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Biomedical subjects

A Sher

Publications and source records attributed to A Sher.

At least 91 records · Page 5Linked to original sources
PubMed1997

Perforin-mediated cytolysis plays a limited role in host resistance to Toxoplasma gondii.

Resistance of perforin knockout (PKO) mice to infection with Toxoplasma gondii was assessed in models of acute infection and during chronic disease. PKO mice vaccinated with the attenuated mutant, ts-4, displayed severely defective CTL responses against tachyzoite-infected targets. Lysis of the NK target, YAC-1, was also severely impaired in PKO mice following ts-4 vaccination. In contrast, wild-type mice developed high levels of CTL and NK lytic activity after ts-4 vaccination. Despite severely defective lytic activity, vaccinated PKO animals were completely resistant to challenge with the virulent strain RH, which normally causes a lethal acute infection. Resistance was attributable to production of IFN-gamma, which remained unimpaired in the PKO animals. In contrast, when PKO mice were infected with low virulence parasite strain ME49, which progresses to the cyst-forming stage after passage through an acute phase, accelerated mortality was observed beginning at 75 days postinfection. A three- to fourfold increase in brain cyst numbers was also found by day 30 in infected PKO animals. Nevertheless, the PKO strain produced normal levels of IFN-gamma after ME49 infection, ruling out impaired production of the latter cytokine as a cause of increased susceptibility. Together, these results show that perforin-dependent cytolytic function is not required for host resistance to lethal acute infection in preimmunized animals, but that the latter activity contributes to the control of infection during the chronic stage.

Animals↗
PubMed1997

Defects in cell-mediated immunity affect chronic, but not innate, resistance of mice to Mycobacterium avium infection.

To investigate the role of cell-mediated immunity in the control of Mycobacterium avium infection, we studied the effects of targeted gene disruptions in components of the T lymphocyte-dependent, macrophage-mediated response on resistance of mice to this pathogen. Normal mice developed a chronic, asymptomatic infection, with rapid induction of mRNAs for IFN-gamma, IL-12, and TNF-alpha in spleen, liver, and lung. Bacterial loads in gene knockout, scid, and wild-type mice were indistinguishable for the first 4 wk of infection. However, by 8 wk postinfection, scid mice as well as animals with a targeted disruption of the IFN-gamma gene showed enhanced bacterial growth compared with wild-type controls. In contrast, knockout mice lacking the genes for the TNF-alpha p55/p75 receptors or inducible nitric oxide synthase not only developed comparable bacterial loads to wild-type animals, they also failed to display the splenomegaly and profound suppression of mitogen-induced lymphocyte proliferative responses evident in infected wild-type controls. Thus, M. avium is clearly distinct from other intracellular pathogens (e.g., Leishmania monocytogenes, Toxoplasma gondii, and Mycobacterium tuberculosis) whose initial replication in the host is tightly controlled by Th1-dependent effector mechanisms. Instead, the major effect of host cell-mediated immunity is to limit bacterial growth during the chronic phase of infection. Surprisingly, inducible nitric oxide appears to be more important for the immunopathology than for the host resistance induced by this bacterial pathogen.

Animals↗
PubMed1997

Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii.

The induction by IFN-gamma of reactive nitrogen intermediates has been postulated as a major mechanism of host resistance to intracellular pathogens. To formally test this hypothesis in vivo, the course of Toxoplasma gondii infection was assessed in nitric oxide synthase (iNOS)-/- mice. As expected, macrophages from these animals displayed defective microbicidal activity against the parasite in vitro. Nevertheless, in contrast to IFN-gamma-/- or IL-12 p40-/- animals, iNOS-deficient mice survived acute infection and controlled parasite growth at the site of inoculation. This early resistance was ablated by neutralization of IFN-gamma or IL-12 in vivo and markedly diminished by depletion of neutrophils, demonstrating the existence of previously unappreciated NO independent mechanisms operating against the parasite during early infection. By 3-4 wk post infection, however, iNOS knockout mice did succumb to T. gondii. At that stage parasite expansion and pathology were evident in the central nervous system but not the periphery suggesting that the protective role of nitric oxide against this intracellular infection is tissue specific rather than systemic.

