Immunity In Mouse Model Research Articles

The Role of Gamma Interferon in Immune Resistance to Vaginal Infection by Herpes Simplex Virus Type 2 in Mice

We investigated the role of interferon gamma (IFN-γ) in a mouse model of immunity to vaginal infection by herpes simplex virus type 2 (HSV-2). Within 8 h after immune mice were challenged intravaginally with HSV-2, IFN-γ concentrations in vaginal secretions reached levels that can be antiviral in vitro. This rapid synthesis of IFN-γ occurred in immune-challenged mice but not in nonimmune-challenged mice, indicating that it required memory T cells. Immunostaining and in situ hybridization revealed that the IFN-γ was synthesized by cells whose morphological appearance suggested that they were lymphocytes and macrophage-like cells in the mucosa. The presence of IFN-γ in vaginal secretions was correlated with upregulation of MHC class II antigens in the epithelium and with vigorous (30-fold) recruitment of T and B lymphocytes into the vagina. In vivo administration of anti-IFN-γ to immune mice 17 h before virus challenge blocked the subsequent appearance of IFN-γ in vaginal secretions, blocked upregulation of class II antigens, blocked adherence of T cells to endothelium and their recruitment into the vagina, and markedly reduced immunity against reinfection of the vaginal epithelium.

Molecular cloning, functional characterization and mRNA expression analysis of the murine chemokine receptor CCR6 and its specific ligand MIP-3α

We have cloned the murine CCR6 receptor and its ligand, the β-chemokine mMIP-3α. Calcium mobilization assays performed with mCCR6 transfectants showed significant responses upon addition of mMIP-3α. Murine MIP-3α RNA is expressed in thymus, small intestine and colon, whereas mCCR6 RNA is expressed in spleen and lymph nodes. RT-PCR analysis of FACS-sorted lymphoid and antigen presenting cell subsets showed mCCR6 expression mainly in B cells, CD8 − splenic dendritic cells and CD4 + T cells. The cloning and functional characterization of the mCCR6 and mMIP-3α will allow the study of the role of these proteins in mouse models of inflammation and immunity.

HLA transgenic mice as humanized mouse models of disease and immunity.

The application of molecular genetics to human disease in the past decade has been helpful in elucidating the genetic influences involved in the induction and pathogenesis of various autoimmune diseases. Among the numerous genes studied for their role in disease development, polymorphisms within HLA class I and class II loci play a significant role in predisposition to disease. HLA molecules are encoded by genes on the short arm of chromosome 6. Crystal structures of MHC molecules show a peptide binding cleft which contains the variable region of MHC molecules. Genetic polymorphism at the MHC determines the specificity and affinity of peptide binding and T cell recognition. HLA molecules play a pivotal role in T cell repertoire selection in the thymus and antigen presentation in the periphery. Analysis of T cell responses in humans has involved the use of T cell lines or clones in vitro from naturally primed individuals. On the other hand, MHC restriction, mapping of epitope recognition, and T cell function in murine systems have been determined by in vivo studies. Various experimental animal models of autoimmune diseases have been studied, contributing greatly to our basic understanding of the disease. For example, type II collagen‐induced arthritis (CIA) 1 in mice and rats has been used as an experimental model for RA. Even though the model differs in the manner polyarthritis is induced, disease expression is broadly similar to RA, with the occurrence of symmetrical peripheral polyarthritis and systemic inflammation. Although growing knowledge of the functions of T and B cells in the immune response has shed light on their role in disease induction, the pathogenic mechanisms of most autoimmune diseases remain unresolved. There are many unanswered questions as to how tolerance to self is usually maintained, because autoreactive T cells can be found in normal as well as diseased individuals. How is tolerance broken in autoimmunity? Do specific autoantigens trigger the immune system to mount tissue-destructive responses? These questions need to be solved for most of the autoimmune diseases. Although the strongest MHC association with an autoimmune disease is between HLA class I B27 and spondyloarthropathies, class II alleles are implicated in most other cases. For example, RA is strongly associated with alleles of the DRB1 locus, whereas diabetes shows a stronger association with DQB1 alleles. HLA-DR and -DQ alleles are inherited en bloc and are known to occur in linkage disequilibrium. To better understand the role of HLA molecules in autoimmune diseases, transgenic animals expressing human HLA genes associated with disease have been developed. The generation of transgenic mice expressing functional HLA molecules has been an important step toward the creation of an in vivo model for enhancing our understanding of the function of human molecules in disease induction and predisposition. The potential value of HLA transgenic animals as a “humanized” disease model was first illustrated in the HLA-B27

The effects of H2 and non-H2 genes on the survival of Onchocerca lienalis microfilariae in the mouse.

