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1.
Cell Death Dis ; 7: e2059, 2016 Jan 14.
Article in English | MEDLINE | ID: mdl-26775710

ABSTRACT

In endometriosis, the increased survival potential of shed endometrial cells (which normally undergo anoikis) is suggested to promote lesion development. One mechanism that may alter anoikis is autophagy. Using an autophagic flux inhibitor hydroxychloroquine (HCQ), we identified that it reduces the in vitro survival capacity of human endometriotic and endometrial T-HESC cells. We also identified that HCQ could decrease lesion numbers and disrupt lesion histopathology, as well as increase the levels of peritoneal macrophages and the IP-10 (10 kDa interferon-γ-induced protein) chemokine in a mouse model of endometriosis. We noted that RNA levels of a subset of autophagic markers were reduced in lesions relative to uterine horns from endometriosis-induced (untreated) mice. In addition, the RNA levels of autophagic markers were decreased in uterine horns of endometriosis-induced mice compared with those from controls. However, we noted that protein expression of LC3B (microtubule-associated protein 1 light-chain 3ß; an autophagic marker) was increased in uterine horns of endometriosis-induced mice compared with uterine horns of controls. By immunohistochemical staining of a human endometriosis-focused tissue microarray, we observed LC3B expression predominantly in epithelial relative to stromal cells in both eutopic and ectopic endometria. Via transmission electron microscopy, cells from eutopic endometria of endometriosis-induced mice contained more lipid droplets (rather than autophagosomes) compared with uterine horns from controls. Collectively, our findings indicate that the autophagic pathway is dysregulated in both ectopic and eutopic endometrium in a murine model of endometriosis and that HCQ has potential as a therapeutic agent for women afflicted with endometriosis.


Subject(s)
Endometriosis/genetics , Hydroxychloroquine/therapeutic use , Animals , Autophagy , Disease Models, Animal , Endometriosis/pathology , Female , Humans , Hydroxychloroquine/administration & dosage , Mice
2.
Mucosal Immunol ; 7(6): 1429-1439, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24781051

ABSTRACT

T cells have a critical role in immune surveillance at mucosal surfaces. SHIP1(-/-) mice succumb to mucosal inflammatory disease that afflicts the lung and small intestine (SI). The basis of this condition has not been defined. Here we show that SHIP1 is required for the normal persistence and survival of T cells in mucosal tissues. We find that CD4 and CD8 effector T cells are reduced; however, Treg cells are increased in the SI and lungs of SHIP1(-/-) and CD4CreSHIP(flox/flox) mice. Furthermore, a subset of T cells in the SI of SHIP1(-/-) mice are FasL(+) and are more susceptible to extrinsic cell death. Mechanistic analyses showed that SHIP1 associates with the death receptor CD95/Fas and treatment with a Caspase 8 inhibitor prevents SHIP1 inhibitor-mediated T-cell death. Notably, mucosal inflammation in SHIP1(-/-) mice is reduced by treatment with a Caspase 8 inhibitor. We also find that the incidence of Crohn's disease (CD) and pneumonia is significantly increased in mice with dual T and myeloid lineage SHIP1 deletion but not in single lineage-deleted mice. Thus, by promoting survival of protective T cells, thereby preventing an inflammatory myeloid response, SHIP1 maintains an appropriate balance of innate immune function at mucosal surfaces necessary for immune homeostasis.


Subject(s)
Crohn Disease/immunology , Intestinal Mucosa/immunology , Phosphoric Monoester Hydrolases/immunology , Pneumonia/immunology , Respiratory Mucosa/immunology , T-Lymphocytes/immunology , Animals , Caspase 8/genetics , Caspase 8/immunology , Cell Survival/genetics , Cell Survival/immunology , Crohn Disease/genetics , Crohn Disease/pathology , Fas Ligand Protein/genetics , Fas Ligand Protein/immunology , Inositol Polyphosphate 5-Phosphatases , Intestinal Mucosa/pathology , Mice , Mice, Knockout , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases , Phosphoric Monoester Hydrolases/genetics , Pneumonia/genetics , Respiratory Mucosa/pathology , T-Lymphocytes/pathology , fas Receptor/genetics , fas Receptor/immunology
3.
Genes Immun ; 15(4): 233-40, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24598798

