Impairment of mucosal immunity by parenteral nutrition: depressed nasotracheal influenza-specific secretory IgA levels and transport in parenterally fed mice.

OBJECTIVE: To examine the effects on mucosal selective transport of polymeric IgA (pIgA) and the ability of exogenous pIgA to provide protection despite altered mucosal transport. SUMMARY BACKGROUND DATA: Parenteral nutrition significantly impairs established antipseudomonal immunity and IgA-mediated antiviral immunity in association with gut-associated lymphoid tissue mass atrophy. Lack of enteral feeding also induces mucosal effects. METHODS: After immunization, nasotracheal levels of influenza-specific IgA were measured in cannulated mice randomized to chow feeding or parenteral nutrition. Nonimmune animals were randomized to chow or total parenteral nutrition, and after 5 days of diet were given a mixture of two antiinfluenza monoclonal antibodies, pIgA and IgG. Four hours after injection, nasal washes were collected and influenza-specific antibody levels were determined by enzyme-linked immunosorbent assay to calculate the selective transport index of IgA relative to IgG. In the final experiment, immunized animals were randomized to chow or parenteral feeding, and after 5 days, parenterally fed animals received either normal mouse serum or antiviral pIgA before viral challenge. Viral shedding was measured at 42 hours after challenge. RESULTS: Parenteral nutrition significantly reduced virus-specific IgA in nasotracheal washes. Parenteral nutrition depressed the selective transport index, demonstrating impaired mucosal transport of pIgA. Parenterally fed animals given specific antiviral pIgA but not normal mouse serum eliminated virus from the airway and regained mucosal protection, demonstrating adequate residual transport for immunity if adequate pIgA is present. CONCLUSION: Although both decreased IgA production due to gut-associated lymphoid tissue atrophy and impaired mucosal transport occur when enteral feeding is not provided, residual transport can provide antiviral protection if exogenous antiviral pIgA is available. Production, rather than transport, may be the most important factor in maintaining established respiratory tract IgA-mediated immunity.

Impairment of mucosal immunity by total parenteral nutrition: requirement for IgA in murine nasotracheal anti-influenza immunity.

Secretory IgA (SIgA) is the primary mucosal Ig and has been shown to mediate nasotracheal (NT) mucosal immunity in normal immune BALB/c mice. This finding has been challenged by a report of NT immunity without IgA in knockout mice, suggesting that IgA may not be necessary for the protection of mucosal surfaces. Although other protective mechanisms may become active in the congenital absence of SIgA, these mechanisms are not the primary means of protection in normal mice. In this paper we show that feeding chemically defined total parenteral nutrition (TPN) to genetically normal, immune ICR mice by the i.v. route results in loss of nasal anti-influenza immunity and a significant drop in influenza-specific SIgA in the upper respiratory tract compared with chow-fed mice (p < 0.005), while the serum influenza-specific IgG titer is unaffected. Loss of upper respiratory tract mucosal immunity is not related to serum Ab, because 10 of 13 TPN-fed mice shed virus into their nasal secretions despite adequate serum anti-influenza IgG titers. The number of IgG Ab-secreting cells in the nasal passages and spleens of TPN-fed mice was unaffected, while both the number and the percentage of splenic IgA-secreting cells were decreased relative to those in chow-fed animals. The loss of immunity is due to the route of nutrition, not the composition of the diet, because TPN solution fed orally via gastrostomy instead of i.v. maintains NT anti-influenza mucosal immunity. We hypothesize that delivery of nutrition via the gut triggers the release of gastrointestinal neuropeptides necessary for maintenance of the mucosal immune system.

Progression of influenza viral infection through the murine respiratory tract: the protective role of sleep deprivation.