The effect of H2 and non-H2 genes in a mouse model of protective immunity against Onchocerca lienalis microfilariae have been investigated. Non-H2 effects were determined using CBA, BALB/c, B10, SJL and TO strains. All were permissive for establishment of a primary infection with microfilariae, although significant differences in parasite recoveries were evident amongst the various strains. The effect of H2 genes upon a primary infection was investigated using H2 congenic B10 and BALB strains, B10, B10.S, B10.BR, B10.D2/n, BALB/c, BALB.B, and BALB.K. Significant H2 effects were seen among the relatively weak responder B10 strains, but were not present among the relatively strong responder BALB strains. These results support a dominant effect of non-H2 genes following primary exposure to microfilariae, and a 'fine tuning' effect of H2 genes that is apparent only in weaker responding strains. Upon reinfection of all the strains investigated, a gradation of protection was detected that appeared to be exclusively dependent upon H2.

Immunospecific reduction of antioligonucleotide antibody-forming cells with a tetrakis-oligonucleotide conjugate (LJP 394), a therapeutic candidate for the treatment of lupus nephritis.

A discrete tetravalent conjugate, 7a (LJP 394), consisting of four oligonucleotides attached to a common carrier or platform was prepared. Single-stranded oligonucleotide 20-mers consisting of alternating deoxycytidine-deoxyadenosine nucleotides, (CA)10, were attached to a tetrabromoacetylated platform by displacement with sulfhydryl-terminated linkers. The tetrabromoacetylated platform 3a was synthesized in three steps using triethylene glycol bis-(chloroformate). The single-stranded conjugate was characterized by polyacrylamide gel electrophoresis, DNA sequencing, phosphate analysis, carbon and nitrogen combustion analysis, and correlation of stoichiometry to conversion in the conjugation process. HPLC and capillary electrophoretic methods were developed to evaluate purity. The tetrakis, single-stranded conjugate was annealed with a stoichiometric amount of a complementary single-stranded oligonucleotide 20-mer consisting of alternating thymidine-deoxyguanosine nucleotides, (TG)10. The double-stranded conjugate LJP 394 was characterized by melt temperature and hyperchromicity, phosphate analysis, and carbon and nitrogen combustion analysis. LJP 394 inhibits binding of DNA to anti-double-stranded oligonucleotide antibodies and reduces anti-oligonucleotide-specific plaque (antibody)-forming cells in an immunized mouse model by a proposed mechanism involving cross-linking B cell surface immunoglobins.

Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice.

Our study investigates the recall of immunity in the mouse model of memory immunity to tuberculosis infection. The results provide evidence that recall of immunity is expressed as an accelerated accumulation of potent effector cells in the infected target organs. These effector cells were recruited from the resting pool of memory cells and were immediately triggered to exert their effector functions, leading to a massive release of Th1 cytokines detectable both in splenic extracts and in the serum within the first 24 h of infection. During a primary infection, in contrast, a 14-day delay was observed before significant cytokine levels were reached. After the initial effector phase, the cells blasted and entered into clonal expansion, resulting in a rapid increase in the total number of CD4 CD45RBlow cells in the spleen. The recall of memory immunity was highly efficient and controlled an infectious challenge within the first week. The molecules recognized by the memory effector subset were the proteins secreted from Mycobacterium tuberculosis during growth. By separating the CD4 population into CD45RBhigh and CD45RBlow subsets, the memory effector cells were demonstrated to reside predominantly in the activated population of CD45RBlow CD44high LFA-1high L-selectinlow cells. The key antigenic targets recognized by these cells were identified as Ag85B and a secreted 6-kDa protein (ESAT-6) that elicited the release of exceedingly high levels of IFN-gamma. ESAT-6 was biochemically purified, characterized, and the gene encoding the protein was cloned.

