bluuebunny/crossref_metadata_2025_split huggingface dataset:
Requirement for In Vivo Production of IL-4, But Not IL-10, in the Induction of Proliferative Suppression by Filarial Parasites
Authors: MacDonald Andrew S. , Maizels Rick M. , Lawrence Rachel A. , Dransfield Ian , Allen Judith E. 
Published: December 2022

Abstract
Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filariasis. We have previously reported that adherent peritoneal exudate cells (PEC) from mice transplanted with adult Brugia malayi parasites suppress the proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We now show that infection of mice with the infective larval (L3) stage of B. malayi generates a similar population of PEC. Suppressive cells are generated within 7 days of infection and mediate their effects through a nitric oxide-independent pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the microfilarial stage of the parasite induces IFN-γ production and does not generate a similar form of suppression. Production of host IL-4 was necessary to allow the generation of suppressive PEC, given that IL-4-deficient mice implanted with adult parasites failed to induce proliferative block. However, IL-10-deficient mice implanted with adult parasites resulted in T cell suppression, indicating that IL-10 is not essential for the induction of hyporesponsiveness. Neither IL-4 nor IL-10 were directly responsible for ablating cellular proliferation in vitro, as the addition of neutralizing Ab to either cytokine did not reverse the proliferative block. Thus, IL-4 produced in vivo in response to filarial L3 and adult parasites is essential for the induction of proliferative suppression but is not itself the suppressive factor.
Development of Th1 and Th2 Populations and the Nature of Immune Responses to Hepatitis B Virus DNA Vaccines Can Be Modulated by Codelivery of Various Cytokine Genes
Authors: Chow Yen-Hung , Chiang Bor-Luen , Lee Yueh-Lun , Chi Wei-Kuang , Lin Wen-Chang , Chen Yen-Teen , Tao Mi-Hua 
Published: December 2022

AbstractIn this study, we provide direct evidence that the magnitude and nature of the immune response to a DNA vaccine can be differentially regulated by codelivery of various mouse cytokine genes. Mice immunized with a hepatitis B virus (HBV) DNA vaccine and the IL-12 or IFN-γ gene exhibited a significant enhancement of Th1 cells and increased production of anti-HBV surface IgG2a Ab, as well as a marked inhibition of Th2 cells and decreased production of IgG1 Ab. In contrast, coinjection of the IL-4 gene significantly enhanced the development of specific Th2 cells and increased production of IgG1 Ab, whereas Th1 differentiation and IgG2a production were suppressed. Coinjection of the IL-2 or the granulocyte-macrophage-CSF gene enhanced the development of Th1 cells, while the development of Th2 cells was not affected, and the production of IgG1 and IgG2a Ab were both increased. The CTL activity induced by HBV DNA vaccination was most significantly enhanced by codelivery of the IL-12 or IFN-γ gene, followed by the IL-2 or granulocyte-macrophage-CSF gene, whereas codelivery of the IL-4 gene suppressed the activity. When challenged with HBV surface Ag (HBsAg)-expressing syngeneic tumors, significant reduction of tumor growth was observed in mice that were coadministered the IL-12 gene but not the IL-4 gene. Taken together, these results demonstrate that application of a cytokine gene in a DNA vaccine formulation can influence the differentiation of Th cells as well as the nature of an immune response and may thus provide a strategy to improve its prophylactic and therapeutic efficacy.
Cutting Edge: Infection of Mice Lacking the Common Cytokine Receptor γ-Chain (γc) Reveals an Unexpected Role for CD4+ T Lymphocytes in Early IFN-γ-Dependent Resistance toToxoplasma gondii
Authors: Scharton-Kersten Tanya , Nakajima Hiroshi , Yap George , Sher Alan , Leonard Warren J. 
Published: December 2022

AbstractMice lacking the common cytokine receptor γ-chain (γc) gene exhibit defective development of NK cells and CD8+ T cells and greatly diminished production of IFN-γ. Because resistance of SCID mice to Toxoplasma gondii requires IL-12-dependent IFN-γ production by NK cells, we expected that γc-deficient mice would succumb rapidly to the parasite. Surprisingly, however, most γc-deficient mice survived the acute phase of T. gondii infection. As in wild-type mice, this resistance required IL-12 and IFN-γ; nevertheless, whereas wild-type mice depleted of CD4+ T cells survived, anti-CD4+ treated γc-deficient mice displayed diminished production of IFN-γ and all succumbed to acute infection. These data not only reveal a role for CD4+ T lymphocytes in IFN-γ-dependent host defense but also establish SCID and γc-deficient mice as powerful complementary tools for assessing the function of NK vs CD4+ T cells in immunopathophysiologic responses.
Local Synthesis of C3 Within the Splenic Lymphoid Compartment Can Reconstitute the Impaired Immune Response in C3-Deficient Mice
Authors: Fischer Michael B. , Ma Minghe , Hsu Nelson C. , Carroll Michael C. 
Published: December 2022

