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J J Meissler

Publications and source records attributed to J J Meissler.

17 recordsLinked to original sources
PubMed2001

Morphine inhibits mucosal antibody responses and TGF-beta mRNA in gut-associated lymphoid tissue following oral cholera toxin in mice.

In this study, we investigated the effect of morphine on the mucosal immune system using fragment cultures of ileal segments, Peyer's patches (PPs), and mesenteric lymph nodes. Mice were implanted s.c. with a morphine slow release pellet. Control groups received a naltrexone slow release pellet, a placebo pellet, or both a morphine and a naltrexone pellet. After 48 h, mice were orally immunized with cholera toxin (CT) and were boosted orally 1 wk later. Animals were sacrificed 1 wk after the booster immunization, and PPs, mesenteric lymph nodes, and ileal segments were cultured in 24-well plates for 12 days. Morphine resulted in a highly significant inhibition of CT-specific IgA and IgG production in fragment culture supernatants of all three tissues compared with placebo. Naltrexone blocked the reduction in Ab levels induced by morphine, indicating that the effect is opioid receptor mediated. Morphine did not significantly alter total IgA levels in any of the tissue culture supernatants. Morphine also inhibited CT-specific IgA and IgG levels in serum. By flow cytometry, morphine did not alter the lymphoid cell composition in PPs compared with placebo. The effect of morphine on TGF-beta, IL-5, and IL-6 mRNA expression in PPs and ileal segments was determined following oral immunization with CT. Morphine significantly decreased TGF-beta mRNA compared with that in the placebo group, and naltrexone blocked this effect. These results indicate that morphine inhibits Ag-specific IgA responses in gut-associated lymphoid tissue at least partially through the inhibition of TGF-beta, a putative IgA switch factor, in the gastrointestinal tract.

Administration, Oral↗
PubMed2001

Administration of mu-, kappa- or delta2-receptor agonists via osmotic minipumps suppresses murine splenic antibody responses.

Previously, our laboratory has shown that morphine given by implantation of a 75-mg slow-release pellet for 48 h suppresses murine splenic antibody responses to sheep red blood cells (SRBCs) in a plaque-forming cell (PFC) assay. However, the use of slow-release pellets for such studies is limited, as these pellets are only available in fixed doses and similar pellets for kappa and delta agonists have not been developed. In the present study, we investigated the feasibility of administering opioids via Alzet osmotic minipumps to assess their immunomodulatory effects. Groups of mice received minipumps dispensing morphine sulfate, which has primary activity at the mu opioid receptor; U50,488H, which is a kappa-selective agonist; deltorphin II, which is a delta2-selective agonist; or DPDPE, which has greater selectivity for delta1 than delta, receptors. Morphine, U50,488H and deltorphin II were all immunosuppressive, with biphasic dose-response curves exhibiting maximal (approximately 50%) suppression of the PFC response at doses of 0.5 to 2 mg/kg/day 48 h after pump implantation. Further, immunosuppression by morphine sulfate, U50,488H or deltorphin II was blocked by simultaneous implantation of a minipump administering the opioid receptor-selective antagonists CTAP (1 mg/kg/day), nor-binaltorphimine (5 mg/kg/day), or naltriben (3 mg/kg/day), respectively. DPDPE was inactive at doses lower than 10 mg/kg/day. We conclude that osmotic minipumps are a practical and useful way of administering opioids to study their effects on the immune system, and give further evidence that immunosuppression induced in vivo by opioid agonists is mediated not only via mu, but also via kappa and delta2 opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2000

Morphine increases susceptibility to oral Salmonella typhimurium infection.

This study examined the effect of morphine on oral infection with virulent Salmonella typhimurium. Animals were treated with a 75-mg slow-release morphine pellet followed by inoculation with salmonellae. Morphine markedly sensitized mice to oral infection, as assessed by survival, mean survival time, and colony culture. By 24 h after Salmonella inoculation, morphine-treated mice had a 105-fold difference in number of organisms in the Peyer's patches, compared with controls. The opioid antagonist naltrexone significantly blocked Salmonella colonization in Peyer's patches and reduced Salmonella burden in other organs, indicating that morphine acts at least in part via an opioid receptor-mediated pathway. The data show that morphine markedly potentiates Salmonella infection at the gastrointestinal portal of entry and enhances subsequent dissemination of Salmonella organisms. The results have implications for potentiating gastrointestinal opportunistic infections in intravenous drug abusers and in opioid-medicated postsurgical patients.

Animals↗
PubMed2000

Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages.