Neonatal group B streptococcal infections

Group B streptococci remain a leading cause of life-threatening neonatal infection worldwide. The current estimate of incidence in the United States is 1.8 cases per 1000 live births, with a case-fatality ratio of 10% to 20%. Advances in understanding of the pathogenesis of septic shock and meningitis are yielding new approaches to the treatment of these serious infections. Selective intrapartum chemoprophylaxis with ampicillin has been shown to be both effective and cost effective and is gaining more widespread acceptance as a preventive measure. Conjugate vaccines consisting of type-specific group B streptococci capsular polysaccharides coupled to tetanus toxoid or protein membrane antigens of group B streptococci have been shown to prevent neonatal infection in a mouse model of maternal immunization. Such vaccines are now in trials of safety and immunogenicity in humans.

Rat model of delirium: atropine dose-response relationships.

The authors report dose-response relationships for atropine in their rat model of human delirium. In this model, anticholinergic mechanisms are an important cause and may be a neurochemical final common pathway for diverse etiologies of delirium. Four intravenous (i.v.) bolus doses of atropine (27.5, 13.5, 6.875, and 3.44 mg/kg) were studied along with the originally reported dose of 55 mg/kg and saline control. Subsequent iv infusions were also proportionately reduced. EEG frequency and amplitude, maze performance, and subjective behavioral descriptions were taken over 320-minute study periods. Repeated-measures analysis of variance compared data between groups, and effect sizes were calculated. Dosages to be used in future studies are discussed.

Impaired resistance to infection does not increase the virulence of Salmonella htrA live vaccines for mice

We have described a new class of live attenuated salmonella vaccines harbouring lesions in htrA, a stress protein gene previously. The virulence and invasiveness of Salmonella htrA mutants was investigated in three models of increased susceptibility to Salmonella infection. These included BALB/c mice, either given sublethal whole body irradiation (350 R) or administered rabbit anti-TNFα antiserum, and (CBA/N♀XBALB/c♂) F1 male mice which express the xid sex-linked B cell defect of CBA/N mice and are more susceptible to salmonellae than female littermates. Salmonella typhimurium htrA mutants derived from virulent strains, C5046 (C5 htrA::Tn phoA) and BRD726 (SL1344 Δ htrA) were not more invasive in immunosuppressed mice than in normal controls in the three mouse models of defective immunity. The results indicate that susceptibility to S. typhimurium htrA vaccines derived from virulent parents is not enhanced by conditions of impaired resistance to infection.

Novel immunosuppressive agents. Potent immunological activity of some benzothiopyrano[4,3-c]pyrazol-3-ones

A unique class of immunosuppressive agents has been found be the use of a mouse model of immunity. A number of bensothiopyrano[4,3-c]pyrazol-3-ones are potent inhibitors of both the humoral and cellular immune response developed in mice in response to El4 tumor cells. These compounds exhibit a selectivity for inhibiting the humoral response. Structure-activity relationships and Hansch analyses of data from the mouse model are discussed. One of the most potent compounds, 2-(4'-chlorophenyl)bensothiopyrano[4,3-c]pyrazol-3-one (1, CP-17 193), exhibits ED50 values for inhibiting the humoral and cellular responses in the range of 0.5-2 mg/kg, po, in the mouse model and also inhibits antibody production to several other antigens and prolongs skin graft survival in mice. These compounds are shown in several ways to be distinct from the lymphocytotoxic drugs cyclophosphamide and azathioprine.

The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells.

