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1.
Cancer Immunol Immunother ; 50(3): 125-33, 2001 May.
Article in English | MEDLINE | ID: mdl-11419179

ABSTRACT

The T-cell-specific receptor, CTLA-4, has been demonstrated to be a potent negative regulator of lymphocyte activation, the functional significance of which has been demonstrated in murine tumor models using blocking antibodies. However, the mechanism(s) involved in enhancing tumor regression has not been identified. In this study, we determined whether IFN gamma was playing a role in this activity. In vitro, anti-CTLA-4 enhanced IFN gamma production by lymph node cells obtained from tumor-bearing mice (351 pg/ml vs 77 pg/ml). Additionally, fibrosarcoma-challenged animals treated with anti-CTLA-4 had elevated levels of the IFN-inducible enzyme 2-5-OAS in draining lymph nodes (850 pM vs 260 pM for controls) and an increased amount of IFN gamma in tumor lysates (at day 7, 620 pg/100 micrograms vs 160 pg/100 micrograms in controls). The importance of IFN gamma was demonstrated by the ability of neutralizing antibodies to completely abrogate the anti-tumor effects of anti-CTLA-4. Moreover, fibrosarcoma cells were shown to be exquisitely sensitive to IFN gamma-mediated class I upregulation and histological examination of tumors from anti-CTLA-4-treated mice revealed a trend toward increased tumor cell apoptosis and decreased angiogenesis. These studies have demonstrated that one mechanism for the anti-tumor effects of anti-CTLA-4 relates to its ability to augment IFN gamma production, resulting in an increased expression of class I on the tumor, enhanced apoptosis, and a decrease in blood vessel growth.


Subject(s)
Antigens, Differentiation/metabolism , Immunoconjugates , Interferon-gamma/metabolism , 2',5'-Oligoadenylate Synthetase/metabolism , Abatacept , Animals , Antigens, CD , Antigens, Differentiation/blood , Antigens, Differentiation/immunology , Apoptosis , CTLA-4 Antigen , Cancer Vaccines , Dose-Response Relationship, Drug , Female , Fibrosarcoma/therapy , Flow Cytometry , Immunoglobulin G/metabolism , Immunosuppressive Agents/pharmacology , Immunotherapy , Interferon-gamma/biosynthesis , Lymph Nodes/cytology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mitosis , Neoplasm Transplantation , Neoplasms, Experimental/prevention & control , Neoplasms, Experimental/therapy , Platelet Endothelial Cell Adhesion Molecule-1/biosynthesis , Time Factors , Up-Regulation
2.
Inflammation ; 23(1): 75-86, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10065763

ABSTRACT

The in vitro chemotactic activity of chemokines have been well documented. However, study of their in vivo effects where components of rolling, adherence and diapedesis are pre-requisites to leukocyte infiltration have not been examined in higher species. In this study, we examined the biological activity of the CC chemokine, MIP-1alpha, in rhesus monkeys. Following an intradermal injection, a significant cellular infiltrate and an increase in the number of inflamed vessels were observed. This response peaked at 24 h and was sustained for up to 48 hours after injection. Phenotypically, the specific infiltrate consisted exclusively of CD68+ monocytes with no increase in other cell types over the saline injected controls. These studies represent the first examination of the in vivo effects of MIP-1alpha in higher species and indicate that MIP-1alpha is a selective monocyte recruiting agent in vivo.


Subject(s)
Chemotaxis, Leukocyte , Macaca mulatta/physiology , Macrophage Inflammatory Proteins/pharmacology , Monocytes/drug effects , Monocytes/physiology , Animals , Chemokine CCL3 , Chemokine CCL4 , Chemotaxis, Leukocyte/physiology , Humans , Immunohistochemistry , Injections, Intradermal
3.
J Exp Med ; 187(12): 2009-21, 1998 Jun 15.
Article in English | MEDLINE | ID: mdl-9625760

