Immunological aspects of tumor-macrophage interactions.
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Animals↗
Biomedical subjects
K Huygen
Publications and source records attributed to K Huygen.
Specific lymphoproliferation, gamma interferon production, and serum immunoglobulin G directed against a purified 32 kDa mycobacterial protein antigen (P32) in patients with active tuberculosis.
Twenty-one patients treated for active tuberculosis were examined for immune reactivity to purified protein derivative (PPD) and to a purified 32-kDa protein antigen (P32) from Mycobacterium bovis, strain BCG. Lymphoproliferation of peripheral blood leucocytes to PPD and P32 was positive in 95% and 71% of the patients respectively. A positive IFN-gamma response was detected in 62% against PPD and in 48% against P32. Low blastogenesis and IFN-gamma production were observed, especially in patients with poor general health and advanced tuberculous lesions. Twelve out of twelve (100%) of the tuberculin-positive healthy volunteers responded to PPD and P32 with mean lymphoproliferation and IFN-gamma values that were higher than in the patient group. Twelve tuberculin-negative control subjects were completely unreactive to PPD and P32 antigen. On the other hand, IgG antibodies in the serum were detected in 95% of the patients against PPD, in 77% of the patients against P32 but in none of the tuberculin-positive or negative healthy volunteers. The highest IgG levels against PPD were found in those patients with the lowest in vitro lymphoproliferation and IFN-gamma production (r = -0.54; P less than 0.05). Nonspecific interferon production following induction with Newcastle disease virus, Corynebacterium parvum, or phytohaemagglutinin was comparable in the control and patient groups. Finally, low IFN-alpha titres were detected in the serum of about 50% of the patients.
Antigens, Bacterial↗
H-2-linked control of in vitro gamma interferon production in response to a 32-kilodalton antigen (P32) of Mycobacterium bovis bacillus Calmette-Guérin.
A 32-kilodalton protein antigen (P32) was previously purified to homogeneity from culture filtrate of Mycobacterium bovis BCG (J. De Bruyn, K. Huygen, R. Bosmans, M. Fauville, R. Lippens, J. P. Van Vooren, P. Falmagne, H. G. Wiker, M. Harboe, and M. Turneer, Microb. Pathog. 2:351-366, 1987). Spleen cells from BCG-sensitized mice produce significant amounts of gamma interferon (IFN-gamma) in response to this P32 protein. The amount of secreted IFN-gamma is influenced by mouse genotype, with C57BL/6 (H-2b), C57BL/10 (H-2b), and 129/Sv (H-2b) mice producing about four times more than BALB/c (H-2d), CBF1 (H-2d/b), and DBA/2 (H-2d) mice do. Analysis of seven recombinant inbred strains derived from the BALB/c x C57BL/6 cross and of congenic mice differing in major histocompatibility complex-coding chromosome 17 fragments indicates a probable H-2-linked control of this IFN-gamma induction, with H-2b cells producing high titers and H-2d cells producing low titers in response to the P32 antigen.
Animals↗
Fifty cases of human immunodeficiency virus (HIV) infection: immunoultrastructural study of circulating lymphocytes.
The peripheral lymphocytes of 50 cases of human immunodeficiency virus (HIV) infection (13 of acquired immune deficiency syndrome (AIDS), 17 of AIDS related complex (ARC), and 20 healthy carriers) were studied immunoultrastructurally. The prevalence of "tubuloreticular structures" and "tubular confronting cisternae" increased with the progression of the disease. Numerous tubular confronting cisternae were noted in patients presenting with a high serum acid labile alpha-interferon values. The patients with depressed natural killer cell activity were characterised by circulating immature natural killer cells with abundant multivesicular bodies that were devoid of "parallel tubular arrays". With an immunogold staining technique the location of HIV antigen was detected ultrastructurally, both at the surface of "hand-mirror" natural killer cell lymphocytes and inside vacuolised cells, probably corresponding to infected T4 lymphocytes. These findings indicate the usefulness of electron microscopic techniques in evaluating the pathology and the pathogenetic outcome of AIDS.