Sleep deprivation is reported to have both beneficial and harmful effects upon host defenses. In the work reported herein, we address the effects of sleep deprivation on the mucosal anti-influenza defenses of both immune and nonimmune BALB/c mice. Sleep deprivation does not depress existing mucosal antiviral defenses in the respiratory tracts of BALB/c mice; in fact, it may actually be beneficial. Nasal mucosal immunity is not adversely affected in immune mice by sleep deprivation. In nonimmune mice, sleep deprivation slows or prevents the progress of nasal influenza viral infection down the trachea into the lungs. By 72 hours post-infection, 12 of 12 control mice shed virus into bronchioalveolar lavages (BAL) while only 2 of 12 sleep deprived mice shed virus (p<0.001). BAL levels of IL-1beta and interferon alpha were increased in sleep deprived animals, suggesting that sleep deprivation may exert its beneficial effects on the respiratory tract by upregulating the production of antiviral cytokines.

Individual neuropeptides regulate gut-associated lymphoid tissue integrity, intestinal immunoglobulin A levels, and respiratory antibacterial immunity.

BACKGROUND: Total parenteral nutrition (TPN) leads to atrophy of the gut-associated lymphoid tissue (GALT) and a significant decrease in intestinal immunoglobulin A (IgA) levels, a major constituent of mucosal immunity. Bombesin (BBS) prevents TPN-induced GALT atrophy and maintains intestinal IgA levels. BBS, a neuropeptide analogous to gastrin-releasing peptide in humans, stimulates the release of other gut neuropeptides including cholecystokinin (CCK), gastrin, and neurotensin (NT). This study investigates the ability of CCK, gastrin, or NT to individually prevent TPN-induced GALT atrophy and preserve respiratory immunity. METHODS: Experiment 1: Male mice were randomly assigned to receive chow, TPN, TPN plus CCK, TPN plus gastrin, or TPN plus NT. After 5 days of feeding, Peyer's patches (PP) from the proximal and distal small bowel were harvested and analyzed for cell yields. PP cells were also analyzed for GALT cell type. Small bowel IgA levels were measured by enzyme-linked immunosorbent assay (ELISA). Experiment 2: Mice were randomly assigned to receive either liposomes containing Pseudomonas antigen or liposomes without antigen. After 10 days, mice were randomly assigned to the same five treatment groups, fed for 5 days, and then given intratracheal Pseudomonas. Mortality was assessed after 48 hours. RESULTS: Experiment 1: GALT cell reductions due to IV-TPN were greater in the distal than proximal small bowel. All three neuropeptides prevented most TPN-induced GALT atrophy due mainly to the maintenance of the B-cell and T-cell populations in the PP of the distal bowel. Intestinal IgA levels were significantly higher in the animals treated with neuropeptides than animals treated with TPN only; however, these IgA levels were not maintained at levels observed in chow-fed animals. Experiment 2: Immunization resulted in significantly lower mortality in animals fed chow, TPN plus CCK, and TPN plus gastrin. TPN alone and TPN plus NT resulted in loss of immunity and mortality rate at comparable levels to unimmunized animals. CONCLUSIONS: Supplementation of IV-TPN with CCK, gastrin, and NT prevents GALT atrophy, primarily in the distal bowel. Intestinal IgA levels improve but not to normal levels. CCK and gastrin reversed IV-TPN-induced effects on antibacterial pneumonia in immunized animals while NT did not.

Bombesin recovers gut-associated lymphoid tissue and preserves immunity to bacterial pneumonia in mice receiving total parenteral nutrition.