Acute Disease↗
PubMed1997

Role of natural killer cells in innate resistance to protozoan infections.

Natural killer cells are now recognized as major effectors of innate resistance to protozoan parasites. The principal mechanism by which they control the growth of these pathogens is indirect, involving cytokine production rather than cytolytic activity. Recent studies have identified a series of positive and negative signals provided by cytokines and cellular interactions which regulate protozoa-induced natural killer cell function.

Animals↗
PubMed1997

Critical roles for the Bcl-3 oncoprotein in T cell-mediated immunity, splenic microarchitecture, and germinal center reactions.

Chromosomal translocations of bcl-3 are associated with chronic B cell lymphocytic leukemias. Previously, we have shown that Bcl-3, a distinct member of the I kappa B family, may function as a positive regulator of NF-kappa B activity, although its physiologic roles remained unknown. To uncover these roles, we generated Bcl-3-deficient mice. Mutant mice, but not their littermate controls, succumb to T. gondii owing to failure to mount a protective T helper 1 immune response. Bcl-3-deficient mice are also impaired in germinal center reactions and T-dependent antibody responses to influenza virus. The results reveal critical roles for Bcl-3 in antigen-specific priming of T and B cells. Altered microarchitecture of secondary lymphoid organs in mutant mice, including partial loss of B cells, may underlie the immunologic defects. The implied role of Bcl-3 in maintaining B cells in wild-type mice may related to its oncogenic potential.

Animals↗
PubMed1997

Cytokine regulation of schistosome-induced granuloma and fibrosis.

Schistosomiasis mansoni, a major cause of hepatic fibrosis in many developing countries, triggers a granulomatous inflammatory reaction in response to its eggs that lodge in the liver. The egg antigens are eliminated slowly, and the persistent granulomatous response leads to prolonged matrix synthesis and hepatic fibrosis. In mice, soluble egg antigens (SEA) induce interleukin 4 synthesis, promoting a dominant T helper type 2 lymphocyte accumulation with the release of additional cytokines (IL-5, IL-10), which not only suppress Th1 lymphocyte subset cytokines, but mediate the characteristic pathophysiology. Manipulation of the cytokine profile with antagonists or exogenous cytokine delivery alters the course of the hepatic inflammation and fibrosis. In the evolution of the granulomatous response to the S. mansoni eggs, transforming growth factor beta (TGF-beta) is also produced that may modulate inflammation and regulate fibrogenesis. In TGF-beta 1-gene targeted mutant mice that over-express TGF-beta 1 (TGF-beta 1 transgenics) or in which TGF-beta 1 has been inactivated (TGF-beta 1-/-; null mutation) or partially inactivated (TGF-beta 1+/-; null mutation heterozygotes), the altered production of TGF-beta 1 impacts on S. mansoni granuloma and hepatic fibrosis. In addition to the Th1/Th2 cytokine balance, modulation of TGF-beta 1 may change the outcome of chronic inflammatory fibrotic disease.

Animals↗
PubMed1997

The indications for polysomnography and related procedures.

This paper is a review of the literature on the use of polysomnography in the diagnosis of sleep disorders in the adult. It is based on a search of MEDLINE from January 1966 through April 1996. It has been reviewed and approved by the Board of Directors of the American Sleep Disorders Association and provides the background for the accompanying ASDA Standards of Practice Committee's Parameters for the Practice of Sleep Medicine in North America. The diagnostic categories reviewed are: sleep-related breathing disorders; other respiratory disorders; narcolepsy; parasomnias and sleep-related epilepsy; restless legs syndrome and periodic limb movement disorders: insomnia; and circadian rhythm sleep disorders. Where appropriate, previously published practice parameters papers are cited and discussed. The relevant published peer-reviewed literature used as the basis for critical decisions was compiled into accompanying evidence tables and is analyzed in the text. In the section on the assessment of sleep apnea syndrome, options for estimating pretest probability to select high risk patients are also reviewed. Sleep-testing procedures other than standard polysomnography are also addressed (daytime polysomnography, split-night studies, oximetry, limited full respiratory recordings, and less-than-full respiratory recording) and treatment-related follow-up studies are discussed.