ABSTRACT

SHIP-1 has an important role in controlling immune cell function through its ability to downmodulate PI3K signaling pathways that regulate cell survival and responses to stimulation. Mice deficient in SHIP-1 display several chronic inflammatory phenotypes including antibody-mediated autoimmune disease, Crohn's disease-like ileitis and a lung disease reminiscent of chronic obstructive pulmonary disease. The ileum and lungs of SHIP-1-deficient mice are infiltrated at an early age with abundant myeloid cells and the mice have a limited lifespan primarily thought to be due to the consolidation of lungs with spontaneously activated macrophages. To determine whether the myeloid compartment is the key initiator of inflammatory disease in SHIP-1-deficient mice, we examined two independent strains of mice harboring myeloid-restricted deletion of SHIP-1. Contrary to expectations, conditional deletion of SHIP-1 in myeloid cells did not result in consolidating pneumonia or segmental ileitis typical of germline SHIP-1 deficiency. In addition, other myeloid cell abnormalities characteristic of germline loss of SHIP-1, including flagrant splenomegaly and enhanced myelopoiesis, were absent in mice lacking SHIP-1 in myeloid cells. This study indicates that the spontaneous inflammatory disease characteristic of germline SHIP-1 deficiency is not initiated solely by LysM-positive myeloid cells but requires the simultaneous loss of SHIP-1 in other hematolymphoid lineages.


Subject(s)
Lung/immunology , Macrophage Activation , Macrophages/immunology , Myelopoiesis/immunology , Phosphoric Monoester Hydrolases/immunology , Pneumonia/immunology , Animals , Chronic Disease , Ileum/enzymology , Ileum/immunology , Inflammation/enzymology , Inflammation/immunology , Inflammation/pathology , Inositol Polyphosphate 5-Phosphatases , Lung/enzymology , Lung/pathology , Macrophages/enzymology , Macrophages/pathology , Mice , Mice, Knockout , Myelopoiesis/genetics , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/immunology , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases , Phosphoric Monoester Hydrolases/genetics , Phosphoric Monoester Hydrolases/metabolism , Pneumonia/enzymology , Pneumonia/genetics
4.
Methods Mol Biol ; 900: 433-41, 2012.
Article in English | MEDLINE | ID: mdl-22933082

ABSTRACT

Inflammatory diseases of the mucosal surfaces are rising worldwide and particularly in the Western world that is witnessing unprecedented increases in the number and incidence of both asthma and inflammatory bowel disease. The laboratory mouse allows the application of the full panoply of modern genetic, immunological and biochemical tools to increase our understanding of how inflammation arises and how it might be controlled at mucosal surfaces. Here we provide a detailed description of how to systematically assess inflammatory disease in the lung and intestines of the laboratory mouse. We provide histopathology examples from SHIP mutant mice that are the only known genetic mutant to suffer from pulmonary consolidation, asthma, and Crohn's disease. The intent of this chapter is to facilitate increased surveillance of mucosal inflammation in studies where the laboratory mouse is utilized so that we can better understand the cell types, genes, and microorganisms that contribute to mucosal inflammatory disease and thereby develop more effective therapies and preventive strategies.


Subject(s)
Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/pathology , Models, Genetic , Molecular Biology/methods , Animals , Eosinophils/pathology , Inositol Polyphosphate 5-Phosphatases , Mice , Mice, Transgenic , Phosphoric Monoester Hydrolases/deficiency , Phosphoric Monoester Hydrolases/metabolism
5.
J Neuroimmunol ; 125(1-2): 103-13, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11960646

ABSTRACT

Ntera2/D1 cells had an A1 B8 Bw6 Cw7 DR3 DR52 major histocompatibility complex (MHC) genotype. Its neuronal derivative, hNT neurons, expressed A1 B8 Bw6 MHC class I molecules, but did not activate, and its hNT supernatant suppressed allogeneic mixed lymphocyte cultures (MLC) >98% (p<0.01), phytohemagglutinin (PHA)-activated T-cell proliferation >87% (p<0.01), even 48 h after stimulation, suppressed phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced T-cell proliferation >99% (p<0.001), and reduced interleukin-2 (IL-2) production (p<0.01), while maintaining T cells in a quiescent G(0)/G(1) state without lowering their viability. This immunosuppressive activity was attributed to a 40-100-kDa anionic hNT protein with an isoelectric point of 4.8.


Subject(s)
Interleukin-2/biosynthesis , Neurons/immunology , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Brain Tissue Transplantation/immunology , Cell Communication/immunology , Cell Division/immunology , Culture Media, Conditioned , Gene Expression/immunology , Histocompatibility Antigens Class I/genetics , Humans , Lymphocyte Activation/immunology , Neoplastic Stem Cells/cytology , Neoplastic Stem Cells/immunology , Neurons/cytology , T-Lymphocytes/immunology , Tumor Cells, Cultured
6.
Exp Biol Med (Maywood) ; 226(11): 1061-7, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11743143

