of AP-1- and Elk-dependent transcription. This TSP1 peptide-dependent activation of AP-1 was inhibited by both heparin and the MAP/ERK kinase inhibitor PD98059, providing a functional link between adhesion molecule interaction and nuclear transactivation events via the MAP kinase pathways. These findings have implications for the role of extracellular TSP1 and TSP1 fragments in the regulation of T cell function during hemostasis, wound repair, and other inflammatory responses.
Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Stimulate the Induction of Th2 Responses by Up-Regulating B7.2 Expression
Authors: Delgado Mario , Leceta Javier , Gomariz Rosa P. , Ganea Doina 
Published: January 2023

Abstract
Vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two structurally related neuropeptides produced within the lymphoid microenvironment, modulate several immunologic functions. We have recently demonstrated that VIP and PACAP enhance the macrophage costimulatory activity for naive CD4+ T cells exposed to allogeneic or anti-CD3 stimuli through the differential regulation of the B7 costimulatory molecules. In this study, we report on the role of VIP and PACAP on macrophage B7 expression and costimulatory function for Ag-primed CD4+ T cells, and on the macrophage-induced regulation of Th1/Th2 differentiation in vitro and in vivo. VIP and PACAP up-regulate the costimulatory activity of macrophages for Ag-primed CD4+ T cells. VIP-/PACAP-treated macrophages gain the ability to induce Th2-type cytokines such as IL-4 and IL-5 and reduce Th1-type cytokines such as IFN-γ and IL-2. In vivo administration of VIP or PACAP in Ag-immunized mice reduce the numbers of IFN-γ-secreting cells and enhance the numbers of IL-4-secreting cells. One of the consequences of the VIP-/PACAP-induced shift in cytokine profile is a change in the Ag-specific Ig isotype, increasing IgG1 and decreasing IgG2a levels. Finally, the preferential differentiation into Th2 effector cells after Ag stimulation induced by VIP-/PACAP-treated macrophages is mediated through the up-regulation of B7.2 expression.
TNF-α Inhibits HIV-1 Replication in Peripheral Blood Monocytes and Alveolar Macrophages by Inducing the Production of RANTES and Decreasing C-C Chemokine Receptor 5 (CCR5) Expression
Authors: Lane Brian R. , Markovitz David M. , Woodford Nina L. , Rochford Rosemary , Strieter Robert M. , Coffey Michael J. 
Published: January 2023

Abstract
The pathogenesis of HIV-1 infection is influenced by the immunoregulatory responses of the host. Macrophages present in the lymphoid tissue are susceptible to infection with HIV-1, but are relatively resistant to its cytopathic effects and serve as a reservoir for the virus during the course of disease. Previous investigators have demonstrated that increased serum levels of TNF-α contribute to the clinical symptoms of AIDS and that TNF-α stimulates the production of HIV-1 in chronically infected lymphocytic and monocytic cell lines by increasing HIV-1 gene expression. Although previous studies have suggested that TNF-α may increase HIV-1 infection of primary human mononuclear cells, some recent studies have indicated that TNF-α suppresses HIV-1 infection of macrophages. We now demonstrate that TNF-α suppresses HIV-1 replication in freshly infected peripheral blood monocytes (PBM) and alveolar macrophages (AM) in a dose-dependent manner. As TNF-α has been shown to increase the production of C-C chemokine receptor (CCR5)-binding chemokines under certain circumstances, we hypothesized that TNF-α inhibits HIV-1 replication by increasing the expression of these HIV-suppressive factors. We now show that TNF-α treatment of PBM and AM increases the production of the C-C chemokine, RANTES. Immunodepletion of RANTES alone or in combination with macrophage inflammatory protein-1α and -1β block the ability of TNF-α to suppress viral replication in PBM and AM. In addition, we found that TNF-α treatment reduces CCR5 expression on PBM and AM. These findings suggest that TNF-α plays a significant role in inhibiting monocytotropic strains of HIV-1 by two distinct, but complementary, mechanisms.
NK and CTL Recognition of a Single Chain H-2Dd Molecule: Distinct Sites of H-2Dd Interact with NK and TCR
Authors: Chung Doo Hyun , Dorfman Jeffrey , Plaksin Daniel , Natarajan Kannan , Belyakov Igor M. , Hunziker Rosemarie , Berzofsky Jay A. , Yokoyama Wayne M. , Mage Michael G. , Margulies David H. 
Published: January 2023