OBJECTIVE: To study the ability of bombesin (BBS) to recover gut-associated lymphoid tissue (GALT) and preserve immunity in a lethal model of Pseudomonas aeruginosa (Ps) pneumonia in mice receiving total parenteral nutrition (TPN). SUMMARY BACKGROUND DATA: TPN causes depression of mucosal immunity compared with enterally fed animals, which may explain the increased incidence of pneumonia in parenterally fed trauma patients. BBS prevents this TPN-induced GALT atrophy, depressed gastrointestinal and respiratory tract IgA levels, and impaired antiviral IgA-mediated mucosal immunity. The authors examined whether some supplement could be added to TPN to avoid this GALT atrophy and lower the incidence of infectious complications in the parenterally fed animal. METHODS: Male mice were randomized to chow or intravenous (IV) TPN. After 5 days of IV TPN, mice received 0, 1, 2, or 3 days of BBS IV three times a day and then were killed to harvest Peyer's patch, intraepithelium, and lamina propria for cell yields. Gastrointestinal and respiratory tract IgA levels were analyzed by enzyme-linked immunosorbent assay. Next, mice underwent intranasal inoculation with liposomes alone (nonimmune) or liposome-containing Ps polysaccharide. Ps immune mice were catheterized and randomized to chow, IV TPN, or IV TPN + BBS. The liposome group received chow but no IV catheter. These mice were given an LD90 dose of intratracheal Ps, and death rates were recorded. RESULTS: GALT and gastrointestinal and respiratory tract IgA levels improved to those in chow-fed mice after 3 days of BBS. Immunization reduced the death rate from 92% in chow-fed liposome-only animals to 20% in immunized animals. TPN-fed animals lost their mucosal immunity, with a death rate of 86% compared with 21% in the TPN + BBS group. CONCLUSION: The results demonstrate that BBS reverses TPN-induced changes in GALT and preserves mucosal immunity. Ps immunization reduces the death rate in a gram-negative pneumonia model and maintains gastrointestinal and respiratory immunity in Ps immune mice receiving IV TPN.

Glutamine-enriched total parenteral nutrition preserves respiratory immunity and improves survival to a Pseudomonas Pneumonia.

BACKGROUND: Addition of 2% glutamine (GLN), a specific lymphocyte fuel, prevents deleterious effects of TPN on gut-associated lymphoid tissue and IgA while preserving IgA-mediated upper respiratory immunity to influenza virus. We examined whether a 2% GLN-enhanced TPN solution preserves respiratory immunity to a lethal and clinically relevant pneumonia challenge. MATERIALS AND METHODS: Male ICR mice were randomized to chow (n = 20), TPN (n = 20), or an isonitrogenous, isocaloric TPN-2% GLN solution (n = 17). All groups were immunized 10 days before surgery with Pseudomonas polysaccharide-containing liposomes (LIP) to confer immunity except for a nonimmune chow-fed LIP control group (n = 21) which received LIP without Pseudomonas. Mice received 5 days of diet and then were given an LD90 dose of 1.2 x 10(8) intratracheal Pseudomonas bacteria, and mortality was recorded. RESULTS: Immunization reduced mortality compared with LIP alone. TPN impaired immunity and reduced survival while GLN maintained immunization effectiveness. CONCLUSIONS: Pseudomonas immunization reduces mortality to Pseudomonas pneumonia, but this immunity is lost with TPN. Addition of 2% GLN to TPN preserves immunity in the respiratory tract and reduces mortality to a lethal bacterial challenge compared with standard TPN.

Route and type of nutrition influence mucosal immunity to bacterial pneumonia.

OBJECTIVE: To develop a model of established respiratory immunity against Pseudomonas aeruginosa pneumonia and to investigate the effects of route and type of nutrition on this immunity. SUMMARY BACKGROUND DATA: Diet influences the ability of gut-associated lymphoid tissue (GALT) to maintain mucosal immunity. Complex enteral diets and chow maintain normal GALT populations against established IgA-mediated antiviral respiratory immunity. Both intravenous and intragastric total parenteral nutrition (TPN) produce GALT atrophy, but only intragastric TPN preserves established antiviral immunity. The authors hypothesized that both GALT-depleting diets (intragastric and intravenous TPN) would impair immunity against bacterial pneumonia. METHODS: P. aeruginosa was administered intratracheally to determine the mortality rate at increasing doses, and liposomes containing P. aeruginosa antigens were used to generate effective respiratory immunization. In the final experiment, mice received liposomes containing P. aeruginosa antigens to establish immunity and then were randomized to chow, complex enteral diets, intragastric TPN, or intravenous TPN. After 5 days of diet, mice received live intratracheal P. aeruginosa, and the death rate was recorded at 24 and 48 hours. RESULTS: The LD50 and LD100 were 9 x 10(7) and 12 x 10(7), respectively. Immunization reduced the mortality rate from 66% to 12%. This immunization was maintained in mice fed chow or a complex enteral diet and was lost in animals receiving intravenous TPN. Intragastric TPN partially preserved this respiratory immunity. CONCLUSIONS: Protection against bacterial pneumonia can be induced by prior antigenic immunization. This protection is lost with intravenous TPN, partially preserved with a chemically defined enteral diet, and completely preserved with chow or complex enteral diets. Both route and type of nutrition influence antibacterial respiratory tract immunity.