Adult↗
PubMed1997

Developmental differences determine larval susceptibility to nitric oxide-mediated killing in a murine model of vaccination against Schistosoma mansoni.

A persistent paradox in our understanding of protective immunity against Schistosoma mansoni infection in animals vaccinated with attenuated parasites has been that attrition of challenge parasites occurs during migration through the lungs in vivo, although parasites recovered from the lungs appear to be relatively resistant to cytotoxic effector mechanisms in vitro. We have compared the susceptibilities of different stages of larvae to killing by nitric oxide (NO), which was previously shown to be involved in the larvicidal function of cytokine-activated cytotoxic effector cells. Lung-stage larvae obtained 1 week after infection were not killed in vitro by NO generated either by a chemical NO donor or by activated cells. In contrast, parasites obtained from the portal system of control mice or from the lungs of vaccinated mice 2.5 weeks following challenge infection were killed by NO. As previously shown for mammalian cell targets, the effects of NO in susceptible larval stages may involve enzymes required for aerobic energy metabolism, since similar cytotoxicity was demonstrated by chemical inhibitors of the citric acid cycle or mitochondrial respiration. Taken together with previous observations of enhanced Th1 activity and expression of NO synthase in the lungs of vaccinated mice at 2.5 weeks after challenge infection, these observations elucidate the immune mechanism of vaccine-induced resistance to S. mansoni infection. Moreover, they suggest that conversion to a less metabolically active state may allow pathogens to escape the effects of the important effector molecule NO.

Age Factors↗
PubMed1997

Unimpaired down-modulation of the hepatic granulomatous response in CD8 T-cell- and gamma interferon-deficient mice chronically infected with Schistosoma mansoni.

The granulomatous response to schistosome eggs is a CD4 T-cell-dependent, Th2-cytokine-dominated immunopathologic response. As infection proceeds to chronicity, both granuloma formation and egg-induced cytokine production become downregulated, and previous experiments have implicated CD8 T cells in this process. One mechanism by which CD8 T cells could suppress immunopathology is through the production of the counterregulatory cytokine gamma interferon (IFN-gamma), but no in vivo evidence exists to directly support this hypothesis. In this study, we analyzed hepatic granuloma formation and egg-induced cytokine production in Schistosoma mansoni-infected gene knockout mice deficient in either CD8 lymphocytes or IFN-gamma. Surprisingly, we found that neither immunologic component plays an essential function in the control of granuloma and cytokine responses during either the acute or chronic stage of infection. Thus, other mechanisms may be more important in the regulation of immunopathology in schistosomiasis.

Animals↗
PubMed1997

Dual-energy X-ray absorptiometry predicts bone formation in lower limb callotasis lengthening.

The rate of regenerate bone mineral content (BMC) acceleration was studied using dual-energy X-ray absorptiometry (DEXA) in callotasis lengthening of the lower limb. Eleven youngsters (age range 5-17 years) undergoing callotasis lengthening for congenital, post-traumatic or post-infective conditions were studied longitudinally. Patients were initially scanned once a week until completion of the lengthening phase, and at 2-week intervals thereafter until removal of the fixator. They were subsequently followed up at regular intervals on an outpatient basis for up to 2 years after removal of the fixator (average, 14 months). The BMC accretion slopes exhibited by the patients and the rate of new bone formation allowed the identification of three groups. In the fast formation group, the rate of new bone formation was 0.3-0.6% per day. In the moderate formation group the rate of new bone formation is 0.1-0.3% per day, while in the poor formation group the rate of new bone formation is < 0.1% per day. From the analysis of time graphs, a direct correlation emerged between early bone formation and subsequent bone mineral content accretion. Measurement of BMC during callotasis lengthening in the lower limb allows precise monitoring of the process. It may prove useful to prevent complications occurring after removal of the fixator at an unduly early stage, such as plastic deformation and fracture through the regenerate bone. It may be used to predict the bone formation rate in a given patient, and to implement measures to try to influence it.