AbstractMice bearing a disrupted C3 locus (C3−/−) have an impaired Ab response to T-dependent Ags (bacteriophage φX 174 and nuclear protein-keyhole limpet hemocyanin) characterized by a reduction in number and size of germinal centers and impaired retention of Ag by follicular dendritic cells. To test the importance of C3 synthesized locally within the lymphoid compartment during an immune response to T-dependent Ag, we reconstituted C3−/− mice with wild-type bone marrow of MHC-identical littermates. Engraftment not only restored local C3 synthesis in the spleen, but also rescued the impaired humoral response. The major source of C3 mRNA was MOMA-2+ macrophages localized within the white pulp areas of the spleen. Interestingly, C3 expression is apparently regulated as C3 mRNA was not detected in splenic sections of nonimmune mice. Furthermore, local C3 synthesis by donor macrophages reversed the impaired Ag trapping by splenic follicular dendritic cells in C3-deficient mice.
Bone Marrow Transplantation Induces Either Clonal Deletion or Infectious Tolerance Depending on the Dose
Authors: Bemelman Frederike , Honey Karen , Adams Elizabeth , Cobbold Stephen , Waldmann Herman 
Published: December 2022

Abstract
The concept of immunologic tolerance arose from bone marrow transplantation in neonatal or irradiated mice, in which the predominant mechanism is clonal deletion of donor-specific T cells by donor hemopoietic cells in the recipient thymus. A short term treatment with nonlytic CD4 and CD8 mAbs can induce tolerance to tissue allografts or reversal of spontaneous autoimmunity. Such tolerance to skin or heart allografts is dependent on “infectious” tolerance mediated by regulatory CD4+ T cells. We show here, for multiple minor Ag differences, that while a large inoculum of donor marrow produces significant deletion of Ag-reactive cells as expected, a low marrow dose generates tolerance with little evidence of clonal deletion. Only this low dose tolerance can be transferred to unmanipulated recipients via CD4+ T cells, can be passed onto naive T cells as if infectious, and can act to suppress rejection of third party Ags when “linked” on F1 grafts.
A Common Immunoregulatory Locus Controls Susceptibility to Actively Induced Experimental Allergic Encephalomyelitis and Experimental Allergic Orchitis in BALB/c Mice
Authors: Teuscher Cory , Hickey William F. , Grafer Constance M. , Tung Kenneth S. K. 
Published: December 2022

Abstract
Previous studies have shown that differential susceptibility to actively induced experimental allergic encephalomyelitis (EAE) and experimental allergic orchitis (EAO) exists among various BALB/c substrains. Of eight substrains studied for EAE and 13 for EAO, BALB/cJ mice are phenotypically the most resistant to disease induction. Resistance to both diseases is controlled by single recessive mutations unlinked to any of the known alleles distinguishing BALB/cJ mice. In this study, segregation analysis employing a second generation backcross population shows that resistance to both EAE and EAO is due to a mutation in a common immunoregulatory gene. The role of immunoregulatory cells in controlling EAE resistance was examined using adoptive transfer protocols. BALB/cJ mice immunized with spinal cord homogenate plus adjuvants generate immunoregulatory spleen cells (SpC) that, when transferred to naive BALB/cByJ recipients, reduce the incidence and severity of EAE. Treatment of such cells with either cytotoxic monoclonal anti-Thy1.2 or anti-CD4 plus C′ before transfer abrogates the ability of BALB/cJ SpC to inhibit disease. In contrast, neither SpC from adjuvant-immunized BALB/cJ nor spinal cord homogenate- plus adjuvant-primed BALB/cByJ donors influences the incidence or severity of disease observed in recipients. In addition, the role of environment in influencing susceptibility to EAE and EAO in BALB/c mice is documented. Taken together, these results support the existence of a common disease susceptibility locus in the pathways leading to two autoantigenically distinct CD4+ T cell-mediated, organ-specific, autoimmune diseases.
Triggering of Peritoneal Macrophages with IFN-α/β Attenuates the Expression of Inducible Nitric Oxide Synthase Through a Decrease in NF-κB Activation
Authors: López-Collazo Eduardo , Hortelano Sonsoles , Rojas Armando , Boscá Lisardo 
Published: December 2022