In vitro comparison of the biologic activities of monoclonal monomeric IgA, polymeric IgA, and secretory IgA.

Secretory IgA (S-IgA), a major humoral mediator of mucosal immunity, is a polymeric Ig containing an unusual extra polypeptide, secretory component (SC), added during transcytosis through epithelial cells. Polymeric S-IgA is more effective than monomeric IgA (mIgA) and IgG in neutralizing viruses. It is not known whether this increased efficacy is due solely to the polymeric structure of the molecule or whether SC itself makes S-IgA more efficient; a quantitative in vitro comparison of the biologic activities of S-IgA and pIgA has not been reported. We prepared purified pIgA and mIgA mAbs directed toward the H1 hemagglutinin of PR8 influenza virus and purified monoclonal S-IgA (made from monoclonal pIgA injected into a Lewis rat and collected as S-IgA from bile) and compared their abilities to carry out hemagglutination inhibition (HI) and neutralization of the infectivity of PR8 influenza virus in vitro. The polymeric Igs (pIgA and S-IgA) were 5 times more effective than mIgA in HI and 7 to 10 times more effective than mIgA in virus neutralization. Addition of SC to pIgA did not modify its ability to mediate HI and had only a minimal effect (S-IgA was 1.4 times more effective) on its ability to neutralize influenza virus in vitro. Trypsin preincubation partially abolished mIgA- or pIgA-mediated, but not S-IgA-mediated, viral neutralization. Thus, although S-IgA is more stable functionally than pIgA, the addition of SC does not influence, positively or negatively, the biologic activity associated with the Fab of S-IgA.

Effects of short-term sleep deprivation on murine immunity to influenza virus in young adult and senescent mice.

Sleep has been proposed as an innate host defense, exerting effects on both specific and nonspecific immunity. In one of the more striking papers dealing with the effects of sleep on specific immunity, Brown et al (Reg. Immunol. 1989; 2: 321-325) reported that depriving influenza virus-immune mice of sleep for 7 hours following total respiratory tract viral challenge abrogated anti-viral immunity within the lungs and lowered the level of anti-influenza antibody in lung homogenates. In the solidly-immune convalescent mouse, nasobronchial immunity to influenza virus has been shown to be due to secretory IgA (S-IgA) within the mucosal mucocilliary blanket, while serum IgG has been shown to mediate protection within the lung parenchyma. In this study we attempted to duplicate the work of Brown et al in solidly immune mice. We were unable to abrogate mucosal anti-influenza viral immunity with a single post-viral-challenge sleep-deprivation episode, nor were we able to depress this immunity with one pre- and two post-challenge sleep-deprivation episodes in young adult or old mice, or with two pre-challenge sleep-deprivation episodes in old mice. Sleep deprivation did not depress the level of serum influenza-specific IgG antibodies, and resulted in increased influenza-specific serum IgG compared with normally sleeping mice in aged immune mice boosted 3 weeks before challenge and sleep deprived once before and twice after challenge (p = 0.005). No differences in anti-viral respiratory immunity were apparent between young and old mice. We conclude that short-term sleep deprivation has minimal effects on pre-existing mucosal and humoral immunity in either the young adult or the senescent mouse.