AIDS-Related Complex↗
Purification, characterization and identification of a 32 kDa protein antigen of Mycobacterium bovis BCG.
An immunogenic protein called P32 has been purified from Sauton zinc deficient culture filtrate of Mycobacterium bovis BCG using successively hydrophobic chromatography on Phenyl-Sepharose, ion exchange on DEAE-Sephacel and molecular sieving on Sephadex G-100. The final preparation was found to be homogeneous as based on several analyses. This P32 protein was a constituent of BCG cells grown in normal conditions. It represented about 3% of the soluble fraction of a cellular extract, and appeared as the major protein released in normal Sauton culture filtrate. This protein was found to have a molecular weight of 32,000 by SDS-polyacrylamide gel electrophoresis and in molecular sieving. Its amino acid composition showed an abundance of acidic amino acids (or their amides). The NH2-terminal amino acid sequence (6 amino acids) was determined. Purified P32 was tested by various crossed immunoelectrophoresis techniques, and was shown to belong to the antigen 85 complex in the reference system for BCG antigens. It was more precisely identified as antigen 85A. The protein antigen elicited a weak delayed hypersensitivity reaction in guinea pigs sensitized with heat-killed or living BCG. No delayed hypersensitivity reaction was observed in living BCG sensitized mice, however, it induced significant amounts of gamma interferon in cultured spleen cells from BCG-sensitized mice. Moreover, P32 either pure or as part of BCG soluble extract promoted substantial antibody levels when injected in rabbits.
Amino Acids↗
Analysis of the interferon system in African patients with acquired immunodeficiency syndrome.
Serum interferon and in vitro production of alpha and gamma interferon by peripheral blood leucocytes were examined in 21 African patients with acquired immunodeficiency syndrome (AIDS) and in 15 African patients with AIDS-related complex. Interferon was detected in the serum of 44% of the patients with AIDS-related complex and in 70% of the patients with full-blown AIDS, and was characterized as an acid-labile alpha interferon. When compared to healthy blood donors, the interferon response of peripheral blood leucocytes to Newcastle Disease virus was impaired in 7 of 12 patients with AIDS-related complex and in 16 of 20 AIDS patients (p less than 0.005). Also, production of gamma interferon following stimulation with phytohaemagglutinin was diminished in 5 of 11 patients with AIDS-related complex and in 13 of 17 patients with AIDS (p less than 0.005). A high correlation was observed between the presence of circulating interferon and decreased in vitro production of gamma interferon, but not of alpha interferon. These results suggest that the impairment of in vitro production of gamma interferon can be used as a preclinical marker of AIDS.
Acquired Immunodeficiency Syndrome↗
Influence of in vivo immunosuppressive drugs on production of lymphokines.
The influence in vivo of immunosuppressive drugs (cyclosporine, azathioprine, and corticosteroids) on the production of various lymphokines (alpha and gamma interferon, interleukin 2), both in organ transplant recipients and in normal volunteers taking 100 mg hydrocortisone orally has been studied. To avoid interference with the rejection process or viral infection, patients were studied in a steady state with low maintenance immunosuppression consisting of prednisolone combined with azathioprine or with cyclosporine. In patients treated with both drug regimens, significant depression of production of the three lymphokines was found. Normal volunteers challenged with 100 mg hydrocortisone showed inhibition of production of interleukin 2 and alpha and gamma interferon in 4 hr, a time corresponding to the nadir of T cell lymphopenia, affecting the OKT4 subset preferentially. The percentage of OKT8 cells remained unchanged. Percentages of large granular lymphocytes increased, but their absolute number was not significantly modified. Changes in lymphocyte markers were fully reversible after 24 hr, but interleukin 2 production remained markedly depressed, showing that the redistribution patterns induced by corticosteroids on lymphocyte subsets may be dissociated from functional consequences.