Abstract
Triggering peritoneal macrophages with IFN-γ and a low concentration of LPS induced the expression of the inducible form of nitric oxide synthase (iNOS). This process was significantly inhibited when IFN-α/β was added during the initial 2 h after the start of IFN-γ/LPS activation. Evaluation of the transcriptional activity using run-on assays indicated that IFN-α/β inhibited the transcription of iNOS. Transfection experiments using a 1.7-kb promoter sequence corresponding to the 5′ flanking region of the murine iNOS gene showed decreased promoter activity in the presence of type I IFNs. Analysis of the transcription factors that participate in iNOS expression revealed a marked decrease of NF-κB activation, a nuclear factor required for the transcription of this gene. The degradation of IκBα and IκBβ, which is required for the translocation of NF-κB to the nucleus, was inhibited in the presence of IFN-α/β. However, the activity of other transcription factors such as IFN regulatory factor 1, which is involved in the expression of iNOS in response to IFN-γ, was not affected by IFN-α/β stimulation. These results suggest that in the presence of IFN-α/β, the activity of the iNOS promoter is impaired, and this attenuated nitric oxide synthase expression could be important in pathophysiologic situations in which secretion of type I IFNs occurs.
Distinct Homing Pathways Direct T Lymphocytes to the Genital and Intestinal Mucosae in Chlamydia-Infected Mice
Authors: Perry Linda L. , Feilzer Karen , Portis John L. , Caldwell Harlan D. 
Published: December 2022

Abstract
Immunity to genital tract infection with Chlamydia trachomatis is mediated by type 1 CD4+ T lymphocytes. To define the signals that govern lymphocyte trafficking to the genital mucosa, integrins expressed by infiltrating T cells and endothelial addressins displayed on local vasculature were characterized during the course of infection. All T cells expressed the αLβ2 heterodimer that binds vascular ICAM-1, and most displayed enhanced levels of the α4β1 integrin that interacts with VCAM-1. αE and β7low integrin chains were detected on approximately 15 and 30% of infiltrating T cells, respectively. Lymphocytes derived from the spleen or draining lymph nodes expressed this same integrin profile, suggesting that cells are recruited to the genital mucosa from the systemic circulation without significant selection pressure for these markers. Immunofluorescent staining for the corresponding vascular addressins revealed intense expression of VCAM-1 on small vessels within Chlamydia-infected genital tracts and up-regulation of ICAM-1 on endothelial, stromal, and epithelial cells. Mucosal addressin cell adhesion molecule-1 was not detected within genital tissues. These results indicate that T lymphocyte homing to the genital mucosa requires the interaction of αLβ2 and α4β1 with endothelial ICAM-1 and VCAM-1, respectively, which is the same pathway that directs lymphocytes to systemic sites of inflammation. Homing pathways defined for the intestinal mucosa and assumed to be relevant to all mucosal sites are not well represented in the genital tract. The identification of T lymphocyte trafficking pathways shared between systemic and mucosal tissues should facilitate vaccine strategies aimed at maximizing immune responses against Chlamydia and other pathogens of the urogenital tract.
Identification of a Sequence That Mediates Promiscuous Binding of Invariant Chain to MHC Class II Allotypes
Authors: Siebenkotten Ina M. , Carstens Cornelia , Koch Norbert 
Published: December 2022

AbstractThe invariant chain (Ii) shows promiscuous binding to a great variety of MHC class II allotypes. In contrast, the affinities of the Ii-derived fragments, class II-associated Ii peptides, show large differences in binding to class II allotypes. The promiscuous association of Ii to all class II polypeptides therefore requires an additional contact site to stabilize the interaction to the polymorphic class II cleft. We constructed recombinant molecules containing the class II binding site of Ii (CBS) and tested their association with HLA-DR dimers. The CBS fused to the transferrin receptor mediates binding of transferrin receptor-CBS to class II dimers. Within the CBS, deletion of a sequence N-terminal to the groove-binding motif abolished binding of Ii to DR. A promiscuous class II binding site was identified by reinsertion of the N-terminal residues, amino acids 81–87, of Ii into an Ii mutant that lacks the groove-binding segment. DR allotype-dependent association of Ii was achieved by insertion of antigenic sequences. The promiscuous association, in contrast to the class II allotype-dependent binding of Ii, is important to prevent interaction of class II dimers to nascent polypeptides in the endoplasmic reticulum.
A Bispecific Monoclonal Antibody Directed Against Both the Membrane-Bound Complement Regulator CD55 and the Renal Tumor-Associated Antigen G250 Enhances C3 Deposition and Tumor Cell Lysis by Complement
Authors: Blok Vanessa T. , Daha Mohamed R. , Tijsma Odette , Harris Claire L. , Morgan B. Paul , Fleuren Gert Jan , Gorter Arko 
Published: December 2022

