thymosin and Candidiasis

Treatment of systemic infection with Candida albicans with a combination of an antifungal agent (i.e. fluconazole) and a thymus-derived immunostimulant (i.e. thymosin alpha 1 (T alpha 1)) in mice immunosuppressed by morphine treatments was investigated. In normal mice, fluconazole given after infection with 10(6) C. albicans cells was more effective than in mice treated with morphine. Combination treatment with fluconazole and T alpha 1 prolonged survival and reduced the fungal burden in the kidneys of immunosuppressed mice. We also investigated the influence of this combined treatment on killing properties of polymorphonuclear leucocytes (PMN) and natural killer (NK) cell activity, inhibited by morphine administrations. Treatment with T alpha 1 or fluconazole as single agents promoted a recovery of normal NK cell activity and intracellular killing of C. albicans by PMN, while the combination significantly increased both of these responses, probably through the modulation of lymphokine production. Our data suggest that the additive effect of T alpha 1 and fluconazole is due to a direct antifungal action and activation of the immunocompetence.

Topics: Animals; Candida albicans; Candidiasis; Colony Count, Microbial; Drug Therapy, Combination; Fluconazole; Immunosuppression Therapy; Kidney; Killer Cells, Natural; Male; Mice; Morphine; Neutrophils; Survival Rate; Thymalfasin; Thymosin

A peptide, parathymosin alpha, containing approximately equal to 105 amino acid residues, has been isolated from rat thymus, and the sequence of the first 30 residues at the NH2 terminus has been determined. In this region, it shows 43% structural identity with thymosin alpha 1 and prothymosin alpha. The common sequences do not include residues 2-9, which accounts for the poor reactivity of parathymosin alpha with an antibody directed against this epitope in thymosin alpha 1. Parathymosin alpha appears to modulate the action of prothymosin alpha in protecting sensitive strains of mice against opportunistic infection with Candida albicans.

Topics: Adjuvants, Immunologic; Amino Acid Sequence; Amino Acids; Animals; Candidiasis; Immunity; Mice; Protein Precursors; Rats; Thymosin; Thymus Gland; Tissue Distribution

Three parameters of cell-mediated immunity, namely, (a) resistance to infection with Candida albicans, (b) in vivo release of migration inhibitory factor (MIF) into the circulation and (c) delayed hypersensitivity were markedly reduced when mice of such normally resistant high responder strains as C57B1/10SNJ and C57B1/KsJ became hyperglycaemic after treatment with alloxan. When the alloxan diabetic mice were inoculated daily intraperitoneally with thymosin fraction 5, beginning 3 days before infection, resistance to infection was greatly enhanced. When the mice were administered 5 micrograms thymosin fraction 5 for 3 days before sensitization and for 3 days before challenge, the amount of MIF released in vivo into the circulation after the antigenic challenge was much greater. When the mice were treated daily with 5 micrograms thymosin fraction 5, beginning on the day of sensitization, the capacity to develop delayed footpad reactions was increased. Thus, the treatment of alloxan diabetic mice with thymosin fraction 5 enhanced the three parameters of cell-mediated immunity that were under investigation.

Topics: Animals; Candidiasis; Diabetes Mellitus, Experimental; Hypersensitivity, Delayed; Immunity, Cellular; Immunity, Innate; Interferon-gamma; Macrophage Migration-Inhibitory Factors; Mice; Mice, Inbred C57BL; Thymosin

Nine inbred murine strains were either highly resistant or highly susceptible to intravenous challenge with 4 X 10(4) to 1 X 10(5) cells of Candida albicans. The resistant strains had the capacity to develop delayed footpad reactions on appropriate sensitization and challenge; the susceptible strains did not have this innate capacity. Administration of thymosin fraction 5 beginning on the day of infection greatly increased the resistance of the susceptible strains to infection, but decreased the resistance of the resistant strains. In contrast, thymosin fraction 5 enhanced the delayed footpad responses of resistant-sensitized mice to specific antigen, but did not have a detectable effect on the delayed footpad reactions of the susceptible strains. Reinfection of the two types of strains had different effects, in that, depending on the strain, resistance could be increased, decreased, or not influenced at all.