Effect of sleep deprivation on serum influenza-specific IgG.

Intra-pulmonary protection against influenza virus in immune mice, largely dependent upon serum lgG, is reported to be suppressed by 7 hours of sleep deprivation following viral challenge. This implies that sleep deprivation may accelerate the catabolism of influenza-specific antibodies. To determine the effects of sleep deprivation on the catabolism of serum antibodies, BALB/c mice were passively immunized intravenously with lgG anti-influenza monoclonalantibodies and catabolism kinetics monitored for 6 days. Mice were then sleep-deprived for either 9 hours (one episode) or for 9 hours followed by 6 hours on the consecutive day (two episodes) and the serum titer of influenza-specific monoclonal antibodies monitored for an additional 8 days via ELISA. One episode of sleep-deprivation had only minor effects on lgG catabolism; however, two episodes of sleep-deprivation caused significant changes in the kinetics of lgG catabolism, resulting in elevated lgG levels (p = 0.02) for 2 days post-sleep deprivation. Elevation of serum influenza-specific lgG (p = 0.005) was also seen in actively immune mice following two episodes of sleep-deprivation. Serum chemistries ruled out dehydration as a cause of the increased antibody levels; however, some anomalies were noted: total protein and albumin were elevated, although not significantly, and P and Ca were decreased. Thus, our data do not support the hypothesis that sleep-deprivation lowers existing serum antibody titers by accelerating antibody catabolism.

Glycyl-L-glutamine-enriched total parenteral nutrition maintains small intestine gut-associated lymphoid tissue and upper respiratory tract immunity.

BACKGROUND: i.v. administration of a total parenteral nutrition (TPN) solution results in small intestinal gut-associated lymphoid tissue (GALT) atrophy, lowers small intestinal immunoglobulin A (IgA) levels, and impairs upper respiratory tract secretory IgA-mediated mucosal immunity; isonitrogenous supplementation of TPN with 2% glutamine attenuates these changes. This experiment examines whether a 2% glycyl-L-glutamine-enriched TPN solution reverses i.v. TPN-induced changes as effectively as L-glutamine. METHODS: Male Institute of Cancer Research (ICR) mice underwent intranasal inoculation with H1N1 influenza virus to establish immunity. After 3 weeks, mice were randomized to chow, i.v. feeding of a TPN solution, glutamine-enriched TPN, or glycyl-L-glutamine-enriched TPN. After 4 days of feeding, mice were challenged intranasally with influenza virus and killed at 40 hours to determine viral shedding from the respiratory tract; normal convalescent mice do not shed virus because they possess intact IgA-mediated mechanisms Lymphocytes were isolated from Peyer's patches, the intraepithelial layer, and lamina propria to determine cell yields. RESULTS: Total lymphocyte yield in the Peyer's patches, the intraepithelial layer, and lamina propria decreased with TPN but remained normal with glutamine and glycyl-L-glutamine. Upon challenge, 70% of the mice in the TPN group shed virus in nasal secretions, whereas only 20% of the glutamine-treated group, 18% of glycyl-L-glutamine group and none of the Chow group were virus positive. CONCLUSIONS: L-Glutamine and glycyl-L-glutamine have similar effects on i.v. administered TPN-associated (GALT) atrophy and decreased upper respiratory tract immunity.

Recovery of gut-associated lymphoid tissue and upper respiratory tract immunity after parenteral nutrition.