In this study we investigated the capacity of morphine to modulate expression of cytokines in peritoneal macrophages. Mice were implanted subcutaneously with a 75-mg morphine slow-release pellet, and 48 h later resident peritoneal macrophages were harvested. Control groups received placebo pellets, naltrexone pellets, or morphine plus naltrexone pellets. Adherent cells were stimulated with lipopolysaccharide (LPS: 10 microg/mL) plus interferon-gamma (IFN-gamma: 100 units/mL) to induce cytokine production. After 24 h RNA was extracted for analysis of cytokine mRNA levels by reverse transcriptase-polymerase chain reaction, or supernatants were collected after 48 h for determination of cytokine production by enzyme-linked immunosorbent assay (ELISA). Morphine enhanced mRNA expression of interleukin (IL)-12 p40 and tumor necrosis factor alpha (TNF-alpha) compared with controls, whereas IL-10 levels were unchanged by drug treatment. ELISA data showed that both IL-12 p40 and p70 were increased by morphine. The enhancement of IL-12 at both the mRNA and protein levels was antagonized by naltrexone, indicating that the modulation of this cytokine by morphine is via a classic opioid receptor. These results are particularly interesting in light of our previous observation that 48 h after morphine pellet implantation, the peritoneal cavity is colonized with gram-negative and other enteric bacteria. The enhancement of IL-12 by morphine might be related to morphine-induced sepsis.

Adjuvants, Immunologic↗
PubMed1998

Nitric oxide mediates immunosuppression induced by Listeria monocytogenes infection: quantitative studies.

Our laboratory has shown that immunization of mice with an attenuated strain of Salmonella typhimuriuminduces profound suppression in the capacity of splenocytes to mount an in vitro antibody plaque-forming cell (PFC) response to sheep red blood cells (SRBC) and to proliferate in response to mitogens. In vitro addition of NG-monomethyl-L-arginine (NMMA), an inhibitor of nitric oxide (NO) synthase, to cell cultures from Salmonella-immunized mice completely blocked suppression of the PFC responses, implicating that NO is the suppressor factor. The present study quantified the role of nitric oxide in immunosuppression induced by Listeria monocytogenes, a gram positive intracellular pathogen of macrophages. Listeria infection resulted in suppression of the PFC assay at inoculating doses of greater than 6.5x10(3)colony forming units, with no suppression observed at lower doses. Suppression correlated with increased nitrite production. Addition of NMMA to spleen cell cultures taken from Listeria-infected mice completely blocked suppression of the PFC response, and returned nitrite production to baseline levels. In regard to Listeria-induced suppression of responses to the mitogen, Concanavalin A (Con A), the parameters were different from those observed for the PFC response. There was a direct correlation between the log10of the inoculating dose of Listeria and degree of immunosuppression, with suppression observed at doses as low as 1x10(3)cells. Addition of NMMA to the Con A-stimulated cultures resulted in reduced nitrite levels, but only partial restoration of the proliferative responses. Co-culture of splenocytes from Listeria inoculated mice with normal splenocytes in media with NMMA and reduced levels of L-arginine resulted in complete reversal of suppressed responses to Con A. Similar differences in ease of reversing suppression of the PFC response, as compared with responses to Con A, were previously noted using cells taken from Salmonella-infected mice. The present results show that a gram positive intracellular pathogen of macrophages, L. monocytogenes, induces immunosuppression in mouse spleen cells by a nitric oxide mediated mechanism that closely parallels that induced by the gram negative pathogen, S. typhimurium.

Animals↗
PubMed1998

Immunosuppression and nitric oxide production induced by parenteral live Salmonella vaccines do not correlate with protective capacity: a phoP::Tn10 mutant does not suppress but does protect.

Previous work from our laboratory showed that an aroA mutant strain of S. typhimurium, SL3235, induces profound immunosuppression 7 days post-parenteral inoculation, and that the suppression is mediated by nitric oxide. Suppression was measured by the capacity of spleen cells to mount a primary in vitro plaque-forming cell response to sheep red blood cells in Mishell-Dutton cultures. In the present studies, the capacity of a panel of strains of attenuated Salmonella with various genetic lesions was tested. Most of the strains were S. typhimurium, but several were S. dublin. It was found that a variety of Salmonella strains induced suppression, demonstrating that suppressive capacity is not unique to SL3235 or to S. typhimurium. A strong correlation was obtained between the log10 of the microbial burden (cfu spleen-1) on the seventh day post-vaccine inoculation and the degree of immunosuppression. Strains that gave high spleen counts gave greater suppression. Microbial burden also correlated with the size of the spleen and the amount of nitrite produced by spleen-cell cultures, a measure of nitric oxide. Finally, the degree of immunosuppression was found to be linearly related to the log10 of the amount of nitrite produced. The capacity of the various strains of Salmonella to protect against challenge with virulent S. typhimurium, strain W118-2, was also tested. No correlation was found between suppressive and protective capacities of the various strains. Two strains suppressed, but did not protect. While most strains that protected grew or persisted in vivo, a phoP::Tn10 mutant of S. typhimurium did not grow or persist; this phoP mutant did not cause immunosuppression, but gave 100% protection against challenge with wild type S. typhimurium, suggesting that such mutants have advantageous properties as live vaccines.

