Recombinant human interleukin 1 alpha enhances anti-Listeria resistance in both genetically resistant and susceptible strains of mice.

In this study we show that recombinant human IL-1 alpha (rhIL-1 alpha) protects both genetically resistant and susceptible strains of mice against Listeria monocytogenes infection. Similar levels of protection were observed in all strains tested. These data suggest that innate susceptibility to an infectious agent may not abrogate the ability of rhIL-1 alpha to enhance antibacterial resistance.

Alterations in body composition following intestinal bypass for morbid obesity.

The efficacy of the jejunolieal bypass operation, performed as a weight-reducing procedure in the morbidly obese patient, was assessed by measurements of body composition. In 20 patients measurements were performed by multiple isotope dilution, before and following jejunoileal bypass. Prior to bypass the excess body weight was due primarily to an increase in body fat (BF), which accounted for 52 percent of body weight. The nonfatty component of body composition, the lean body mass, although slightly increased in size, was essentially normal. Two distinct patterns were observed following bypass. In 12 patients followed for 8.4 +/- 1.5 months, there was a 21 percent decrease in body weight, resulting entirely from a loss of BF. The total exchangeable potassium and intracellular water volume, both measures of the body cell mass (BCM), were unchanged. In the second group of eight patients followed for 13.9 +/- 2.1 months, the mean body weight decreased by 27 percent or 38.8 Kg., due to a 26.6 Kg. reduction in BF and a 13.0 Kg. decrease in the BDM. This was accompanied by a relative expansion of the extracellular mass. As a result, the mean Nae/Ke ratio increased significantly (p less than 0.05) from a normal prebypass value of 0.95 +/- 0.7 to 1.46 +/- 0.11 following bypass. Thus in eight of the 20 patients following jejunoileal bypass, there was an undesirable loss of BCM with a relative expansion of extracellular supporting component of body composition, a pattern characteristic of malnutrition.

Effect of parenteral nutrition on body composition in the critically ill patient.

The efficacy of intravenous hyperalimentation in the critically ill patient was evaluated by body composition measurements performed with a multiple isotope dilution technic. The size of the body cell mass was evaluated by measuring the total exchangeable potassium and the intracellular water volume. The total exchangeable sodium and the extracellular water volume were both measured to evaluate the extracellular supporting component of body composition. These measurements were performed in two groups of severely ill patients who were in a chronic catabolic state. The first group of sixteen patients received intravenous hyperalimentation and the second group of eighteen patients served as controls in that they were not hyperalimented. Similar measurements were performed in sixteen normal volunteers to define the normal range for the various body composition parameters. In the nonalimented patients, there was a significant decrease in the body cell mass accompanied by an expansion of the extracellular supporting component of body composition. Similar changes occurred in the patients receiving intravenous hyperalimentation. However, the magnitude of these changes was not great. Thus, intravenous hyperalimentation tended to preserve the body cell mass and prevent expansion of the extracellular component of body composition.

Effect of aflatoxin B1 on in vitro production of interleukin-1 by bovine mononuclear phagocytes.

In this study we examined the effects of preincubation with aflatoxin B1 (AFB1) on the ability of bovine monocytes to produce the immunological mediator interleukin-1 (IL-1). Monocytes preincubated for 6-24 h with 10 micrograms ml-1 AFB1 demonstrated a diminished capacity to release IL-1 activity in response to bacterial lipopolysaccharide (LPS). Preincubation for less time, or with lower concentrations of AFB1, did not affect IL-1 release. Pretreatment of monocytes with AFB1 also resulted in diminished release of IL-1 activity in response to in vitro infection with Listeria monocytogenes. Incubation with AFB1 reduced the amount of IL-1 beta mRNA in LPS-stimulated bovine monocytes; however, this was observed only at high concentrations of AFB1 that non-specifically reduced steady-state transcription of actin mRNA. We therefore concluded that AFB1 does not specifically suppress monocyte release of IL-1, other than through its general inhibition of mRNA transcription.

Influence of endotoxin-protein in immunoglobulin G isotype responses of mice to Brucella abortus lipopolysaccharide.