ABSTRACT

Calorie restriction without essential nutrient deficiency (calorie restriction, CR) abrogates experimental carcinogenesis and extends healthful life span. To test whether CR influences cell-cycle protein expression during the hepatocellular proliferation induced by 70% partial hepatectomy (PH), BALB/c mice were separated into two groups, fed comparable semi-purified diets for 10 weeks that differed 40% in caloric offering, and were then subjected to PH. When PH was performed, CR mice weighed 36% less than ad libitum (AL)-fed mice (P < 0.01), but liver-to-body weight ratios were similar. During the regenerative hyperplasia, hepatocytes of CR mice demonstrated evidence of accelerated entrance and passage through G1 and S phases, and an earlier exit from the cell cycle. The first peak of DNA synthesis occurred 6 hr earlier, and the second peak was significantly greater among CR mice with 38% +/- 13% bromodeoxyuridine (BrdU)-positive hepatocytes, compared with 14% +/- 4% in AL mice (P < 0.01). More E2F-1 expression was induced at the hepatic G1/S boundary just prior to each peak of DNA synthesis in regenerating livers of CR mice (P < 0.01), and 8 hr earlier among CR mice. More hyperphosphorylated retinoblastoma p110 was detected during hepatic G1 and the G1-S transition among CR mice, coincident with the early hepatocellular proliferative wave. Cyclin A was induced during the first peak of DNA synthesis 4 hr earlier among CR mice, and it continued 4 hr longer in AL mice, indicating an earlier post-replicative exit by hepatocytes in CR mice. p21 was induced during the G1 phase at 4 hr post-PH, and was maximally expressed during and after peak DNA synthesis in both dietary groups. These results indicate that CR influences cell cycle protein expression levels, causing hepatocytes to enter into S phase earlier and exit abruptly from the cell cycle, and they support the premise that CR enhances induced cell responsiveness by influencing cell cycle regulatory controls.


Subject(s)
Cell Cycle , Energy Intake , Liver/metabolism , Age Factors , Animals , Binding Sites , Blotting, Western , Cell Division , DNA/biosynthesis , Female , Hepatectomy , Liver/physiology , Mice , Mice, Inbred BALB C , Regeneration , S Phase , Time Factors
7.
Biol Blood Marrow Transplant ; 6(5): 513-22, 2000.
Article in English | MEDLINE | ID: mdl-11063380

ABSTRACT

This project was designed to investigate the application of bone marrow transplantation to a progressive and ultimately fatal systemic autoimmune disease. Male (NZW x BXSB)F1 (W/BF1) mice develop acute systemic autoimmune disease characterized by degenerative coronary vascular disease (CVD) with myocardial infarctions, hypertension, thrombocytopenia, glomerulonephritis, and persistently elevated levels of circulating immune complexes. After preliminary studies established the onset of disease between 10 and 12 weeks of age, 6- to 8-week-old male W/BF1 mice were targeted for transplantation with either T-cell-depleted bone marrow or purified hematopoietic stem cells from haploidentical B6C3/F1 mice. Posttransplantation flow cytometric analysis of splenocytes demonstrated donor phenotypes in W/BF1 recipient mice that had received T-cell-depleted marrow or hematopoietic stem cell preparations (lineage negative, CD71 negative) from B6C3/F1 donors. Survival of W/BF1 mice transplanted with bone marrow from normal B6C3/F1 donors was very high, and assessment at 100 days after transplantation revealed reduction in onset and severity of disease. Autoantibodies to cardiolipin and double-stranded DNA were markedly reduced to levels present in normal mice. Immunohistochemistry of heart and kidney tissue revealed significant amelioration of degenerative CVD and glomerulonephritis in the majority of W/BF1 recipients of marrow transplants from B6C3/F1 donors. All engrafted W/BF1 mice displayed normal immunologic competence 100 days posttransplantation.


Subject(s)
Autoimmune Diseases/therapy , Bone Marrow Transplantation , Coronary Disease/prevention & control , Hematopoietic Stem Cell Transplantation , Lupus Erythematosus, Systemic/therapy , Lymphocyte Depletion , Animals , Autoimmune Diseases/complications , Autoimmune Diseases/pathology , Coronary Disease/etiology , Crosses, Genetic , Flow Cytometry , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/pathology , Lupus Nephritis/pathology , Lupus Nephritis/prevention & control , Lymphocyte Activation , Lymphocyte Culture Test, Mixed , Male , Mice , Mice, Inbred BALB C , Mice, Inbred MRL lpr , Mice, Inbred NZB , Mice, Inbred Strains , Models, Animal , Radiation Chimera , Rosette Formation , Spleen/cytology , T-Lymphocytes, Cytotoxic
8.
Proc Soc Exp Biol Med ; 218(3): 218-22, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9648939