Animals↗
PubMed1998

Salmonella typhimurium infection in mice induces nitric oxide-mediated immunosuppression through a natural killer cell-dependent pathway.

Splenocytes isolated from C57BL/6J female mice 3 to 7 days after inoculation with an attenuated strain of Salmonella typhimurium produced high levels of nitric oxide (39 to 77 microM) and gamma interferon (IFN-gamma). Additionally, spleen cell cultures from Salmonella-inoculated mice were markedly suppressed in their ability to generate an in vitro plaque-forming cell (PFC) response to sheep erythrocytes. Depletion of natural killer (NK) cells from the immune splenocyte population markedly reduced nitric oxide production, prevented suppression of PFC responses, and completely abrogated IFN-gamma release. Treatment of NK cell-depleted immune cells with IFN-gamma restored nitric oxide production to levels comparable to those of intact immune cells and also restored the immunosuppression. These results suggest that NK cells regulate the induction of nitric oxide-mediated immunosuppression following infection with S. typhimurium through the production of IFN-gamma.

Animals↗
PubMed1997

Morphine induces sepsis in mice.

Gram-negative sepsis and subsequent endotoxic shock remain major health problems in the United States. The present study examined the role of morphine in inducing sepsis. Mice administered morphine by the subcutaneous implantation of a slow-release pellet developed colonization of the liver, spleen, and peritoneal cavity with gram-negative and other enteric bacteria. In addition, the mice became hypersusceptible to sublethal endotoxin challenge. The effects were blocked by the simultaneous implantation of a pellet containing the opioid antagonist naltrexone. These findings show that morphine pellet implantation in mice results in the escape of gram-negative organisms from the gastrointestinal tract, leading to the hypothesis that morphine used postoperatively or chronically for analgesia may serve as a cofactor in the precipitation of sepsis and shock. In addition, morphine-induced sepsis may provide a physiologically relevant model of gram-negative sepsis and endotoxic shock.

Analgesics, Opioid↗
PubMed1995

Decreases in macrophage mediated antitumor activity with aging.

We have demonstrated that immunotherapy of young (6-10 weeks old), and aged, (greater than 24 months old), tumor bearing mice with biological response modifiers enhanced survival and inhibited tumor growth, while treatment of aged mice had little or no effect. We hypothesized that the antitumor activity in young mice was principally mediated by activated macrophages (M phi) and predicted that the change in aged mice was caused by an intrinsic M phi defect which develops with advancing age. To directly test our hypothesis, we examined the antitumor activity of resident peritoneal M phi, purified and activated in vitro with IFN gamma plus LPS. Paralleling the results seen in vivo, M phi from aged mice exhibited reduced antitumor activity in comparison with M phi from younger mice. Moreover, there was reduced capacity of in vitro activated M phi from aged mice to produce TNF, IL-1 and nitric oxide, which are critical monokines and effector molecules that have been established to either directly inhibit tumor growth or cause tumor cell destruction. These studies establish that peritoneal M phi from aged mice have an intrinsic defect which prevents them from fully expressing their antitumor potential.

Aging↗
PubMed1995

Immunotherapy of a plasmacytoma with attenuated salmonella.

An attenuated strain of Salmonella typhimurium, SL3235, developed as a prototypic typhoid vaccine, is shown to retard growth of a murine plasmacytoma, TEPC-183, and to prolong survival of tumor-bearing mice. Live salmonella, but not acetone-killed organisms, had antitumor activity. The immunotherapeutic effect was demonstrable when the tumor was injected intralesionally or intraperitoneally. Increased survival, longer mean time to death, and retardation of tumor growth were found when the salmonella were given intralesionally as late as the sixth day post-tumor injection. Timing of salmonella inoculation, as well as the salmonella dose, had an effect on treatment efficacy. Injection of salmonella intraperitoneally exerted a strong antitumor effect when given as late as the third day post-tumor inoculation. The highest dose (2 x 10(6)) of salmonella was less effective than doses 10- or 100-fold lower. TEPC-183 plasmacytoma is rapidly growing and highly immunosuppressive, so the ability of the salmonella to exert therapeutic activity against it is a measure of the potency of the vaccine. These observations are of interest, as they show that a genetically engineered, avirulent strain of Salmonella has immunotherapeutic properties similar to those of BCG and other biological response modifiers, and might have clinical potential as an antitumor agent.