Abstract
Tumor cells may inhibit the induction of a complement-mediated inflammatory response through overexpression of membrane-bound regulators of complement activation. Therefore, it is of interest to determine the most efficient approach to block these membrane-bound complement regulators on tumor cells. In the present study, we first generated a bispecific mAb directed against both CD55, using the functional blocking mAb MBC1, and the highly expressed HLA class I molecule as a model for a tumor-associated Ag, using the mAb W6/32. Tumor cells opsonized with bispecific mAb W6/32*MBC1, then exposed to complement and subsequently stained for C3 deposition, were assessed by flow cytometric analysis. We found that opsonization with W6/32*MBC1 resulted in a 92% enhancement of C3 deposition on renal tumor cells as compared with opsonization with W6/32 alone and a 17% enhancement of the C3 deposition as compared with incubation with a mixture of both parental mAb. Based on these results, we developed a bispecific mAb recognizing both CD55 and the relatively low expressed renal tumor-associated Ag G250. Increasing concentrations of the bispecific mAb G250*MBC1 resulted in a 25 to 400% increase in C3 deposition on renal tumor cells as compared with C3 deposition in the presence of the parental mAb G250 alone. G250*MBC1 enhanced C3 deposition by 21% in comparison with a mixture of both parentals. Furthermore, opsonization of tumor cells with G250*MBC1 rendered these cells more sensitive to complement-mediated lysis. In conclusion, the bispecific mAb G250*MBC1 induces deposition of C3 and tumor cell lysis more efficiently than G250 alone.
B Cell Sensitization to Helminthic Infection Develops In Utero in Humans
Authors: King Christopher L. , Malhotra Indu , Mungai Peter , Wamachi Alex , Kioko John , Ouma John H. , Kazura James W. 
Published: December 2022

AbstractHuman neonates are generally deficient in their ability to generate humoral immunity. This deficiency is thought to reflect physiologic immaturity of T and B cell function and lack of previous exposure to exogenous Ags. To determine whether neonatal humoral immunity can be modified by maternal helminth infection during pregnancy, we assessed Ig production by cord blood lymphocytes from healthy newborns of mothers living in an area of Kenya where schistosomiasis, bancroftian filariasis, and geohelminth infections are endemic. Twelve of 40 and 17 of 39 cord blood lymphocyte preparations from healthy newborns in Coast Province, Kenya, spontaneously made polyclonal IgE (range, 0.15–21 ng/ml) and IgG (1.6–10.1 ng/ml) in vitro. In vitro IgE synthesis by cord blood lymphocytes (CBL) was, on the average, 10-fold less than that of PBMC of Kenyan mothers (1.1–98 ng/ml) and was undetectable for CBL from newborns delivered in the United States. Schistosome and filarial Ags stimulated a 3- to &gt;100-fold increase in the production of polyclonal IgE and parasite-specific IgG Abs by lymphocytes from 10 of 40 and 6 of 39 Kenyan newborns, respectively. CBL observed to have helminth Ag-driven B cell responses were more likely to be from newborns of schistosome- or filaria-infected mothers than from uninfected mothers (p &lt; 0.05). These data indicate that the human fetus can be sensitized in utero to produce helminth-specific B cells and that neonatal B cells are intrinsically capable of IgE and IgG production.
Cutting Edge: Pig Islet Xenografts Are Susceptible to “Anti-Pig” But Not Galα(1,3)Gal Antibody Plus Complement in Gal o/o Mice
Authors: McKenzie Ian F. C. , Koulmanda Maria , Mandel Tom E. , Sandrin Mauro S. 
Published: December 2022

Abstract
Hyperacute rejection due to Galα(1,3)Gal (Gal) Ab plus complement (C′) is a major problem in xenografting vascularized organs from pigs to primates, but the fate of neovascularized xeno islets is unclear. Nonendocrine islet cells are Gal+, and there is a large rise in Gal Abs after transplantation, but graft remnants persist for some days in monkeys and humans. To define the role of αGal Ab plus C′ in porcine islet graft rejection, cultured porcine fetal islets were grafted to mice lacking the α(1,3)galactosyltransferase gene. Anti-Gal Ab plus C′ did not cause islet damage or rejection in mice lacking the α(1,3)galactosyltransferase gene, even when additional Ab plus C′ was given; in addition, hyperimmune mice (titer &gt;1/20,000) did not reject pig islets, showing that islets are resistant to Gal Ab plus C′. However, islets can be destroyed by polyclonal mouse anti-pig Abs. Thus, the focus of islet xenografting should not be on Gal Ab plus C′.
The Alloreactive T Cell Response Against the Class Ib Molecule H2-M3 Is Specific for High Affinity Peptides
Authors: Dabhi Vikram M. , Hovik Rolf , Van Kaer Luc , Fischer Lindahl Kirsten 
Published: December 2022