ABSTRACT

Reduced dietary calories can delay the onset and diminish the severity of murine autoimmunities of numerous inbred and hybrid mutant strains. We sought to determine whether the precipitous, autoimmune, crescentic glomerulonephritis of recombinant inbred SCG/Kj mice could be abrogated similarly by calorie restriction. Weanling SCG/Kj mice develop hematuria and proteinuria, and 50% die as 16-week-old young adults. In this study, 113 4-week-old SCG/Kj mice were fed either ad libitum a milled chow (Group A, n = 50), or a semipurified diet (Group B, n = 29), or were fed a calorie-restricted semipurified diet (Group C, n = 34), so that mice of Group C consumed approximately 32% fewer calories, but similar amounts of essential dietary constituents as those of Group B. Calorie restriction of Group C provided modest (P = 0.05) or substantial survival advantage (P = 0.001) compared to the ad libitum feeding of Groups B or A, respectively. Progression to severe glomerular pathology was delayed among Group C mice, with more than a 5-week delay to heavy proteinuria (>100 mg/dl), a >4-week delay to hematuria, and a >5-week delay to median mortality, representing a 20% or 25% extension of median life span, compared to ad libitum-fed Group B and A mice, respectively. Mean glomerular histopathology scores were also lower in calorie-restricted mice compared to the ad libitum-fed cohorts (P = 0.001). Titers of anti-ss-DNA, ds-DNA, and ANCA autoantibodies developed in weanlings prior to the full imposition of calorie restriction and were not reduced significantly by calorie restriction.


Subject(s)
Autoimmune Diseases/prevention & control , Energy Intake , Glomerulonephritis/prevention & control , Animals , Autoantibodies/blood , Autoimmune Diseases/genetics , Autoimmune Diseases/mortality , Diet, Reducing , Female , Glomerulonephritis/immunology , Glomerulonephritis/pathology , Kidney Glomerulus/pathology , Lymph Nodes/pathology , Mice , Mice, Inbred Strains , Proteinuria , Spleen/pathology , Survival Rate
9.
Proc Soc Exp Biol Med ; 218(3): 223-8, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9648940

ABSTRACT

Transplantation of MHC-compatible, T-cell-depleted, bone marrow cells has successfully treated autoimmunities, immunodeficiencies, malignancies, and developmental deficiencies of the hematopoietic system. Recombinant inbred SCG/Kj mice develop spontaneous crescentic glomerulonephritis, systemic vasculitis, and a lymphoproliferative disorder early in life. To determine whether the precipitous autoimmune disease of SCG/Kj mice could be treated by bone marrow transplantation, 30 SCG/Kj mice were engrafted with T-cell-depleted, bone marrow (TCDM) from allogeneic, MHC-compatible, autoimmune-resistant C3H/He donors, and 30 SCG/Kj mice served as controls and received TCDM from syngeneic, SCG/Kj donors. A significant survival advantage was evident from SCG/Kj mice engrafted with C3H/He TCDM (p < 0.005), and an 89% extension of median survival compared to recipients of SCG/Kj TCDM. Within 28 weeks post-transplantation, 62% of mice engrafted with SCG/Kj TCDM had died with clinical signs of fatal crescentic glomerulonephritis. This result compared with only 10% of mice engrafted with C3H/He TCDM. Mice engrafted with SCG/Kj TCDM developed significantly greater titers of autoantibodies to ss-DNA, ds-DNA, and myeloperoxidase (ANCA) (p < 0.001), had shorter latencies to the development of, and a greater incidence of proteinuria, hematuria, and peripheral lymphadenopathy, and a greater mean grade of glomerular lesion (p < 0.001), than mice engrafted with C3H/He TCDM. These findings indicate that the genetic defect of the SCG/Kj strain of mice resides within the hematopoietic stem cells and provokes the speculation that bone marrow transplantation might be a useful means of treating progressive crescentic glomerulonephritis in humans.


Subject(s)
Autoimmune Diseases/prevention & control , Bone Marrow Transplantation , Glomerulonephritis/prevention & control , Animals , Autoantibodies/blood , DNA/immunology , DNA, Single-Stranded/immunology , Female , Glomerulonephritis/genetics , Glomerulonephritis/immunology , Hyperplasia , Kidney Glomerulus/pathology , Lymph Nodes/pathology , Male , Mice , Mice, Inbred C3H , Mice, Inbred Strains , Peroxidase/immunology , Spleen/pathology , Survival Rate
10.
J Leukoc Biol ; 61(6): 654-66, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9201256

ABSTRACT

Studies of the effects of retroviruses on the immune system, which date back through thirty years of investigations, are reviewed. In the earliest published studies in the 1960s, it was demonstrated that mice infected with oncogenic viruses were immunosuppressed. Since then, numerous articles have been published describing profound immunodeficiencies observed in vivo in humans infected with human immunodeficiency virus and in animals such as cats infected with the feline immunodeficiency virus. In vitro investigations have shown that inactivated retroviruses or transmembrane envelope protein p15E as well as a synthetic 17-amino acid peptide (CKS-17) impressively conserved within the transmembrane envelope protein of several animal or human retroviruses are highly immunosuppressive. More recently, dysfunction of cytokines produced by CKS-17 at both a cellular and molecular level have been found to mimic influences observed in vivo in patients infected with the human immunodeficiency virus. CKS-17 has also been shown to induce cAMP in vitro. The significance of these observations to understanding the immunological disturbances observed in malignancy, cytokine biosynthesis, and modulations of immune functions through cAMP is discussed.