Animals↗
PubMed1995

Mouse strain differences in immunosuppression by opioids in vitro.

An in vitro assay was used to compare the effect of opioids on antibody production by splenocytes from C3HeB/FeJ, C57BL/6J, C57BL/6ByJ and B6C3F1/J mice immunized with sheep red blood cells (SRBC). Spleen cells were removed from mice that had been injected 2 wk prior with SRBC. These mice received no opioids in vivo. Dissociated spleen cells taken from each of the mouse strains were exposed to morphine with or without naloxone, or to U50,488H with or without norbinaltorphimine (nor-BNI), for 5 days in a Mishell-Dutton culture, with added SRBC as antigen. Immune responsiveness was assessed by the number of plaque-forming cells (PFC) per culture. The results showed a profound difference in the effects of the opioids on the spleen cells of the four mouse strains. Spleen cells of C3HeB/FeJ mice were suppressed approximately 50% in the number of PFC both by morphine (10(-5) to 10(-8) M) and by U50,488H (10(-5) to 10(-11) M). Suppression was blocked by pretreatment with naloxone or norbinaltorphimine, respectively. In contrast, spleen cells taken from C57BL/6J mice were not suppressed by either opioid, at doses ranging from 10(-5) to 10(-11) M. Spleen cells of B6C3F1/J mice were suppressed by U50,488H, but not morphine. Cells of C57BL/6ByJ mice gave inconsistent results in experiments measuring suppression by morphine, and U50,488H. Overall, these studies confirm our previous work showing that opioids directly affect the function of cells of the immune system via classical opioid receptors. In addition, the results show that mouse strain is a major variable in evaluating the immunomodulatory effects of opioids.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Macrophage nitric oxide mediates immunosuppression in infectious inflammation.

A vaccine strain of live, attenuated Salmonella typhimurium induces profound immunosuppression in inoculated mice 7 days after injection. Immunosuppression to mitogens and inability to mount plaque-forming responses to sheep red blood cells occurs in spite of many parameters of upregulated macrophage function and protection against challenge with virulent Salmonella. Studies show that macrophage nitric oxide mediates the immunosuppression and presumably also the early-onset protective capacity of the vaccine. A model of "bystander lymphocyte autotoxicity" is presented to explain the mechanism of immunosuppression. The model proposes that Salmonella-activated macrophages generate nitric oxide which inactivates lymphocytes in the vicinity, so they become dysfunctional. Inhibition of nitric oxide by NG-monomethyl-L-arginine reverses immunosuppression. Evidence is presented that supports a relationship between the microbial burden in the spleen, the degree of nitric oxide produced, and the extent of immunosuppression. It is proposed that this model of microbial immunosuppression mediated by nitric oxide is generalizable for understanding immunosuppression and loss of delayed-type hypersensitivity induced by other microbes, such as Mycobacteria and measles virus. The model could account for anergy during mycobacterial infections, particularly when the burden of acid-fast bacilli is high, as well as loss of skin test reactivity to tuberculin during measles infection.

Animals↗
PubMed1992

Immunosuppression induced by nitric oxide and its inhibition by interleukin-4.

Mice immunized with attenuated Salmonella typhimurium, strain SL3235, while protected against virulent challenge, are unable to mount in vivo and in vitro antibody responses to non-Salmonella antigens, such as tetanus toxoid and sheep red blood cells, and exhibit profoundly suppressed responses to B and T cell mitogens. Suppression of antibody responses is mediated by macrophage (M phi)-released soluble factors, and is completely reversed by treatment with interleukin (IL)-4. The present report identifies the suppressor factor as nitric oxide (NO), and provides evidence for a mechanism by which IL-4 abrogates suppression. Suppressed antibody responses correlated with high levels of NO secretion by splenocytes of SL3235-immunized mice. NO production was observed only in cultures consisting of the adherent cell fraction of immune splenocytes. Further, immunosuppression was reversed by NG-monomethyl-L-arginine (NMLA), a competitive inhibitor of NO synthesis, and was completely blocked by the addition of excess L-arginine. Treatment with IL-4, or anti-interferon (IFN)-gamma monoclonal antibody (mAb), also abrogated suppression. Optimal reversal of suppression was observed only when NMLA, IL-4, or anti-IFN-gamma mAb, was added at day 0 of the 5-day plaque-forming cell assay. Treatment with either IL-4 or anti-IFN-gamma mAb also lead to a sharp inhibition of NO production by immune spleen cells. Moreover, the addition of IL-4 to splenic adherent M phi inhibited their ability to generate NO. Our data characterize an immunoregulatory pathway, involving IFN-gamma and NO, by which M phi mediate immunosuppression and identify IL-4 as a potent inhibitor of this pathway.