Absorptiometry, Photon↗
PubMed1997

Change of foot size with weightbearing. A study of 2829 children 3 to 18 years of age.

The change of foot length and width with age has been reported in a few anthropometric studies in the literature. However, the relationship with body height rarely is reported, and the dynamic effect of weightbearing on foot size has not been documented. In this series, 2829 children 3 to 18 years of age of equal gender distribution were included in the study. The foot length and width on weightbearing and nonweightbearing were measured with a special precision electronic caliper. The foot length and width were found to increase linearly from the age of 3 years until 12 years in girls and 15 years in boys. This was followed by a phase during which the increase plateaued. The foot length and width increased significantly on weightbearing at all ages in both genders with a mean of 2.1 to 4.4 mm or 3.1% to 4.8%, respectively. The foot length and width also were found to correlate significantly with the body height in both genders, with a correlation coefficient of 0.96 to 0.98. No significant differences were found between the sizes of the dominant and nondominant foot in either gender.

Adolescent↗
PubMed1996

Genes for chemokines MuMig and Crg-2 are induced in protozoan and viral infections in response to IFN-gamma with patterns of tissue expression that suggest nonredundant roles in vivo.

MuMig and Crg-2 are IFN-inducible murine chemokines whose human homologues, HuMig and IP-10, respectively, share activity in vitro as T cell chemoattractants. We analyzed the expression of the genes Mumig, crg-2, and IFN-gamma during experimental infections with Plasmodium yoelii, Toxoplasma gondii, and vaccinia virus. Mumig, crg-2, and IFN-gamma were induced in multiple organs. During the acute phase of each infection as well as after i.p. injection of rIFN-gamma, levels of Mumig mRNA in the liver were as high or higher than levels in any of the other organs. In contrast, the organs showing the highest expression of crg-2 and IFN-gamma varied among the experimental models, with induction of these latter two genes colocalizing. Differences in relative levels of expression of Mumig and crg-2 in liver and spleen were not demonstrably due to expression of the genes in different cell types within these organs. We showed that both Mumig and crg-2 are induced in the liver in hepatocytes and in the spleen in CD11b+ cells. IFN-gamma was necessary for induction of Mumig during infections with T. gondii or vaccinia virus. In contrast, induction of crg-2 was not completely dependent on IFN-gamma. These data demonstrate that despite the overlap in activities within chemokine subsets, chemokine genes show differences in their patterns of expression and in their responses to inducers that suggest nonredundant roles in vivo. Moreover, the pattern of induction of crg-2 is consistent with Crg-2 acting primarily locally, while the pattern for Mumig induction suggests that MuMig may have a systemic role during infection.

Animals↗
PubMed1996

In the absence of endogenous IFN-gamma, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection.