OBJECTIVE: The authors characterize the recovery of parenteral nutrition-induced changes in gut-associated lymphoid tissue (GALT) and upper respiratory tract immunity with enteral nutrition and provide further information defining the effects of enteral feeding on mucosal immunity. SUMMARY BACKGROUND DATA: The small intestine plays a prominent role in development and maintenance of mucosal immunity, both intestinal and extraintestinal, primarily through immunoglobulin A (IgA)-mediated mechanisms. Prior research has shown that mice fed total parenteral nutrition (TPN) have reduced GALT T and B cells, the cells responsible for IgA production, as well as impaired upper respiratory tract immunity to viral challenge of previously immunized animals. The recovery of TPN-induced changes in GALT and upper respiratory tract immunity after enteral refeeding is studied. METHODS: Male institute of Cancer Research mice received 5 days of TPN followed by 0 to 4 days of chow. Small intestinal GALT was characterized by flow cytometry. In a second experiment, animals were immunized intranasally with moused-adapted influenza virus. Three weeks later, one group received a 5-day course of TPN followed by enteral refeeding for 5 days. A second group received TPN alone. Both groups were challenged with intranasal virus and killed 40 hours postchallenge to determine viral shedding from the upper respiratory tract. RESULTS: Animals fed TPN only had significantly fewer GALT lymphocytes compared with those chow-fed control subjects. Peyer's patch counts increased after a single day of refeeding, returning to normal levels by 48 hours. Lamina propria counts remained significantly depressed after 24 hours of refeeding, but also returned to normal after 48 hours of refeeding. The T-cell and B-cell populations mimicked total cell patterns. Lamina propria CD4+/CD8+ ratio returned to normal only after 72 hours of refeeding. None of the 9 animals refed enterally for 5 days were positive for viral shedding, compared with 8 of 12 matched TPN-fed animals. CONCLUSIONS: Enteral refeeding after TPN is associated with rapid repletion of GALT cellularity, initially within Peyer's patches and subsequently within the lamina propria. Refeeding corrects the impairment of IgA-mediated upper respiratory tract antiviral immunity occurring with TPN administration. This work further enhances the authors' knowledge of the underlying immunologic differences influenced by routes of nutrition.

Effect of glutamine-enriched total parenteral nutrition on small intestinal gut-associated lymphoid tissue and upper respiratory tract immunity.

BACKGROUND: Our prior work shows that total parenteral nutrition (TPN) causes small intestinal gut-associated lymphoid tissue (GALT) atrophy, lowers small intestinal immunoglobulin A (IgA) levels, and impairs secretory IgA-mediated mucosal immunity of the upper respiratory tract. These experiments examine whether an isonitrogenous 2% glutamine-enriched TPN solution prevents these changes. METHODS: Institute of Cancer Research mice were randomized to chow (chow), intravenous feeding of a TPN solution (TPN), or glutamine-enriched TPN (glutamine) groups. After mice were fed for 5 days, lymphocytes were isolated from Peyer's patches, the intraepithelial layer, and lamina propria to determine cell yields and phenotypes. Total small intestinal IgA levels were analyzed by means of enzyme-linked immunosorbent assay. In a second series of experiments, mice underwent intranasal inoculation with H1N1 virus to establish immunity. After 3 weeks mice were randomized to chow, TPN, or glutamine groups. After feeding for 5 days, mice were rechallenged with intranasal virus and killed at 40 hours to determine viral shedding from the upper respiratory tract. RESULTS: Total lymphocyte yield in the Peyer's patches, the intraepithelial layer, and lamina propria, small intestinal IgA levels, and the CD4+/CD8+ ratio in the lamina propria decreased with TPN but remained normal with glutamine. On rechallenge, 87% of the mice in the TPN group shed virus in nasal secretions, whereas only 38% of the glutamine-treated group (p < 0.05 versus TPN) and 7.1% of the chow group (p < 0.002 versus TPN) were virus positive. CONCLUSIONS: Isonitrogenous supplementation of TPN with 2% glutamine improves IgA-mediated protection in the upper respiratory tract and normalizes GALT populations.

Effect of bombesin on impairment of upper respiratory tract immunity induced by total parenteral nutrition.