Subject(s)
Immunologic Deficiency Syndromes/etiology , Immunologic Deficiency Syndromes/virology , Immunosuppressive Agents/pharmacology , Retroviridae Infections/etiology , Retroviridae Infections/immunology , Retroviridae Proteins, Oncogenic/pharmacology , Amino Acid Sequence , Animals , Humans , Molecular Sequence Data , Retroviridae Infections/pathology
11.
Mol Cell Endocrinol ; 129(2): 145-55, 1997 May 16.
Article in English | MEDLINE | ID: mdl-9202398

ABSTRACT

Mammary specific expression of elevated levels of mouse mammary tumor virus (MMTV) contributes to mammary carcinogenesis. Mechanisms which regulate provirus expression have not been completely defined. Using a MMTV-long repeat terminal (MMTV-LRT) directed chloramphenicol-acetyltransferase (CAT) reporter gene system and a human breast cancer cell line T47D, we demonstrate that prolactin (PRL), epidermal growth factor (EGF), or transforming growth factor-alpha (TGF-alpha) act on a mammary cell-specific enhancer at the extreme 5' end of the MMTV-LTR involving sequences -1094 through -858. PRL and either EGF or TGF-alpha exert concerted roles in this activation of these sequences. In contrast, using a plasmid construct lacking this mammary cell-specific enhancer, EGF or TGF-alpha, but not PRL, act synergistically with progesterone to induce CAT activity, indicating that the action of PRL on regulatory elements of the MMTV-LTR is restricted to this mammary cell-specific enhancer involving sequences -1094 through -858. A mobility shift assay was used to demonstrate that PRL, EGF or TGF-alpha induce nuclear factors (MP4, MAF, and MGF) which bind directly to this mammary cell-specific enhancer element.


Subject(s)
Enhancer Elements, Genetic/drug effects , Epidermal Growth Factor/pharmacology , Mammary Tumor Virus, Mouse/genetics , Prolactin/pharmacology , Repetitive Sequences, Nucleic Acid/drug effects , Transforming Growth Factor alpha/pharmacology , Binding Sites , Chloramphenicol O-Acetyltransferase/genetics , Enhancer Elements, Genetic/physiology , Female , Gene Expression Regulation, Viral , Genes, Reporter , Humans , Progesterone/pharmacology , Repetitive Sequences, Nucleic Acid/genetics , Transcription Factors , Transfection , Tumor Cells, Cultured
12.
J Virol ; 70(1): 566-9, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8523571

ABSTRACT

The presence of feline immunodeficiency virus (FIV) proviral DNA, expression of FIV p26 core protein, and production of tumor necrosis factor alpha (TNF-alpha) were assessed in sequential biopsies of spleen and lymph node sections, of mononuclear cells of the peripheral blood, and of the serum of specific-pathogen-free cats during the acute phase of FIV infection. A temporal relationship between TNF-alpha production and FIV p26 expression was noted. Two months following FIV infection, and preceding the detection of FIV viremia, levels of TNF-alpha in serum increased significantly (P = 0.04), and they remained elevated during FIV viremia in the third month postinfection. Immunoprecipitates representing expression of TNF-alpha and of FIV p26 were localized in common foci of lymph nodes of FIV-infected cats during this period of active viremia. With the advent of anti-FIV antibodies, circulating levels of TNF-alpha and p26 antigen and expression of TNF-alpha and p26 in the lymph nodes decreased during the fifth month postinfection, and p26 production became undetectable. With clearance of viremia, burden of proviral DNA in peripheral blood mononuclear cells became reduced (P = 0.041), with provirus remaining integrated principally within lymph nodes (P = 0.046). During aviremia, p26 expression was undetectable in any tissue but remained inducible in vitro. During acute FIV infection, TNF-alpha production and p26 expression are intimately linked.


Subject(s)
Feline Acquired Immunodeficiency Syndrome/immunology , Immunodeficiency Virus, Feline/immunology , Tumor Necrosis Factor-alpha/biosynthesis , Animals , Antibodies, Viral/blood , Base Sequence , Cats , DNA, Viral , Lymph Nodes/cytology , Lymph Nodes/immunology , Molecular Sequence Data , Proviruses/immunology , Spleen/cytology , Spleen/immunology , Viral Core Proteins/biosynthesis , Viral Core Proteins/immunology
13.
Proc Soc Exp Biol Med ; 209(3): 279-85, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7777589