Brucella abortus endotoxin preparations, containing approximately 5 to 6% protein, induce strong immune and adjuvant immunoglobulin G (IgG) responses as compared with Escherichia coli endotoxin preparations, with equivalent amounts of protein, which induce responses in which IgM antibody predominates. Using an enzyme-linked immunoassay with isotype-specific conjugates, we found that antibody of all four subclasses of IgG were evoked during the course of the immune responses of C3H/HeAu mice to B. abortus endotoxin. Secondary responses of endotoxin-hyporesponsive C3H/HeJ mice were similar to those seen in C3H/HeAu mice, although lower levels of antibody were produced during their primary responses. The primary responses of BALB/c athymic mice consisted almost entirely of IgG3, and IgG1 appeared following a second injection. The effects of lipopolysaccharide (LPS)-associated protein on the immunogenic properties of B. abortus endotoxin were examined by comparing responses to endotoxin with those to a purified B. abortus LPS containing less than 1% protein. The endotoxin evoked strong primary and secondary responses in which antibody directed to LPS determinants consisted mainly of IgG3 and those to the protein determinants were largely IgG1 antibody. Primary and secondary responses to purified LPS consisted mainly of IgG3 antibody. The potential mechanism of the contribution of protein to the immunogenic properties of the endotoxin as well as possible immune mechanisms involved in these responses are discussed.

Separate and combined effects of recombinant interleukin-1 alpha and gamma interferon on antibacterial resistance.

Our laboratory has previously reported that administration of murine recombinant interleukin 1 alpha (rIL-1 alpha) substantially enhanced the resistance of mice to Listeria monocytogenes infection. Other investigators have reported that gamma interferon (IFN-gamma) plays a pivotal role in antilisteria resistance. In the present study, we have defined doses of human rIL-1 alpha that enhanced the antilisteria resistance of mice. We then addressed the possibility that combined immunotherapy with rIL-1 alpha and recombinant IFN-gamma (rIFN-gamma) might result in an additive or synergistic enhancement of antibacterial resistance. Simultaneous administration of rIL-1 alpha and rIFN-gamma enhanced antilisteria resistance (at 3 days after infection) to a greater extent than did either cytokine alone, although the results did not imply a synergistic action between the two cytokines. Experiments which examined the effects of the timing of cytokine administration indicated that maximal protection was observed when rIL-1 alpha and rIFN-gamma were administered together concomitantly with the L. monocytogenes challenge. When we compared the separate and combined protective effects of rIL-1 alpha and rIFN-gamma throughout the course of a primary L. monocytogenes infection, we observed an additive effect of the two cytokines only at 3 days after challenge, the time at which the peak bacterial burden occurs in the spleens and livers of infected mice. Histopathological comparisons of livers and spleens from cytokine-treated and control listeria-infected mice verified that cytokine treatment reduced the severity of tissue damage in cytokine-treated listeria-infected mice. In an attempt to provide a potential mechanism for the protective effects of rIL-1 alpha and rIFN-gamma administration, we compared levels of colony-stimulating activity in sera from cytokine-treated and control listeria-infected mice. The highest levels of colony-stimulating activity were detected in sera from control listeria-infected mice; somewhat lower levels were found in sera from listeria-infected mice that received rIL-1 alpha and rIFN-gamma either alone or in combination.

Induction of immune and adjuvant immunoglobulin G responses in mice by Brucella lipopolysaccharide.

The immunogenic and adjuvant properties of Brucella abortus and Escherichia coli lipopolysaccharides (LPSs) were studied in endotoxin-responsive, athymic, and euthymic BALB/c mice and in responsive C3H/HeAu mice and congenic nonresponsive C3H/HeJ mice. Consistent with previous reports, E. coli LPS did not stimulate significant primary or secondary antibody responses in C3H/HeJ mice and induced the production of immunoglobulin M (IgM) and low levels of IgG in C3H/HeAu mice. In contrast, B. abortus smooth and rough LPS stimulated primary and secondary antibody responses and induced the production of IgM and high levels of IgG in both responsive and nonresponsive strains of C3H/He mice and in nude mice. When used as adjuvant, B. abortus LPS augmented the IgG plaque-forming-cell response of C3H/HeAu and BALB/c euthymic mice to the T-dependent antigen sheep erythrocytes. E. coli LPS augmented only the IgM plaque-forming-cell response in the same mouse strains. Neither B. abortus nor E. coli LPS was adjuvant for C3H/HeJ or nude mice. The dichotomy between the antibody and adjuvant responses of both C3H/HeJ mice and athymic mice to B. abortus LPS may be a function of the true thymus independence and dependence of these responses. In addition, the refractiveness of C3H/HeJ and nude mice to B. abortus LPS as adjuvant, but not as mitogen or polyclonal B cell activator, clearly dissociates these phenomena.

rIL-1 alpha enhances adoptive transfer of resistance to Listeria monocytogenes infection.