Adrenal Cortex Hormones↗
Strain variation in interferon gamma production of BCG-sensitized mice challenged with PPD II. Importance of one major autosomal locus and additional sexual influences.
Interferon-gamma (IFN-gamma) production in BCG-sensitized mice challenged with PPD was examined in the sera from BALB/c and C57BL/6 mice. C57BL/6 mice produce about ten times more IFN-gamma than BALB/c mice. Studies on F1, F2, and backcross generations indicate that one partially dominant autosomal locus is involved. Furthermore, females consistently produce more IFN-gamma than males in all of these crosses, though the X chromosome cannot be held responsible for this.
Animals↗
Suppression of CTL responses in vitro by large granular T cells.
The generation of large granular T cells (LGC) that display cytotoxicity similar to activated natural killer (NK) cells was described previously by the authors. To determine whether LGC can regulate the generation of allospecific CTL (C57BL/6, anti-DBA/2), we used primed responding T cells (Thy-1.2) and (Thy-1.1) to perform co-cultures. The cytolytic activities and the phenotype of the harvested T cells were examined after a co-culture period (3-6 days). We observed that the survival of fresh responding T cells was impaired in the co-cultures. Activated (4 days) responding T cells can survive in similar coculture conditions. This led to the conclusion that LGC can inactivate the CTL generation in fresh T-cell populations and that fresh and activated responding cells have different susceptibilities to LGC interactions.
Animals↗
Depressed natural killer function in transplant recipients: an analysis.
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Azathioprine↗
Stimulation of cellular function by thymopentin (TP-5) in three AIDS patients.
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Acquired Immunodeficiency Syndrome↗
Strain variation in interferon gamma production of BCG-sensitized mice challenged with PPD. I. CBA/Ca mice are low producers in vivo, but high producers in vitro.
Three different mouse strains--BALB/c, C57BL/6J, and CBA/Ca--were compared for their production of viral interferon upon Newcastle disease virus (NDV) inoculation and of interferon gamma upon antigenic stimulation with PPD following BCG sensitization. BALB/c mice were found to be low producers for NDV-induced IFN-alpha, beta as well as for in vivo (serum) and in vitro (spleen cell culture) induced IFN-gamma. C57BL/6 mice were high producers under the three conditions tested and CBA/Ca mice, finally, were high IFN-alpha, beta and in vitro IFN-gamma producers, but low in vivo IFN-gamma producers. Development of splenomegaly following BCG inoculation was not directly related to IFN-gamma responsiveness.
Animals↗
In vitro production of gamma interferon is dependent on the mouse genotype.
C57B1/6 and BALB/c mice were compared for their in vitro capacity to produce gamma interferon (IFN-gamma) in response to specific antigen (i.e., Purified Protein Derivative in bacillus Calmette-Guérin sensitized animals) and T-cell mitogen (Concanavalin A). In both cases C57B1/6 spleen cells produced five to ten times more IFN than identically treated BALB/c spleen cells. More detailed analysis of in vitro induced BCG-PPD IFN indicates that the low IFN level in BALB/c cultures is neither caused by classical splenic suppressor cells such as macrophages or T-cells, nor by inactivation of secreted IFN by inhibitory substances.
Animals↗
Failure of athymic-nude mice sensitized with Bacillus Calmette-Guérin to produce interferon in response to purified protein derivative.
Unlike their +/+ and nu/+ littermates, homozygous athymic-nude (nu/nu) mice that had been sensitized with Bacillus Calmette-Guérin (BCG) failed to produce interferon (IFN) in response to purified protein derivative (PPD). Likewise, spleen cells derived from BCG-sensitized nu/nu mice failed to produce IFN when exposed to PPD in vitro. These findings suggest that the T-cell subset that responds to specific antigens (i.e., PPD) is absent in athymic-nude mice.