Topics: Animals; Antigens, Fungal; Arthus Reaction; Candidiasis; Disease Susceptibility; Hypersensitivity, Delayed; Immunity, Cellular; Immunity, Innate; Kidney; Mice; Mice, Inbred AKR; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred DBA; Thymosin; Thymus Hormones

Of nine inbred murine strains sensitized intravenously with killed lyophilized Candida albicans and challenged 3 weeks later with a C. albicans filtrate, four strains were low responders and five were high responders in the in vivo release of migration inhibitory factor (MIF) and gamma interferon (IFN-gamma). An identical distribution of high- and low-responder strains occurred in response to sensitization with Mycobacterium bovis BCG and subsequent challenge with old tuberculin. Treatment of the murine strains with thymosin fraction 5 prior to sensitization and challenge had different effects: (a) the high-responder strains had a decrease in their release in vivo of the two lymphokines; (b) three of five of the low-responder strains had a striking increase in the in vivo release of MIF and IFN-gamma; and (c) one low-responder strain did not have its response altered. A parallelism existed between the capacity of a murine strain to release the two lymphokines in vivo on stimulation with C. albicans antigens and the capacity of that strain to resist intravenous infection with living C. albicans.

Topics: Animals; Antigens, Bacterial; Antigens, Fungal; Candidiasis; Disease Susceptibility; Female; Immunity, Innate; Interferon-gamma; Macrophage Migration-Inhibitory Factors; Mice; Mice, Inbred AKR; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred DBA; Thymosin; Thymus Hormones; Tuberculosis

Animal models for opportunistic infections were developed by using mice immunosuppressed by 5-FU. These mice were susceptible to various microorganisms, while normal mice had greater tolerance to such microbial infections. In these models, thymosin alpha 1 was found to protect mice against lethal infections with Candida albicans, Listeria monocytogenes, Pseudomonas aeruginosa, and Serratia marcescens when it was administered during 5-FU treatment prior to the infections. Thymosin alpha 1 was effective in some infections at 0.4-400 micrograms/kg/day IP, about 1/100 of the dose required for thymosin fraction 5. Activity was also demonstrated against L-monocytogenes and Ps. aeruginosa by counting the viable bacteria in the liver after infection. The protective activity against Candida, elimination of which macrophages were essential, was abrogated by anti-thymocyte serum and/or carrageenan, indicating that thymosin alpha 1 serves to maintain the functions of macrophages by reducing the damage to T cells by 5-FU. On the other hand, the activity against Pseudomonas infection was not affected by anti-thymocyte serum or carrageenan. It is probable that thymosin alpha 1 also exerts its effect on neutrophils without participation of T cells and macrophages.

Topics: Animals; Candida albicans; Candidiasis; Drug Administration Schedule; Enterobacteriaceae Infections; Fluorouracil; Listeria monocytogenes; Listeriosis; Mice; Mice, Inbred Strains; Pseudomonas Infections; Serratia marcescens; Thymosin; Thymus Hormones

Studies were carried out to assess the ability of thymosin alpha 1 to prolong the survival of mice challenged with Candida albicans. Two- to four-month-old mice were treated with graded doses of thymosin alpha 1 before, after, or before and after intravenous challenge with C. albicans. Significant resistance ot lethal infection was afforded by 100 micrograms of thymosin alpha 1 per kg given before or before and after challenge, whereas no protection was found in mice treated with thymosin alpha 1 administered at any dose level after inoculation. Pretreatment with thymosin alpha 1 also prevented the increased susceptibility to C. albicans infection of mice pretreated with cyclophosphamide on day -6. The results showed that thymosin alpha 1 was capable of protecting untreated or cyclophosphamide-pretreated mice from C. albicans infection at an optimal dose and schedule of administration.

Topics: Animals; Candidiasis; Cyclophosphamide; Female; Immunity, Innate; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Thymalfasin; Thymosin; Thymus Hormones; Time Factors

Topics: Adult; Ataxia Telangiectasia; Candidiasis; Chronic Disease; DiGeorge Syndrome; Eczema; Humans; Immunoglobulins; Immunologic Deficiency Syndromes; Lymphocyte Culture Test, Mixed; Male; Thymosin; Thymus Gland; Thymus Hormones; Wiskott-Aldrich Syndrome