The relationship between IFN-gamma and IL-12 in generating innate immune responses and resistance to acute Toxoplasma gondii infection was assessed in T. gondii-exposed IFN-gamma knockout (gko) mice. Gko mice, in contrast to wild-type (wt) animals, rapidly succumbed to infection with either the avirulent ME49 strain or, surprisingly, an attenuated temperature-sensitive mutant strain, ts4. Microscopic examination of peritoneal exudates from infected gko mice demonstrated that mortality is associated with unchecked tachyzoite replication. Nevertheless, both wt and gko animals developed a peritoneal inflammatory response that in gko animals was greater due to a 5- to 10-fold increase in the number of granulocytes recruited to the site of infection. In addition, IL-12 production in gko mice was both unimpaired and functional since a significant, albeit lower than wt, IL-12-dependent NK cell response developed in these animals. Regardless, no evidence for an IFN-gamma-independent protective function for IL-12 or NK cells was apparent since in vivo treatment of gko mice with an IL-12-neutralizing mAb ablated the NK cell response, but did not decrease survival. Together, these data identify distinct functions for IL-12 and IFN-gamma in host resistance to T. gondii: IL-12 precedes and initiates synthesis of IFN-gamma, while the latter lymphokine directly controls parasite growth and diminishes the contribution of IL-4- and IL-5-producing T cell subsets.

Animals↗
PubMed1996

IL-12 enhances vaccine-induced immunity to schistosomes by augmenting both humoral and cell-mediated immune responses against the parasite.

The production of Th1-type cytokines is associated with strong cell-mediated immunity, while Th2-type cytokines typically dominate humoral immune responses. In mice vaccinated a single time with attenuated cercariae of Schistosoma mansoni, the protection induced is associated with Th1 cytokine-dependent, cell-mediated immunity. In contrast, mice vaccinated multiple times display a more Th2-type dominant cytokine response and develop Ab-dependent resistance. We have previously shown that IL-12 enhances cell-mediated immunity in singly vaccinated mice. In the present study, we asked what effects administering IL-12 as an adjuvant would have on the development of a protective humoral response in multiply immunized animals. We found that multiply immunized/IL-12-treated mice displayed a marked increase in resistance to challenge infection, with some animals demonstrating complete protection. The IL-12-vaccinated mice developed strongly polarized Th1 responses but, importantly, also showed significant increases in parasite-specific Ab and, in particular, IgG2a, IgG2b, and IgG1 isotypes. Passive transfer demonstrated an enhanced ability of serum from these animals to protect naive recipients. In addition, animals vaccinated in the presence of IL-12 also developed macrophages with increased nitric oxide-dependent killing activity against the parasites. Together, these data demonstrate that IL-12, initially described as an adjuvant for cell-mediated immunity, may be used to simultaneously to promote both humoral and cell-mediated protective responses against infection.

Animals↗
PubMed1996

Functional diversity of helper T lymphocytes.

The existence of subsets of CD4+ helper T lymphocytes that differ in their cytokine secretion patterns and effector functions provides a framework for understanding the heterogeneity of normal and pathological immune responses. Defining the cellular and molecular mechanisms of helper-T-cell differentiation should lead to rational strategies for manipulating immune responses for prophylaxis and therapy.

Animals↗
PubMed1996

An IL-12-based vaccine approach for preventing immunopathology in schistosomiasis.

Schistosomiasis is a major parasitic disease of developing countries. Pathology in schistosome infection is caused by the host granulomatous response to parasite eggs deposited in the tissues and the ensuing fibrosis. Previous work established that Th2 CD4+ cells play a major role in expanding granulomatous lesions and in fibrosis in murine models. We have used IL-12 both therapeutically to downmodulate this response and as an adjuvant with egg antigens to prevent pathology after subsequent parasite challenge. These effects appears to rely on the induction of IFN-gamma by the injected IL-12. Interestingly, while IL-12 treatment or vaccination downregulates most egg-specific Th2 cytokine responses, IL-10 production in vivo is enhanced. Because we have also shown that IL-12 can be used as an adjuvant to augment protective immunity against this helminth, it may be possible to design a combined parasite Ag/IL-12 vaccine which both limits infection and blocks the tissue pathology caused by eggs of worms escaping the resistance mechanisms evoked by immunization. At a more general level, our results demonstrate the potential of IL-12-based vaccine strategies to block Th2-dependent disease processes including allergy.

Adjuvants, Immunologic↗