Animals↗
Influence of in vivo interferon treatment on mitogen responsiveness of T-and B-cells is dependent on the mouse genotype.
Intravenous inoculation of moderate doses of viral interferon (up to 10(4) I.U./mouse) induced subsequent modification of the mitogen responsiveness of T-and B-lymphocytes from the spleen. The modulation, however, was dependent on the mouse genotype. Whereas BALB/c mice demonstrated enhanced T-cell responses (especially to PHA), C57B1/6 mice were generally suppressed in their T-cell response by the same treatment. B-cell proliferation to LPS showed a moderate enhancement in both strains, probably due to activation of accessory cells.
Animals↗
Synergistic activities of type I (alpha, beta) and type II (gamma) murine interferons.
Type I (alpha, beta) and type II (gamma) murine interferons are able to potentiate each other with respect to the inhibition of encephalomyocarditis (EMC) virus and of herpes simplex virus type 1 (HSV-1) multiplication in a murine cell line (DBT). Examination of two double-stranded RNA-dependent enzymes in DBT cells, the 2-5A synthetase and the 67,000 MW protein phosphokinase indicates that mixed interferon preparations act synergistically at least with respect to an increase in the activity of the former enzyme. The results obtained with gamma interferons of different origin and of different specific activity suggest that interferon itself, rather than the lymphokines present in the interferon preparations, is responsible for the synergistic effect.
2',5'-Oligoadenylate Synthetase↗
Chromatographic behavior, purification, and properties of mouse BCG-induced gamma interferon.
Mouse gamma antigen-induced interferon (IFN) was produced in vivo by injecting PPD into BCG-sensitized mice. The IFN activity present in the serum was partially purified by adsorption on silicic acid and elution with buffer containing ethylene glycol, followed by chromatography of the eluate on Blue-Trisacryl. This method yielded IFN preparations with a specific activity of 1.5 x 10(5) mu/mg protein (10,000-fold purification). BCG IFN showed high affinity for polynucleotides and apparent hydrophobicity, two characteristics which allowed it to bind to Poly I agarose and Phenyl Sepharose, respectively. The chromatographic behavior of BCG IFN on Con A Sepharose indicates that BCG IFN is glycosylated. However, binding of the antiviral activity to the lectin column was only possible when purified IFN was used for chromatography. Although the purification method described here allowed purification of the antiviral activity as a major fraction, molecular heterogeneity was detected under certain chromatographic conditions. Two fractions with different molecular weights of 27,000 and 56,000, respectively, were always obtained by sieving purified BCG IFN on Sephacryl S 200.
Animals↗
Inhibitory effect of interferon on the growth of spontaneous mammary tumors in mice.
Partially purified mouse interferon type I (Mu IFN-beta), crude mouse interferon type II (Mu IFN-gamma) serum, and the interferon inducer polyinosinic acid-polycytidylic acid (poly I:C) were evaluated for their effects on the growth of spontaneously occurring mammary carcinomas in BALB/c mice. As soon as their tumors had reached a palpable size (diameter: 3-5 mm), the mice received three ip injections of Mu IFN-beta, Mu IFN-gamma, or poly I:C per week for 6 weeks. A significant (fourfold to fivefold) reduction in tumor size was achieved with Mu IFN-beta (at 10(6) U/mouse), Mu IFN-gamma (at 10(3) U/mouse), and poly I:C (at 1 mg/mouse). A similar reduction in tumor size was noted when the mice were treated with cyclophosphamide (2.5 mg/mouse, three ip injections per wk for 6 wk). Treatment with Mu IFN-beta combined with Mu IFN-gamma resulted in a greater tumor growth-inhibitory effect than treatment with either Mu IFN-beta or Mu IFN-gamma alone. In addition to inhibiting the growth of primary tumors, interferon also reduced the incidence of lung metastases. However, complete tumor regression was not observed in any mouse while under interferon therapy.
Animals↗