OBJECTIVE: To determine the effect of the neuropeptide bombesin on total parenteral nutrition-induced impairment of upper respiratory tract immunity. DESIGN: Randomized, controlled trial. PARTICIPANTS: Thirty-six adult male Institute for Cancer Research mice weighing 25 to 35 g. INTERVENTIONS: Mice were inoculated intranasally with H1N1 virus. At 3 weeks, mice were randomized to receive chow plus intravenous saline (n = 12), intravenous total parenteral nutrition (n = 12), or intravenous total parenteral nutrition plus bombesin (n = 12) administered 3 times daily at 15 micrograms/kg. After 5 days, mice were rechallenged with intranasal virus and killed at 40 hours to determine viral shedding from the respiratory tract; normal convalescent mice do not shed virus because of intact IgA-mediated mechanisms. MAIN OUTCOME MEASURES: Viral shedding was determined by collection of nasal secretions. Samples were diluted and incubated with a suspension of Madin-Darby canine kidney cells. Viral growth was determined by hemagglutination. RESULTS: Body weight was similar between the total parenteral nutrition and bombesin groups; however, both were significantly lower than that in the chow group (P < .05). After 6 days of feeding, no mice in the chow group shed virus, compared with 6 (50%) of the mice in the total parenteral nutrition group. Of the mice in the bombesin group, only 1 was positive for viral shedding. The total parenteral nutrition group showed increased viral shedding compared with both the chow group (P < .01) and the bombesin group (P < .05). CONCLUSIONS: Exogenous administration of bombesin reversed the total parenteral nutrition-associated impairment of upper respiratory tract immunity to an IgA-mediated infectious challenge. These observations support the concept of a common mucosal immune system, since neuropeptides are endogenous to the gastrointestinal and respiratory tracts. Hormonal modulation of immunity is a promising avenue of treatment for patients who require total parenteral nutrition.

Loss of upper respiratory tract immunity with parenteral feeding.

OBJECTIVE: The authors examine the effect of route and type of nutrition on an established upper respiratory tract immunity and investigate potential mechanisms for increased pneumonia rates in critically injured patients fed parenterally. SUMMARY BACKGROUND DATA: The primary immunologic defense against many mucosal infections is IgA. Prior work shows that mice fed total parenteral nutrition (TPN) solutions either intravenously or intragastrically had small intestinal gut-associated lymphoid tissue (GALT) atrophy along with decreased intestinal IgA compared with animals fed complex enteral diets. The small intestine is postulated to be the origin of most mucosal immunity, both intraintestinal and extraintestinal. The impact of diets affecting GALT, small intestine IgA, and upper respiratory tract immunity is studied. METHODS: Male Institute of Cancer Research mice underwent intranasal inoculation with a mouse-specific influenza virus to establish immunity. Three weeks later, the mice were randomized to chow, intragastric Nutren (Clintec, Chicago, IL), intravenous TPN, or intragastric TPN. After 5 days of feeding, mice were challenged with intranasal virus and killed at 40 hours to determine viral shedding from the upper respiratory tract. RESULTS: Despite similar body weights, there was significant atrophy in the Peyer's patch cells from animals fed the TPN solution intravenously or intragastrically. There was no viral shedding in any animal fed via the gastrointestinal tract, whereas 5 of 10 animals fed intravenous TPN had continued viral shedding. CONCLUSIONS: The IgA-dependent upper respiratory tract immunity was preserved with enteral feeding but not with intravenous feeding. Upper respiratory tract immunity is not dependent on intestinal GALT mass but is influenced by route of nutrition. The underlying mechanisms may explain the higher pneumonia rate in critically injured patients fed parenterally.

Differential effects of total and upper airway influenza viral infection on sleep in mice.