ABSTRACT

Chemokines are essential mediators of normal leukocyte trafficking as well as of leukocyte recruitment during inflammation. We describe here a novel non-ELR CXC chemokine identified through sequence analysis of cDNAs derived from cytokine-activated primary human astrocytes. This novel chemokine, referred to as I-TAC (interferon-inducible T cell alpha chemoattractant), is regulated by interferon (IFN) and has potent chemoattractant activity for interleukin (IL)-2-activated T cells, but not for freshly isolated unstimulated T cells, neutrophils, or monocytes. I-TAC interacts selectively with CXCR3, which is the receptor for two other IFN-inducible chemokines, the IFN-gamma-inducible 10-kD protein (IP-10) and IFN-gamma- induced human monokine (HuMig), but with a significantly higher affinity. In addition, higher potency and efficacy of I-TAC over IP-10 and HuMig is demonstrated by transient mobilization of intracellular calcium as well as chemotactic migration in both activated T cells and transfected cell lines expressing CXCR3. Stimulation of astrocytes with IFN-gamma and IL-1 together results in an approximately 400,000-fold increase in I-TAC mRNA expression, whereas stimulating monocytes with either of the cytokines alone or in combination results in only a 100-fold increase in the level of I-TAC transcript. Moderate expression is also observed in pancreas, lung, thymus, and spleen. The high level of expression in IFN- and IL-1-stimulated astrocytes suggests that I-TAC could be a major chemoattractant for effector T cells involved in the pathophysiology of neuroinflammatory disorders, although I-TAC may also play a role in the migration of activated T cells during IFN-dominated immune responses.


Subject(s)
Chemokines, CXC/metabolism , Lymphocyte Activation , Receptors, Chemokine/metabolism , T-Lymphocytes/immunology , Amino Acid Sequence , Astrocytes , Base Sequence , Calcium/metabolism , Chemokine CXCL11 , Chemokines, CXC/genetics , Chemotaxis, Leukocyte , Chromosomes, Human, Pair 4 , Cloning, Molecular , DNA, Complementary/genetics , Desensitization, Immunologic , Humans , Interferon-gamma/pharmacology , Molecular Sequence Data , Protein Binding , RNA, Messenger/biosynthesis , Receptors, CXCR3 , Sequence Analysis, DNA , Sequence Homology, Amino Acid , T-Lymphocytes/drug effects
4.
Poult Sci ; 68(12): 1710-3, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2560180

ABSTRACT

To study the hormonal effects on hematologic parameters as indicators of chronic stress, exogenous adrenocorticotropin (ACTH) at 6.3 or 20.0 IU/kg/day and hydrocortisone at .25 or 2.5 mg/kg/day were administered parenterally to laying hens. Both ACTH treatments induced significant (P less than .05) heterophilia, monocytosis, eosinophilia, and basophilia. Significantly elevated leucocyte counts and lymphopenia (P less than .05) were observed with the high dosage of ACTH. Both hydrocortisone-treated groups developed an absolute lymphopenia and heterophilia (P less than .05). The low dosage of hydrocortisone induced a significant (P less than .05) monocytosis; the high dosage caused significant (P less than .05) decreases in the total eosinophil and basophil counts as well as an increase in the ratio of heterophils to lymphocytes. The hemopoietic parameters, especially heterophil counts, were sensitive indicators of a hormonal stress response induced by the administration of ACTH and hydrocortisone.


Subject(s)
Adrenocorticotropic Hormone/pharmacology , Chickens/blood , Hydrocortisone/pharmacology , Leukocyte Count/veterinary , Leukocytes/drug effects , Animals , Basophils/drug effects , Eosinophils/drug effects , Female , Granulocytes/drug effects , Lymphocytes/drug effects , Monocytes/drug effects , Poultry Diseases/blood , Stress, Physiological/blood , Stress, Physiological/veterinary
5.
Proc Natl Acad Sci U S A ; 86(23): 9514-8, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2480604