A mouse model of cell-mediated immunity (CMI) and tolerance to protein antigens horse gamma globulin (HoGG) and cytochrome (Cyt C) was investigated. A reliable CMI response as measured in vivo by ear swelling or by an in vitro T-cell proliferation assay could be induced by one of two methods: (a) sensitization by antigen-complete Freund's adjuvant in the base of the tail, or (b) sensitization by s.c. injection of antigen coupled to syngeneic lymphoid cells. The in vivo response exhibited characteristic CMI parameters, delayed kinetics, and transfer by viable T cells. Prior i.v. injection of HoGG-modified lymphoid cells (HoGG-LC) or Cyt C-LC before sensitization resulted in a rapidly induced, dose-dependent, antigen-specific suppression of both in vivo and in vitro manifestations of the CMI response. In addition, tolerance in this system was transferrable by an antigen-specific suppressor T cell (Ts). The Ts were found to diminish the in vivo ear swelling reaction in recipient animals, but had no effect on the in vitro T-cell proliferative response of the recipients. In contrast to the rapid development of tolerance in donor mice (phenotypic tolerance), transferrable Ts were first demonstrable 4--7 d posttolerization. This latter result indicates that at least two mechanisms of tolerance are operative in this system: the rapid induction of clone inhibition of reactive T cells and the slower induction of Ts. These results indicate again that the mode of antigen presentation is crucial in determining the immunologic outcome. In these experiments, cell-bound proteins injected subcutaneously led to delayed hypersensitivity while the same antigens injected intravenously led to tolerance. These results are considered in the light of recent experiments which show that T cells recognize antigens on cells in association with major histocompatibility complex products. We believe the following pathways are involved. In sensitization via subcutaneous injection of HoGG-LC, antigen reaches the lymph node via lymphatic pathways which lead to immunogenic macrophage-associated presentation and the activation of delayed hypersensitivity T cells (TDH). In tolerization via intravenous injection of HoGG-LC, antigen (a) reaches the lymph node via the blood, probably directly meeting the TDH, preventing its subsequent activation by immunogenic HoGG (clone inhibition) and (b) reaches the spleen, also via the blood, activating suppressor T cells.

Endotoxin-induced shunting of erythropoiesis in mice.

ARTICLESEndotoxin-induced shunting of erythropoiesis in miceGJ FruhmanGJ FruhmanPublished Online:01 May 1967https://doi.org/10.1152/ajplegacy.1967.212.5.1095MoreSectionsPDF (700 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByBacterial Lipopolysaccharides Suppress Erythroblastic Islands and Erythropoiesis in the Bone Marrow in an Extrinsic and G- CSF-, IL-1-, and TNF-Independent Manner6 October 2020 | Frontiers in Immunology, Vol. 11Infection with Anaplasma phagocytophilum Induces Multilineage Alterations in Hematopoietic Progenitor Cells and Peripheral Blood CellsInfection and Immunity, Vol. 77, No. 9Diminished Hematopoietic Activity Associated with Alterations in Innate and Adaptive Immunity in a Mouse Model of Human Monocytic EhrlichiosisInfection and Immunity, Vol. 77, No. 9Bone marrow immunosuppression in Salmonella-infected mice is prolonged following influenza virus infectionExperimental Hematology, Vol. 33, No. 12Microcytic anemia and changes in ferrokinetics as late after-effects of glucan administration in murine hepatitis virus-infected C57BL/10ScSnPh miceInternational Journal of Immunopharmacology, Vol. 16, No. 1Plasmodium chabaudi AS: Erythropoietic responses during infection in resistant and susceptible miceExperimental Parasitology, Vol. 75, No. 3Changes in hemopoietic and regulator levels in mice during fatal or nonfatal malarial infectionsExperimental Parasitology, Vol. 71, No. 4Effects of thrombopoietin and erythropoietin on platelet production in rebound-thrombocytotic and normal miceAmerican Journal of Hematology, Vol. 6, No. 3Changes of the Bone Marrow in Endotoxin ShockDAILY VARIATIONS OF MARROW AND SPLENIC ERYTHROPOIESIS, PINNA EPIDERMAL CELL MITOSIS AND PHYSICAL ACTIVITY IN C57Bl/6J MICECell Proliferation, Vol. 7, No. 4The Effects of Repeated. Doses of Bacterial Endotoxin on Erythropoiesis in the Normal and Splenectomized MouseBritish Journal of Haematology, Vol. 22, No. 2The Kinetics of Haematopoiesis in the Calf: II. An Autoradiographical Study of Erythropoiesis in Normal, Anaemic and Endotoxin Treated CalvesResearch in Veterinary Science, Vol. 12, No. 6 More from this issue > Volume 212Issue 5May 1967Pages 1095-1098 Copyright & PermissionsCopyright © 1967 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1967.212.5.1095PubMed5337249History Published online 1 May 1967 Published in print 1 May 1967 Metrics