We have previously demonstrated that administration of recombinant rIL-1 alpha enhances resistance against Listeria monocytogenes infection in mice. In this study we considered the possibility that this cytokine might also augment adoptive immunity conferred by the transfer of listeria-immune spleen cells. Concomitant administration of rIL-1 alpha with large numbers (2 x 10(7) or 10(8)) of listeria-immune spleen cells reduced the protection mediated by the transferred cells. Conversely, rIL-1 alpha co-administered with suboptimal numbers (1-5 x 10(6)) of immune splenocytes augmented anti-listeria resistance in an additive fashion. Although transfer of 10(6) listeria-immune spleen cells alone did not result in significant protection, when 10(6) immune cells were incubated with rIL-1 alpha prior to transfer they conferred significant protection to naive recipients. Time course experiments indicated that the greatest protection was achieved when listeria-immune spleen cells were pretreated with rIL-1 alpha for 2 h prior to adoptive transfer. The protection transferred by 10(6) rIL-1 alpha-pretreated immune spleen cells was not inhibited by TGF beta. This study is the first to use rIL-1 alpha to potentiate the adoptive transfer of resistance to an infectious agent by immune cells.

Human rTNF alpha augments anti-bacterial resistance in mice: potentiation of its effects by recombinant human rIL-1 alpha.

Treatment with human recombinant tumour necrosis factor-alpha (rTNF alpha) significantly enhanced resistance to Listeria monocytogenes infection in mice. The level of protection (which was dose-dependent and maximal at approximately 1.0 microgram per mouse) was similar to that previously reported for the monokine rIL-1 alpha, although somewhat greater amounts of rTNF alpha than rIL-1 alpha were required. Combined administration of suboptimal concentrations of rTNF alpha and rIL-1 alpha resulted in significant enhancement of resistance beyond that obtained with either monokine alone, whereas further increases in anti-listeria resistance were not observed at doses of rTNF alpha or IL-1 alpha that were themselves capable of inducing substantial protection. Combined administration of rTNF alpha and rIL-1 alpha was associated with a delay in onset and lessening in severity of the lymphopenia that accompanied L. monocytogenes infection. The reduced bacterial burden in the spleens and livers of mice treated with rTNF alpha and rIL-1 alpha was associated with a more rapid decline in serum colony-stimulating activity. Peritoneal macrophages from rTNF alpha- and rIL-1 alpha-treated listeria-infected mice did not demonstrate enhanced anti-listeria activity in vitro. These results provide further evidence for the potential benefits of rTNF alpha and other cytokines in promoting anti-bacterial resistance. They further suggest that use of combinations of cytokines is a strategy worthy of further consideration.

Effects of murine recombinant interleukin 1 alpha on the host response to bacterial infection.

The effects of exogenously administered rIL-1 alpha on elimination of viable listeriae from the liver and spleen during the course of a primary Listeria monocytogenes infection was studied. Similar numbers of L. monocytogenes were recovered from rIL-1 alpha-treated and control mice at up to 24 h after infection; however, by 48 h after infection more than 1 log10 fewer viable L. monocytogenes were recovered from the spleens of rIL-1 alpha-treated mice than from Listeria-infected controls. The difference in bacterial burden between IL-1 alpha-treated and control mice increased with time; by 7 days after infection viable L. monocytogenes had been eliminated from most rIL-1 alpha-treated mice, whereas control mice still harbored 10(4) to 10(5) L. monocytogenes per spleen and liver. Histopathologic examination confirmed that rIL-1 alpha-treated mice suffered considerably less damage to the spleen, liver, lung, and brain than did control mice. To determine whether rIL-1 alpha-mediated protection indirectly by augmenting the release of other cytokines, we determined serum levels of colony-stimulating activity and IFN activity in rIL-1 alpha-treated and control Listeria-infected mice. Treatment with rIL-alpha elicited an early burst of serum colony-stimulating activity as compared with sera from Listeria-infected control mice. These data suggest that exogenous administration of rIL-1 initiates release of colony-stimulating activity, and perhaps other cytokines, that accelerate the protective response of the infected host. Prophylactic augmentation of antimicrobial resistance by administration of rIL-1 alpha may be worthy of further evaluation.