ABSTRACT

The definition of human immunodeficiency virus type 1 (HIV-1) immunogenic epitopes is central to the rational design of AIDS vaccine strategies. In this study, we have generated seven HIV-1 reverse transcriptase-specific cytotoxic T-lymphocyte (CTL) clones from the peripheral blood of two seropositive subjects. Epitopes recognized by these CTL clones were identified by using target cells infected with recombinant HIV-1-vaccinia virus vectors expressing truncated reverse transcriptase proteins and further defined by using target cells incubated with overlapping 25-amino acid synthetic reverse transcriptase peptides. Five different CTL epitopes were identified, and in each case recognition was restricted by class I human leukocyte antigens (HLA). Clones maintained specific cytolytic function in continuous culture for up to 11 months, requiring only periodic restimulation with a CD3-specific monoclonal antibody. These results indicate that HIV-1-specific, major histocompatibility class I-restricted CTL recognize multiple epitopes of a single viral gene product in conjunction with different host HLA antigens. In addition, they demonstrate that human virus-specific CTL can be grown in long-term culture without the need for reexposure to viral antigen.


Subject(s)
Cytotoxicity, Immunologic , HIV-1/immunology , T-Lymphocytes, Cytotoxic/immunology , Cell Line , Cell Transformation, Viral , Cells, Cultured , Gene Expression , Genes, Viral , HIV Seropositivity/immunology , HIV-1/enzymology , HIV-1/genetics , Herpesvirus 4, Human/genetics , Humans , RNA-Directed DNA Polymerase/genetics , T-Lymphocytes, Cytotoxic/cytology , Vaccinia virus/genetics , Viral Structural Proteins/genetics
6.
Antimicrob Agents Chemother ; 33(1): 53-7, 1989 Jan.
Article in English | MEDLINE | ID: mdl-2653214

ABSTRACT

Castanospermine and 3'-azido-3'-deoxythymidine (zidovudine) were evaluated in combination against human immunodeficiency virus (HIV) replication in vitro. Castanospermine and 3'-azido-3'-deoxythymidine inhibited HIV type 1 synergistically in acutely infected H9 cells. In addition, they synergistically inhibited both HIV type 1 and HIV type 2 in peripheral blood mononuclear cells. There were no additional toxic effects of these agents in combination. Drug interactions were evaluated by the median-effect principle and the isobologram technique. Combinations of a glycosylation inhibitor, such as castanospermine, with 3'-azido-3'-deoxythymidine deserve consideration for HIV-related chemotherapeutic intervention.


Subject(s)
Alkaloids/pharmacology , Glycoside Hydrolase Inhibitors , HIV-1/physiology , HIV-2/physiology , Indolizines , Virus Replication/drug effects , Zidovudine/pharmacology , Cells, Cultured , Drug Synergism
7.
J Infect Dis ; 158(2): 378-85, 1988 Aug.
Article in English | MEDLINE | ID: mdl-2841378

ABSTRACT

Effective treatment of infections with human immunodeficiency virus type 1 (HIV-1) may require a combination of antiviral drugs that act by different mechanisms. We report that the combination of 2',3'-dideoxycytidine (ddCyd) and recombinant interferon-alpha-A (rIFN-alpha-A) acts synergistically against HIV-1 replication in vitro. Various cell types (peripheral blood leukocytes, a CD4-positive T cell line, and two monocyte-macrophage lines) have been studied. For each set of dose-effect data, the degree of drug interaction was quantitatively assessed with the median-effect principle and the isobologram equation by using a computer analysis. Under various culture conditions using several concentrations of drugs, multiplicities of infectious virus, and assay systems, antiviral synergism was consistently observed against HIV-1 replication without enhanced cell toxicity. Synergism was seen at concentrations as low as 0.02 microM ddCyd plus 4 U of rIFN-alpha-A/mL or 0.01 microM ddCyd plus 8 U of rIFN-alpha-A/mL, whereas 10-fold higher concentrations were usually required to achieve similar effects with single drugs.