ABSTRACT

Gastrointestinal vasculitis is a fatal aspect of systemic lupus erythematosus. Whether lupus-prone strains of mice develop gastrointestinal vasculitis, and whether it is accompanied by elevated titres of anticardiolipin autoantibody is not known. Lupus-prone (NZW X BXSB)F1 (W/BF1) mice, and other strains were examined immunohistologically. Levels of anticardiolipin autoantibody and circulating immune complexes were determined by microELISA. Reciprocal haploidentical marrow transplantations between W/BF1 and autoimmune-resistent B6C3F1 mice were made. Young adult W/BF1 mice had the highest incidence of gastrointestinal vasculitis (61%), and the highest mean titre of anticardiolipin autoantibody. Lesions consisted of subintimal fibrinoid degeneration in arterioles of the duodenum, jejunum and ileum, and were prevented, or alternatively induced by reciprocal marrow transplantations between W/BF1 and B6C3F1 mice. Mice engrafted with W/BF1 marrow which developed vasculitis had higher titres of anticardiolipin autoantibodies than engrafted mice free of vasculitis (P < 0.005). This represents the first report of gastrointestinal vasculitis as an aspect of systemic autoimmunity in lupus-prone mice. The concurrent elevation of anticardiolipin autoantibody and development of vasculitis suggests that anticardiolipin autoantibodies, and their proposed thrombogenic and vascular injury consequences, contribute to development of microvasculitis in lupus-prone mice.


Subject(s)
Antibodies, Anticardiolipin/blood , Gastrointestinal Diseases/etiology , Lupus Erythematosus, Systemic/complications , Vasculitis/etiology , Animals , Antigen-Antibody Complex/blood , Bone Marrow Transplantation , Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/pathology , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Vasculitis/immunology , Vasculitis/pathology
14.
Cancer Res ; 55(6): 1289-95, 1995 Mar 15.
Article in English | MEDLINE | ID: mdl-7882324

ABSTRACT

Calorie restriction reduces mammary mitogenesis and tumorigenesis. To test whether epidermal growth factor (EGF) levels are influenced by calorie intake, 72 four-week-old C3H/HeOu mice were separated into two groups and either fed ad libitum (group AL) or calorie-restricted at a mean 19% (group CR). Three mice from each group were evaluated when 6, 8, 10, and 12 weeks old for submandibular gland transcription of EGF and beta-actin RNA for levels of EGF protein in the submandibular gland, mammary gland, and serum and for immunohistological evidence of EGF protein within the submandibular and mammary glands. Submandibular levels of EGF RNA and protein and mammary and serum levels of EGF protein were similar between dietary groups when mice were 6 and 8 weeks old. Mean EGF:beta-actin RNA transcription in submandibular glands of 12-week-old mice were approximately 10-fold greater in AL compared to CR mice (ratio means, 1.499 versus 0.157, respectively; P < 0.01). Mean submandibular levels of EGF protein were greater in 10-week-old AL compared to CR mice (7017.4 versus 4098.5 ng/mg protein, respectively; P < 0.05) and even greater in 12-week-old AL compared to CR mice (4342.6 versus 137.9 ng/mg protein; P < 0.001). Mean mammary levels of EGF protein were greater among 12-week-old AL compared to CR mice (7.8 versus 5.0 ng/mg protein; P < 0.05). Serum levels of EGF did not differ between dietary cohorts. More anti-EGF immunoprecipitate was present in submandibular and mammary gland sections of 10- and 12-week-old AL compared to CR mice. Lowered EGF levels may contribute to the antiproliferative and antineoplastic effects of calorie restriction.


Subject(s)
Diet, Reducing , Epidermal Growth Factor/analysis , Mammary Glands, Animal/chemistry , Submandibular Gland/chemistry , Animals , Base Sequence , Body Weight , Energy Intake , Epidermal Growth Factor/genetics , Epidermal Growth Factor/immunology , Female , Mice , Mice, Inbred C3H , Molecular Sequence Data , RNA, Messenger/analysis
15.
Cancer Res ; 54(21): 5724-30, 1994 Nov 01.
Article in English | MEDLINE | ID: mdl-7923222

ABSTRACT

To test for a relationship between peripubertal calorie intake, mammary development, and tumorigenesis, weanling C3H/HeOu mice were separated into 3 groups: fed diet either ad libitum (AL) and designated group AL (n = 60); fed a similar, calorie-restricted (CR) diet only during mammary development when 4-12 weeks old and then subsequently fed ad libitum when > or = 13 weeks old (group CR4-12, n = 24); or continuously calorie restricted (group CR, n = 60). Eight weeks of peripubertal calorie restriction provided CR4-12 mice with lasting protection from mammary tumorigenesis (P = 0.004) and lowered cumulative tumor incidence by 33% compared to AL mice. Sustained calorie restriction of group CR mice further reduced mammary tumor incidence compared to both AL (P = 0.000001) and CR4-12 mice (P = 0.009). Calorie intake significantly influenced mammary development and cellular proliferation. Compared to the mammary development of AL mice, calorie restriction reduced the diameter of ductal end buds (189 microns compared to 146 microns; P < 0.01), lowered the end bud [3H]thymidine labeling index from > or = 20 to < or = 13% (P < 0.001), delayed end bud migration and mammary glandular growth (P < 0.01), reduced alveolar budding (P < 0.001), reduced the proportion of alveoli containing at least one [3H]thymidine labeled cell from > or = 50 to < or = 22% (P < 0.001), and lowered the alveolar [3H]thymidine labeling index of labeled alveoli from > or = 14 to < or = 7% (P < 0.001). These findings link peripubertal calorie intake, mammary development, and carcinogenic risk, and show that the abrogation of mammary tumorigenesis by calorie restriction is partially attributable to influences on mammary development.