Animals↗
PubMed1992

Immunosuppression induced by attenuated Salmonella: effect of LPS responsiveness on development of suppression.

A live, avirulent strain of Salmonella typhimurium, SL3235, was previously shown to afford protection against virulent Salmonella challenge in three mouse strains of the C3H lineage, C3H/HeJ, C3HeB/FeJ, and C3H/HeNCrlBR, which differ in their innate susceptibility to Salmonella infection, as well as in their responsiveness to lipopolysaccharide (LPS). Concurrent with protection, however, SL3235 was found to induce greater than 90% reduction in proliferative responses of splenocytes from immunized mice to a panel of B and T cell mitogens. Suppression appeared to be independent of susceptibility to Salmonella infection, since the mitogenic responses of hypersusceptible C3H/HeJ and C3HeB/FeJ, as well as resistant C3H/HeNCrlBR mice, were suppressed. The suppressor cell population in immunized C3HeB/FeJ mice was recently shown to be of monocytic lineage. Using transwell plates, co-culture studies indicated that suppression was mediated by soluble factors. In the present study, the effect of LPS responsiveness on susceptibility to SL3235-induced suppression was evaluated in C3H mice by studying their ability to mount plaque-forming cell (PFC) responses to sheep red blood cells (SRBC) and in vivo antibody responses to tetanus toxoid. Comparison of PFC responses as a function of SL3235 dose in C3HeB/FeJ and C3H/HeJ mice, revealed that the latter strain was markedly more resistant to the development of suppression, as evidenced by the significantly higher (10-35-fold) SL3235 doses needed to achieve comparable suppression to those seen in C3HeB/FeJ mice. In contrast to C3HeB/FeJ mice, suppression in C3H/HeJ mice required direct cell-cell contact. In both mouse strains, suppression was alleviated by pre-treatment of immune splenocytes with either mitomycin C or x-irradiation, indicating that actively proliferating cells are required for suppressor function. Resistance of C3H/HeJ mice to SL3235-induced suppression was not due to a lesser bacterial load in vivo, since a higher number of SL3235 organisms were seen in C3H/HeJ spleens compared to C3HeB/FeJ mice. Rather, resistance of C3H/HeJ mice correlated with their reduced ability to recruit macrophages and other inflammatory cells into the spleen, as evidenced by the significantly smaller degree of splenomegaly induced in these mice following immunization with SL3235.

Animals↗
PubMed1991

Immunosuppression induced by attenuated Salmonella. Reversal by IL-4.

We previously demonstrated that an aroA- strain of Salmonella typhimurium, which provides excellent protection against virulent Salmonella challenge, also rendered immunized mice unable to mount in vivo and in vitro antibody responses to heterologous Ag. Coculture studies using transwell plates indicated that suppression was mediated by soluble factors. The suppressive cells were identified as belonging to the monocytic linkage. Macrophage precursors as well as mature adherent macrophages mediated the observed suppression. In the present study, the mechanism of immunosuppression was investigated. Suppression was found to be genetically nonrestricted as spleen cells from immunized C3HeB/FeJ mice (H-2k) suppressed the anti-SRBC plaque-forming cell (PFC) responses of normal spleen cells from two MHC noncompatible mouse strains, BALB/c (H-2d) and C57BL/6 (H-2b). Time course experiments demonstrated that the addition of spleen cells from immunized mice to normal splenocytes as late as day 4 of a 5-day assay was still markedly suppressive. Furthermore, suppression of the PFC responses was accompanied by a profound inhibition of the capacity of immune splenocytes to produce IL-2 in response to in vitro stimulation by Con A. Coculture studies showed that immune spleen cells were able to suppress IL-2 production by normal splenocytes in a dose-dependent fashion. However, the suppressed PFC responses of immune spleen cells could not be reversed by the exogenous addition of up to 200 U/ml of IL-2, suggesting that immune splenocytes are also defective in their ability to respond to IL-2. In marked contrast, suppression of PFC responses was reduced by more than 50% by the addition of as little as 1 U/ml of IL-4 and was completely abrogated when 5 U/ml of IL-4 were added to in vitro cultures of spleen cells from immunized mice. The antisuppressive action of IL-4 appeared to be via its inhibitory effect on activated macrophages. The implications of the above findings are discussed.

Animals↗