Subject(s)
Antiviral Agents/pharmacology , Deoxycytidine/analogs & derivatives , HIV/physiology , Interferon Type I/pharmacology , Virus Replication/drug effects , Cell Line , Deoxycytidine/pharmacology , Drug Synergism , HIV/drug effects , Humans , Leukocytes/microbiology , Recombinant Proteins , Thymidine/analogs & derivatives , Thymidine/pharmacology , Zalcitabine , Zidovudine
8.
Science ; 240(4848): 64-6, 1988 Apr 01.
Article in English | MEDLINE | ID: mdl-2451288

ABSTRACT

Characterization of the host immune response to human immunodeficiency virus type 1 (HIV-1) is critical to the rational design of an effective AIDS vaccine. In this study, cytotoxic T lymphocytes (CTL) specific for HIV-1 reverse transcriptase (RNA-dependent DNA polymerase) were found in blood samples from HIV-1-infected individuals. CTL targets were prepared by immortalizing B cells from ten seropositive and six seronegative individuals, and then infecting these cells with recombinant vaccinia viruses containing HIV-1 genes. CTL directed against autologous B lymphoblasts expressing HIV-1 reverse transcriptase were detected in fresh blood samples from eight HIV-1 seropositive subjects, but in no seronegative controls. The effector cells were identified as major histocompatibility complex-restricted CD3+CD8+ lymphocytes. Because the HIV-1 pol gene is highly conserved among different isolates and generates both humoral and cellular immune responses, it bears consideration for inclusion in a candidate AIDS vaccine.


Subject(s)
Acquired Immunodeficiency Syndrome/immunology , HIV/enzymology , RNA-Directed DNA Polymerase/immunology , T-Lymphocytes, Cytotoxic/immunology , Antigens, Viral/immunology , B-Lymphocytes/immunology , DNA, Recombinant , Genes, Viral , HIV/genetics , HIV Seropositivity , HLA Antigens/immunology , Humans , Vaccinia virus/genetics , Vaccinia virus/immunology , Viral Vaccines/immunology
9.
Nature ; 328(6128): 345-8, 1987.
Article in English | MEDLINE | ID: mdl-3496541

ABSTRACT

Virus-specific cytotoxic T lymphocytes (CTL) which kill virus-infected cells are thought to be a major host defence against viral infections. Here we report the existence of human immunodeficiency virus (HIV)-specific CTL in persons infected with this virus, the aetiological agent of AIDS (acquired immunodeficiency syndrome). Recombinant HIV-vaccinia viruses were used to express HIV antigens in B-cell lines established from subjects seropositive for HIV and seronegative controls. Circulating lymphocytes capable of killing HIV env-expressing autologous B cells were detected in eight of eight seropositive subjects; in addition, at least three seropositive subjects demonstrated gag-specific cytotoxic responses. No HIV-specific cytotoxicity was observed in seronegative subjects. Selective inhibition of the env-specific cytotoxicity by a CD3-specific monoclonal antibody indicates that the effectors are T cells. This demonstration of a cytotoxic T-cell immune response to HIV in infected individuals should prove useful in investigating the immunopathogenesis of HIV infection further and in evaluating AIDS vaccine strategies.


Subject(s)
Acquired Immunodeficiency Syndrome/immunology , HIV/immunology , T-Lymphocytes, Cytotoxic/immunology , B-Lymphocytes/immunology , Genes , Genes, Viral , HIV/genetics , Homosexuality , Humans , Male , Serotyping , Vaccinia virus/genetics
10.
AIDS Res Hum Retroviruses ; 3(3): 303-15, 1987.
Article in English | MEDLINE | ID: mdl-2829951