Subject(s)
Energy Intake , Mammary Glands, Animal/growth & development , Mammary Neoplasms, Animal/prevention & control , Sexual Maturation/physiology , Animals , Body Weight , Cell Division , Estrus , Female , Mammary Glands, Animal/anatomy & histology , Mammary Neoplasms, Animal/epidemiology , Mice , Mice, Inbred C3H
16.
J Nutr ; 124(10): 2016-23, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7931711

ABSTRACT

Male (NZW x BXSB)F1 (W/BF1) mice develop immune thrombocytopenic purpura (ITP), which involves antiplatelet autoantibodies and shortened platelet life span. To determine whether reduction of dietary energy can prevent the development or reverse the progression of ITP, male W/BF1 mice were separated into five experimental groups and either given free access to semipurified diet (designated Group A, n = 50) or consumed 32% less energy from an otherwise comparable diet (Group B6, n = 20), or were initially allowed free access to diet then switched to energy restriction at ages 14, 17 or 22 wk (Groups B14, n = 10; B17, n = 20; B22, n = 20). Thrombocytopenia was prevented by energy restriction in Group B6 mice. Platelet-associated IgG (PAIgG) autoantibody levels and the number of splenic antiplatelet antibody-forming cells were low (P < 0.01) and the survival of injected IgG-coated RBC was extended in energy-restricted Group B6 mice (P < 0.01) compared with mice in Group A. Group A mice became progressively thrombocytopenic, with platelet counts as low as 34 x 10(10)/L. Progression of thrombocytopenia was reversed when energy restriction was initiated in Groups B14, B17 and B22, with platelet counts > or = 88 x 10(10)/L and reduction of PAIgG. Life span was extended among early onset energy-restricted Group B6 and Group B14 mice (P = 0.0001 and P = 0.005) but not among late onset energy-restricted Group B17 and Group B22 mice (P = 0.06 and P = 0.35) compared with Group A mice.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Energy Intake , Purpura, Thrombocytopenic, Idiopathic/diet therapy , Animals , Autoantibodies/blood , Blood Platelets/immunology , Body Weight , Female , Immunoglobulin G/blood , Male , Mice , Mice, Inbred BALB C , Phagocytes/physiology , Platelet Count , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/mortality , Survival Rate
17.
Proc Natl Acad Sci U S A ; 91(10): 4402-6, 1994 May 10.
Article in English | MEDLINE | ID: mdl-8183920

ABSTRACT

Male (NZW x BXSB)F1 (W/BF1) mice develop systemic autoimmunity involving autoantibodies, thrombocytopenia, lupus nephritis, and coronary vascular disease (CVD) with myocardial infarction. To determine whether this murine lupus-associated CVD can be prevented by the reduction of dietary calories, male W/BF1 mice were separated into five experimental groups and fed either ad libitum (designated group A, n = 50), fed 32% fewer calories of an otherwise comparable diet (designated group B6, n = 20), or initially fed ad libitum and then switched to reduced calorie intake (RCI) feeding at ages 14, 17, or 22 weeks (designated B14, n = 10; B17, n = 20; or B22, n = 20). Occlusive CVD was prevented by RCI. Life-span was significantly extended among the early onset RCI cohorts, B6 and B14 (P = 0.0001 and P = 0.005), compared to group A mice. Mean anti-cardiolipin autoantibody titers and mean levels of circulating immune complexes were also lowered in RCI mice when all RCI mice were compared to ad libitum fed group A mice. Histological grades of both coronary vascular and glomerular lesions were significantly less than those of group A mice (P < 0.001). Immunoprecipitates indicative of immunoglobulin deposition within coronary or glomerular vascular walls were also substantially less than those of group A mice. These findings indicate a possible causal role for anti-cardiolipin autoantibody in development of autoimmune CVD in W/BF1 mice and suggest that regulating dietary calories can influence the mechanism involved in pathogenesis of autoimmune-associated CVD development.