AbstractMHC class Ib molecule H2-M3 presents N-formylated peptides to CD8+ CTLs. Endogenous formylated peptides can come from the N-terminus of each of the 13 proteins encoded by the mitochondrial genome. In peptide competition assays, two of these peptides bind with high affinity, six bind with intermediate affinity, three bind with low affinity, and two do not bind measurably. Alloreactive CTLs from M3-specific, mixed lymphocyte cultures responded strongly against the two peptides with high affinity for M3, occasionally to peptides with intermediate affinity, and not at all to the rest. Long term lines and CTL clones reacted with only the high affinity peptides, demonstrating that alloreactive CTLs depend on specific peptides and that peptide affinity for class I correlates with alloantigenicity.
Multiple Sites of Vλ Diversification in Cattle
Authors: Lucier Mark R. , Thompson Rachel E. , Waire James , Lin Athena W. , Osborne Barbara A. , Goldsby Richard A. 
Published: December 2022

Abstract
Ig repertoire diversification in cattle was studied in the ileal Peyer’s patch (IPP) follicles of young calves and in the spleens of late first-trimester bovine fetuses. To investigate follicular diversification, individual IPP follicles were isolated by microdissection; Vλ diversity was examined by RT-PCR and subsequent cloning and sequencing. When 52 intrafollicular sequences from a 4-wk-old calf were determined and compared, two major groups, one of 23 members and the other of 25, could be delineated. An examination of these groups revealed clear genealogic relationships that implicated in situ diversification of Vλ sequences within the confines of an IPP follicle. Vλ expression was also examined in early (95 and 110 gestational day) fetal bovine spleens. Although earlier studies in cattle and sheep implicated the IPP as a likely site of Ab diversification, a close investigation of Vλ sequences in late first-trimester fetal calves revealed that diversity appears in the early fetal spleen before the establishment of a diverse repertoire in the ileum. When the sequences for the fetal spleen were compared with an existing pool of germline sequences, we found evidence of possible gene conversion events and possible untemplated point mutations occurring in sequences recovered from fetal spleens. We conclude that IPP is not the sole site of Vλ diversification in cattle. Also, as suggested for rabbits, cattle may use both gene conversion and untemplated somatic point mutation to diversify their primary Vλ repertoire.
pp56LckMediates TCR ζ-Chain Binding to the Microfilament Cytoskeleton
Authors: Rozdzial Moshe M. , Pleiman Chris M. , Cambier John C. , Finkel3 Terri H. 
Published: December 2022

AbstractThe TCR ζ-chain (ζ) on mature murine T lymphocytes binds to the microfilament cytoskeleton in response to Ag receptor ligation. Here, we report the role of Src family kinases in ζ-cytoskeletal binding, using mutant mice and a cell-free model system. Binding of ζ to actin in the cell-free system has a specific requirement for ATP and divalent cations, with an apparent Michaelis-Menton constant for ATP in the millimolar range, and can be disrupted by either EDTA or the microfilament poison, cytochalasin D, suggesting that microfilaments provide the structural framework for an active process involving cellular kinases. Indeed, tyrosine-phosphorylated ζ is a predominant form of the ζ-chain bound to polymerized actin, while challenge with alkaline phosphatase prevents ζ-chain association in solution and releases ζ-chain from the bound state. Phosphorylated Src-family kinase pp56Lck also associates with membrane skeleton upon TCR engagement and is a component of the reconstituted cytoskeletal pellet. ζ-Chain phosphorylation and ζ-cytoskeletal binding are abrogated in cell lysates with reduced levels of pp56Lck and in activated mutant murine T cells lacking pp56Lck, implicating pp56Lck as the kinase involved in ζ-chain tyrosine phosphorylation and ζ-cytoskeletal binding. Finally, recombinant Lck Src homology 2 domain preferentially inhibits reconstituted ζ-cytoskeleton association, suggesting that ζ-microfilament binding is dependent on interactions between phosphorylated tyrosine residues in ζ-chain activation motifs and the Src homology 2 domain of the Lck protein tyrosine kinase.