Letterio Bonina

Serum TNFα in mouse typhoid and enhancement of a salmonella infection by anti-TNFα antibodies

Tumour necrosis factor α (TNFα) was detected by the L929 cell assay in the sera of mice 1 h after large i.v. inocula of virulent Salmonella typhimurium C5. TNFα was not detectable in sera from innately susceptible BALB/c mice during the course of a lethal infection commencing from a low inoculum, or from resistant A/J mice during the course of a lethal or sublethal infection, but only 1 h after i.v. challenge with large numbers of organisms. Administration of a single dose of rabbit polyclonal anti-TNFα antiserum on day 1 had no effect on the early course of a lethal infection in A/J mice. However, the same treatment exacerbated a sublethal infection in A/J mice. Anti-TNFα treatment did not accelerate the early bacterial net growth rate in the RES. Instead, the cfu count in treated mice continued to increase past the point at which the host response suppressed a further increase in bacterial numbers (the plateau phase) in normal controls. A second dose of anti-TNFα antiserum on day 4 together with a higher but still sublethal challenge caused a lethal infection in A/J mice. The results indicate that TNFα is important in mediating the plateau phase in a salmonella infection, and its effect may be local.

Biology of salmonella

Proceedings of a NATO Advanced Research Workshop held at Portorosa, Italy in May 1992. This volume presents the invited lectures and extended summaries of the contributed papers. Reports from the epidemiologists emphasize the continuing extent of salmonellosis worldwide, the increasing problem of dr

The restoration of impaired macrophage functions using as immunomodulator the Corynebacterium granulosum-derived P40 fraction

Many microorganisms and compounds of microbial origin exhibit immunomodulatory activities and have been extensively used in immunotherapy of experimental animal tumors and in patients with neoplasia. In this paper we describe the effect of the C. granulosum-derived P40 fraction on the growth and metastatization of the transplantable epithelioma T8 of Guèrin. Moreover, we evaluated the effect of P40 treatment on several depressed macrophage functions of tumor-bearing rats. In particular, the phagocytic and chemotactic activities of such cells were studied, as well as the antiviral intrinsic and extrinsic activities against HSV-1 and the anti-Toxoplasma gondii activity. All these functions were depressed in untreated tumor-bearing rats. Administration of a single intravenous injection of P40 fraction led to the restoration of all depressed macrophage activities to normal values. In particular, the possibility of restoring the antimicrobial activity of macrophages from tumor-bearing rats by treatment with this immunomodulator is of great concern when one considers the increasing incidence of opportunistic infections in immunocompromised hosts. Results are discussed in terms of both the possible mechanism of action of P40 and of its possible target cells.

Role of Interleukin-18 in Peripheral Blood Mononuclear Cells Infected with Human Herpes Virus Type 6

Objective: Interleukin 18 (IL-18) production represents a critical step in the polarization of the Th1 immune response. Human herpes virus type 6 (HHV-6) possesses a peculiar tropism for immunocompetent cells. To understand the relationships among immunocompetent cells, HHV-6 and cytokines, the role of IL-18 during infection of peripheral blood mononuclear cells (PBMC) with HHV-6 was evaluated. Methods: PBMC were obtained from healthy HHV-6-seronegative donors, after centrifugation of heparinized venous blood over a Ficoll-Hypaque gradient. Supernatants from PBMC were analyzed for the presence of cytokines. To study the effects of exogenous recombinant human (rh) IL-18 on HHV-6 replication, the number of cells expressing viral antigens and the amount of extracellular virus were analysed. Results: No basal production of IL-18 was found in supernatants of unstimulated PBMC. Appreciable amounts of the cytokine were produced by lipopolysaccharide (LPS)-stimulated PBMC. HHV-6 infection of LPS-treated PBMC downregulated IL-18 production. It was found that the addition of rhIL-18 to HHV-6-infected PBMC downregulated the percentage of antigen-positive cells and the release of extracellular virus. Conclusion: Impairment of IL-18 release, which is involved in the induction of antiviral cytokines, such as interferon-γ, could represent a strategy of the virus to evade the immune response of the host.