Abstract
We generated transgenic mice expressing a single-chain β2-microglobulin (β2m)-H-2Dd. The cell-surface β2m-H-2Dd molecule was expressed on a β2m-deficient background and reacted with appropriate mAbs. It was of the expected m.w. and directed the normal development of CD8+ T cells in the thymus of a broad TCR repertoire. It also presented both exogenously provided and endogenous peptide Ags to effector CD8+ T cells. In tests of NK cell education and function, it failed to reveal any interaction with NK cells, suggesting that the site of the interaction of NK receptors with H-2Dd was disrupted. Thus, the sites of TCR and NK receptor interaction with H-2Dd are distinct, an observation consistent with independent modes of TCR and NK receptor evolution and function.
Tumor Gangliosides Inhibit the Tumor-Specific Immune Response
Authors: McKallip Robert , Li Ruixiang , Ladisch Stephan 
Published: January 2023

Abstract
Tumor gangliosides are highly immunosuppressive membrane glycosphingolipids that are shed into the tumor cell microenvironment. We directly tested the impact of shed gangliosides on the in vivo antitumor immune response in a syngeneic fully autochthonous system (FBL-3 erythroleukemia cells, C57BL/6 mice, and highly purified FBL-3 cell gangliosides). The major FBL-3 ganglioside was identified as GM1b by mass spectrometry. Substantial ganglioside shedding (90 pmol/108 cells/h), a requisite for their inhibition of the immune function of tumor-infiltrating leukocytes, was detected. Immunosuppression by FBL-3 gangliosides was potent; 5–20 μM inhibited the tumor-specific secondary proliferative response (80–100%) and suppressed the generation of tumor-specific CTLs (97% reduction of FBL-3 cell lysis at an E:T ratio of 100:1). In vivo, coinjection of 10 nmol of FBL-3 gangliosides with a primary FBL-3 cell immunization led to a reduced response to a secondary challenge (the increase in the draining popliteal lymph node mass, cell number, and lymphocyte thymidine incorporation were lowered by 70, 69, and 72%, respectively). Coinjection of gangliosides with a secondary tumor challenge led to a 61, 74, and 42% reduction of the increase in lymph node mass, cell number, and thymidine uptake and a 63–74% inhibition of the increase of draining lymph node T cells (CD3+), B cells (CD19+), and dendritic cells/macrophages (Mac-3+). Overall, the clear conclusion that tumor-derived gangliosides inhibit syngeneic antitumor immune responses implicates these molecules as a potent factor in promoting tumor formation and progression.
The Induction of Virus-Specific CTL as a Function of Increasing Epitope Expression: Responses Rise Steadily Until Excessively High Levels of Epitope Are Attained
Authors: Wherry E. John , Puorro Kristin A. , Porgador Angel , Eisenlohr Laurence C. 
Published: January 2023

Abstract
The role of epitope expression levels in CD8+ T cell priming has been controversial. Yet this parameter is of great importance in the design of rational approaches to optimize CTL responses to a variety of pathogens. In this paper we examine the influence of epitope production on CD8+ T cell priming by exploiting a system that allows a 200-fold range of cell surface epitope expression in vitro with a fixed dose of vaccinia virus. Our results demonstrate that, with the exception of a notable decline at the highest level of epitope, the magnitude of the responding CTL population generated in vivo following equivalent viral infections is essentially proportional to epitope density.