ABSTRACT

The human immunodeficiency virus (HIV) may interact with the Epstein Barr virus (EBV) indirectly by effects on the T4 lymphocyte or directly by effects on EBV transformed B lymphocytes. We have confirmed the susceptibility of EBV transformed B lymphocytes to productive HIV infection, and have evaluated the cytotoxic activity of HIV seronegative and seropositive donors after sensitization by their autologous EBV infected (monoinfected) or EBV and HIV infected (coinfected) transformed cell lines in a 51Cr release cytotoxicity assay. When sensitized by the coinfected cell line and assayed against monoinfected and coinfected cell lines, the cytotoxic activity of the seronegative donors was inhibited when compared to the cytotoxic effectors sensitized by the monoinfected B cell line. The inhibition appeared to be unrelated to direct HIV infection of the T4 effector cells and was reversible by addition of recombinant interleukin-2. Although deficient in their EBV cytotoxic activity in comparison to the seronegative donors, the HIV seropositive donors lysed the coinfected cell line better than the monoinfected cell line, whether or not HIV superinfected cells were used during the sensitization phase. In HIV seronegative donors, HIV may inhibit the immune response to EBV transformed B lymphocytes. This inhibition is not observed in HIV seropositive donors. These studies suggest the development of cytolytic effector mechanisms directed at HIV infected cells during HIV infection.


Subject(s)
B-Lymphocytes/microbiology , Cytotoxicity, Immunologic , HIV Seropositivity/immunology , HIV/physiology , Herpesvirus 4, Human/physiology , Leukocytes, Mononuclear/immunology , Cell Line , Female , HIV Seropositivity/microbiology , Humans , Male , Phenotype
11.
Antimicrob Agents Chemother ; 30(1): 189-91, 1986 Jul.
Article in English | MEDLINE | ID: mdl-3019235

ABSTRACT

Phosphonoformate and recombinant alpha-A interferon synergistically inhibited the replication of human T-cell lymphotropic virus type III in cultured peripheral blood lymphocytes. T-cell proliferative capability was maintained by this combination, and toxicity was minimal.


Subject(s)
Deltaretrovirus/drug effects , Interferon Type I/pharmacology , Organophosphorus Compounds/pharmacology , Phosphonoacetic Acid/pharmacology , Virus Replication/drug effects , Cells, Cultured , Drug Synergism , Foscarnet , Humans , Lymphocytes/microbiology , Phosphonoacetic Acid/analogs & derivatives , Recombinant Proteins/pharmacology
12.
J Clin Microbiol ; 23(6): 1072-7, 1986 Jun.
Article in English | MEDLINE | ID: mdl-2423552

ABSTRACT

Techniques presently available for detection of human T-cell lymphotropic virus type III (HTLV-III) antigens and antibodies are laborious or relatively nonsensitive. We adapted anticomplementary immunofluorescence (ACIF) for these purposes. In HTLV-III-infected cells, specific ACIF was demonstrated by a diffuse speckling pattern that often resulted in a peripheral cellular rim of fluorescence. A 97% concordance was demonstrated between the ACIF assay and other sensitive tests for HTLV-III antibody detection (Western blot and membrane immunofluorescence and fixed-cell immunofluorescence tests). The ACIF assay was both more sensitive and more specific when compared with the enzyme-linked immunosorbent assay. For detection of HTLV-III antigens, the ACIF assay appeared to be as sensitive as the reverse transcriptase assay and more sensitive, with less background reactivity, than the conventional immunofluorescence assay. The ACIF assay often detected low levels of HTLV-III antigens within 3 days of infection in vitro, compared with 5 to 7 days with the indirect immunofluorescence assay, and generally paralleled the reverse transcriptase assay. The ACIF assay is a simple, sensitive, and specific assay for detection of HTLV-III-related antigens and antibodies. It should prove useful in the diagnosis of HTLV-III infection, as well as in studies of pathogenesis.


Subject(s)
Acquired Immunodeficiency Syndrome/diagnosis , Antibodies, Viral/analysis , Antigens, Viral/analysis , Deltaretrovirus/immunology , Fluorescent Antibody Technique , Acquired Immunodeficiency Syndrome/immunology , Cell Line , Complement System Proteins , Deltaretrovirus/enzymology , Enzyme-Linked Immunosorbent Assay , HIV Antibodies , HIV Antigens , Humans , Lymphocytes/immunology , Lymphocytes/microbiology , Male , RNA-Directed DNA Polymerase/metabolism , Retroviridae Infections/diagnosis , Retroviridae Infections/immunology
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