Sleepiness is a common perception during most infectious diseases, including viral infections. Previously, we observed that a lethal strain of influenza virus (H1N1) causes a greater increase in non-rapid eye movement sleep (NREMS) than a nonlethal strain of influenza virus (H3N2), suggesting that the magnitude of sleep responses after viral inoculation depends on the severity of the infection. The aim of the present experiment was to further test this possibility. The effects of total airway infection versus upper airway infection on sleep were tested in two groups of mice using the same strain of virus (H1N1). After 2-3 days of baseline sleep recordings. Swiss-Webster mice were infected intranasally with H1N1 influenza virus. Sleep was determined again for an additional 3 days and 6 hours. Total airway infection significantly increased NREMS beginning about 24 hours after the viral inoculation and significantly suppressed rapid eye movement sleep (REMS) with a longer latency. Both the increase in NREMS and the decrease in REMS lasted until the end of the experiment. Total airway infection also significantly decreased the body weight of the mice. In contrast, upper airway infection did not induce clear changes in sleep and body weight.

Influenza viral infections enhance sleep in mice.

Sleepiness is a common perception during viral infection. Nevertheless, very little is known about the effects of viral infection on sleep. The aim of the present study was to test whether sleep was altered by influenza viral infection in mice. After 2-3 days of baseline sleep recordings, Swiss-Webster mice were infected intranasally with a lethal (H1N1) or a nonlethal (H3N2) strain of influenza virus. Sleep was recorded again for an additional 3 days. Non-rapid eye movement sleep (NREMS) was dramatically increased after inoculation of the H1N1 virus with a latency about 16 hr. Rapid eye movement sleep (REMS) was significantly suppressed after a long latency. Both changes lasted until the end of the recording and occurred in both young (35-day-old) and adult (90- to 100-day-old) animals. Control animals did not show changes in sleep after sham infection with allantoic fluid. The H1N1 virus also caused dramatic decreases in body temperature and locomotor activities with a latency about 4-5 hr after viral inoculation. The H3N2 virus induced very similar changes in sleep, although the effects were much smaller in magnitude than those induced by the H1N1 virus, even though a much higher dose (10-fold) of the H3N2 virus was used. The present study shows that influenza viral infection induces profound and long-lasting increase of NREMS and suppression of REMS. These viral-induced changes in sleep likely represent a host-defense response.

Induction of a secretory IgA response in the murine female urogenital tract by immunization of the lungs with liposome-supplemented viral subunit antigen.

This study demonstrates that liposomes administered to the lower respiratory tract of mice have the capacity to stimulate secretory IgA (s-IgA) antibody production in the female urogenital system. Total respiratory tract immunization of mice with influenza virus subunit antigen simply mixed with negatively charged liposomes induced antigen-specific s-IgA in vaginal secretions, in addition to systemic IgG and s-IgA in the respiratory tract. Immunization of the upper respiratory tract alone or oral immunization were ineffective. These observations demonstrate that, upon stimulation with liposomes, the lymphoid tissue associated with the lung can act as an inductive site for migration of IgA-committed B cells to distant mucosal tissues, including the female urogenital tract. It is concluded that liposomes administered to the lower respiratory tract provide a promising adjuvant system for stimulation of both systemic and mucosal antibody responses against coadministered antigen, including production of s-IgA at distant mucosal sites.

Cytokines in sleep regulation.

The central thesis of this essay is that the cytokine network in brain is a key element in the humoral regulation of sleep responses to infection and in the physiological regulation of sleep. We hypothesize that many cytokines, their cellular receptors, soluble receptors, and endogenous antagonists are involved in physiological sleep regulation. The expressions of some cytokines are greatly amplified by microbial challenge. This excess cytokine production during infection induces sleep responses. The excessive sleep and wakefulness that occur at different times during the course of the infectious process results from dynamic changes in various cytokines that occur during the host's response to infectious challenge. Removal of any one somnogenic cytokine inhibits normal sleep, alters the cytokine network by changing the cytokine mix, but does not completely disrupt sleep due to the redundant nature of the cytokine network. The cytokine network operates in a paracrine/autocrine fashion and is responsive to neuronal use. Finally, cytokines elicit their somnogenic actions via endocrine and neurotransmitter systems as well as having direct effects neurons and glia. Evidence in support of these postulates is reviewed in this essay.