Subject(s)
Arterial Occlusive Diseases/prevention & control , Autoantibodies/blood , Autoimmune Diseases/genetics , Coronary Vessels , Diet, Reducing , Animals , Arterial Occlusive Diseases/genetics , Arterial Occlusive Diseases/immunology , Autoimmune Diseases/prevention & control , Body Weight , Cardiolipins/immunology , Coronary Vessels/pathology , Crosses, Genetic , DNA/immunology , Energy Intake , Female , Male , Mice , Mice, Inbred BALB C , Mice, Inbred Strains
18.
Blood ; 82(10): 3091-7, 1993 Nov 15.
Article in English | MEDLINE | ID: mdl-8219200

ABSTRACT

Male (NZW x BXSB)F1 (W/BF1) mice develop systemic autoimmunity involving autoantibodies, thrombocytopenia, lupus nephritis, and coronary vascular disease with myocardial infarction (CVD). To determine whether this murine lupus-associated CVD could be transferred to otherwise autoimmune-resistant (C57BL/6 x C3H/He)F1 (B6C3F1) mice via W/BF1 T-cell-depleted marrow (TCDM) transplants, or conversely whether the CVD of W/BF1 mice could be prevented by the reciprocal transplant, reciprocal haploidentical transplants of TCDM were performed. CVD developed only in mice with systemic autoimmunity. Mice that developed lupus had glomerulonephritis and thrombocytopenia and also had elevated titres of autoantibodies to double-strand DNA, cardiolipin, and platelets and elevated levels of circulating immune complexes. Of control W/BF1 mice, 80% developed lupus, and of these, 81% developed CVD with a mean grade of 2.5 +/- 0.8. Engraftment of W/BF1 mice with B6C3F1 marrow protected 90% of the recipients from the development of lupus, and none developed CVD. Engraftment of B6C3F1 mice with W/BF1 marrow induced lupus in 60% of the recipients, and of those, 33% developed CVD with a mean grade of 1.3 +/- 0.3. The B6C3F1 recipients of W/BF1 marrow which developed CVD had significantly higher titres of autoantibodies to cardiolipin (aCL; P < .01). These findings show that genetic abnormalities present in the W/BF1 hematopoietic stem cells contribute to autoantibody development, including aCL, and suggest that thrombogenic mechanisms induced by aCL may contribute to the development of CVD in this form of murine lupus erythematosus.


Subject(s)
Antibodies, Anticardiolipin/physiology , Arterial Occlusive Diseases/etiology , Autoimmune Diseases/complications , Bone Marrow Transplantation/adverse effects , Coronary Disease/etiology , Animals , Antibodies, Anticardiolipin/blood , Antigen-Antibody Complex/blood , Arterial Occlusive Diseases/pathology , Arterial Occlusive Diseases/prevention & control , Blood Platelets/immunology , Coronary Disease/pathology , Coronary Disease/prevention & control , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Platelet Count
19.
Blood ; 82(3): 837-44, 1993 Aug 01.
Article in English | MEDLINE | ID: mdl-8338948

ABSTRACT

Male (NZW x BXSB)F1 (W/BF1) mice develop systemic autoimmunity involving autoantibodies, progressive thrombocytopenia, lupus nephritis, and degenerative coronary vascular disease with myocardial infarction. Platelet-associated IgG (PAIgG) on the platelet surface mediates platelet destruction by the reticuloendothelial system in the autoimmune thrombocytopenic purpura (ATP) of W/BF1 mice. Because the epitopes targeted in ATP by PAIgG have not been identifiable using serum from thrombocytopenic W/BF1 mice, we developed seven hybridomas secreting antiplatelet monoclonal antibodies (MoAbs) using splenocytes of thrombocytopenic W/BF1 mice. Epitopes recognized by three MoAbs were similar to those recognized by PAIgG, because eluted IgG from platelets of thrombocytopenic W/BF1 mice inhibited platelet binding by MoAbs in competitive micro-enzyme-linked immunosorbent assay. Hybridoma cells or purified Ig from the ascites of two clones (2A12 and 6A6), when injected into nude mice produced acute thrombocytopenia, elevated the levels of PAIgG, purpura, and megakaryocytosis. MoAbs of two clones also reacted with single-stranded DNA or double-stranded DNA, and one of these clones (4-13) bound to cardiolipin (CL) but was nonpathogenic in nude mice, suggesting that anti-CL and antiplatelet autoantibodies can be distinct. On immunoblotting analysis, antiplatelet MoAbs frequently bound a 100-Kd platelet protein. These MoAbs contribute to an understanding of the etiopathogenesis of ATP and the several antigens and autoantibodies involved.


Subject(s)
Antibodies, Monoclonal/immunology , Blood Platelets/immunology , Purpura, Thrombocytopenic, Idiopathic/immunology , Animals , Antibodies, Antinuclear/immunology , Autoantibodies/immunology , Blood Platelets/chemistry , Cardiolipins/immunology , Female , Humans , Hybridomas , Immunoglobulin Isotypes/immunology , Male , Mice , Mice, Mutant Strains , Mice, Nude , Molecular Weight , Proteins/chemistry , Proteins/immunology
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