Generation of Superoxide Anion and Candidacidal Activity by Lipopolysaccharide-Treated Macrophages from Patients Affected by Neoplasia

Macrophages, derived from in vitro cultured monocytes from both healthy donors and patients affected by metastatic breast cancer, treated or not with Escherichia coli lipopolysaccharide (LPS), were tested for phagocytosis and intracellular killing of Candida albicans and superoxide anion release. We found a marked impairment in intracellular killing closely linked to the lack of superoxide production in macrophages from patients affected by neoplasia treated or not with LPS. On the other hand, the LPS treatment significantly enhanced the phagocytic activity of all the macrophage populations tested, except for phagocytes obtained from patients affected by neoplasia and differentiated in autologous serum.

Inhibition of normal rat macrophage functions by soluble tumor products

SummaryThe phagocytic and chemotactic activities of normal rat peritoneal macrophages were inhibited by sera from tumor-bearing rats (TBR) and 3 M KCl extracts of tumor mass. However, sera from Corynebacterium parvum- or Listeria monocytogenes-treated TBR did not inhibit phagocytosis. On the other hand, sera from C. parvum-treated, but not from L. monocytogenes-treated TBR still inhibited the chemotactic response of the normal macrophages. Furthermore, 3 M KCl extracts of tumors from C. parvum-treated TBR did not inhibit phagocytosis and chemotactic response of the same cells. Similar results were obtained with extracts of tumor masses from L. monocytogenes-treated rats. It is suggested that treatment with bacterial immunomodulators can influence the release from neoplastic cells of soluble products influencing normal macrophage functions.

Selective Depression of Phagocytes Intracellular Killing Activity

Valid resistance to infections is the result of a number of complex interactions between infectious agents and host’s immune response. Virulence of microorganisms, genetic factors, host’s immune mechanisms may in different ways influence the infectious agent host relationship. Phagocytes, including polymorphonucleates and macrophages, are the final effector cells in the elimination of a variety of bacteria and fungi.l

Modulation of the intrinsic antiviral activity by Escherichia coli endotoxin in macrophages from patients with neoplasia.

Macrophages from patients with breast cancer showed an impairment of their antiviral activity. The capability to hinder herpes simplex virus type 2 replication of macrophages from healthy donors and from patients with breast cancer was compared to the in-vitro treatment with Escherichia coli lipopolysaccharide (LPS). The LPS showed a dose-dependent effect on the different macrophage populations studied. Nevertheless, macrophages from healthy donors appeared to be more sensitive to LPS in comparison with macrophages from the patients under our observation. On these cells LPS treatment was not able to modify the antiviral property, when these macrophages were differentiated in autologous serum.

Effects of rufloxacin in Salmonella typhimurium infection in mice

This study was undertaken to investigate the efficacy of rufloxacin, a new quinolone which is interesting due to its pharmacokinetics characterized by a long plasma half-life, in the treatment of systemic salmonella infections in the mouse typhoid model. Innately susceptible BALB/c and resistant CBA mice were used to investigate the efficacy of rufloxacin in controlling systemic salmonella infections when given for brief or prolonged periods. The present study shows that rufloxacin is not only very effective on both mouse strains, but can completely eradicate the salmonellae from livers and spleens when given early in the infection of CBA resistant mice.

Role of exogenous interferons on intrinsic antiviral activity of macrophages from patients affected by neoplasia.

Macrophages derived from in vitro cultured monocytes were infected with herpes simplex virus type 2. A marked impairment in the intrinsic antiviral activity was found in macrophages obtained from patients with breast cancer or melanoma. Moreover, the antiviral activity of macrophages from healthy donors, differentiated in serum from patients with neoplasia, was also impaired. The aim of this work was the evaluation of alpha, beta, gamma exogenous interferon in restoring the intrinsic antiviral activity of macrophages from patients affected by breast cancer or melanoma under different conditions. Pretreatment of macrophages with alpha, beta interferons, but not gamma interferon, restored their impaired intrinsic antiviral activity.