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The in vivo immunological events in dextran sulfate sodium (DSS) -induced colitis were evaluated. Rats were fed water (control) or 5% DSS. Colonic sections were assessed by light microscopy, Gram stain, immunohistochemistry, and electron microscopy. A progressive decline in number and increase in fragmentation of bacteria in the colonic lumen was observed over time. Luminal bacteria were the first to show heat shock protein 60 (HSP60) staining (day 3). Macrophages in close proximity to these bacteria were next to show such staining (day 6), and finally the damaged epithelial cells when colitis became severe (day 15). Ultrastructural assessment showed cell-cell contact interactions between macrophages and dendritic gammadelta T cells. An increase in the number of gammadelta T cells and ED1-positive macrophages in the affected colonic tissue over time was documented. These results suggest colonic bacteria, host macrophages, and gammadelta T cells play specific roles in the immunological reactions in DSS-induced colitis, possibly via an HSP60-mediated mechanism.

Captive great egret (Ardea albus) nestlings were maintained as controls or were dosed with methylmercury chloride at low (0.5), and high doses (5 mg/kg, wet weight) in fish. Low dosed birds were given methylmercury at concentrations comparable to current exposure of wild birds in the Everglades (Florida, USA). When compared with controls, low dosed birds had lower packed cell volumes, dingy feathers, increased lymphocytic cuffing in a skin test, increased bone marrow cellularity, decreased bursal wall thickness, decreased thymic lobule size, fewer lymphoid aggregates in lung, increased perivascular edema in lung, and decreased phagocytized carbon in lung. High dosed birds became severely ataxic and had severe hematologic, neurologic, and histologic changes. The most severe lesions were in immune and nervous system tissues. By comparing responses in captive and wild birds, we found that sublethal effects of mercury were detected at lower levels in captive than in wild birds, probably due to the reduced sources of variation characteristic of the highly controlled laboratory study. Conversely, thresholds for more severe changes (death, disease) occurred at lower concentrations in wild birds than in captive birds, probably because wild birds were exposed to multiple stressors. Thus caution should be used in applying lowest observed effect levels between captive and wild studies.

I mmunological responses are considered to be either humoral, resulting from cloning of B lymphocytes, or cell mediated, resulting from cloning of T lymphocytes. Autoimmune diseases occur when the cloned products attack host tissue. Inflammation is considered a nonspecific response to injury, characterized by exudation of serum into damaged tissue, and identified by the cardinal signs of rubor, calor, dolor, and tumor. However, these classic mechanisms do not fit pathological observations of Alzheimer disease (AD)-affected brain tissue. Although many of the components prominently associated with peripheral immunological and inflammatory states are present in AD lesions, there are no identifiable B lymphocytes or antibodies, and T cells are sparse. Furthermore, the blood-brain barrier is intact, excluding exudation of exogenous serum proteins. Although "neuroinflammation" is the term commonly used to describe the pathological changes, it fails to define adequately the process that is taking place. The reaction is neither a nonspecific response to injury, as classically implied for inflammatory reactions, nor an autoimmune reaction, despite the directed attack against plaques and extracellular tangles. It is most appropriately defined as an innate immunoreaction. The fact that such a reaction can be mounted by brain, an organ frequently described as being immunologically privileged, suggests that a reevaluation is required of the dimensions of the innate immune system, including how it operates at the tissue level. The innate immune system is primitive, while the adaptive immune system, which is directed by peripheral immune organs, is an invention of vertebrates. Even in vertebrates, however, the innate immune system is the first line of defense. Much more needs to be learned about the operation of the innate immune system in health and disease. Arch Neurol. 2000.

Immune changes and their relationships in a frail elderly population (N=116, age 70-103, median 86 years) were defined in comparison to a healthy younger group. Previous immune studies in the elderly have generally focused on one or few parameters without correlation analyses. Furthermore, the study populations have been active elderly in relatively small numbers. A total of 33 immune parameters representing many aspects of the immune system were quantified. Most changes in the frail elderly were parallel to those reported in active elderly. A classification tree analysis revealed that increased plasma activation markers (neopterin and sTNF-R) and increased CD28 expression on CD8 T cells and proliferative response separated the aged and control populations. Statistical procedures utilizing principal components analyses, partial correlations and exploratory factor analyses all indicated that immunologic parameters in frail elderly are grouped in three major clusters of immunologic results. These involved (a) increased plasma levels of neopterin and sTNF receptor indicating elevated IFNgamma and TNF cytokine activity; (b) increased proportion of mature (CD45RO) versus naïve (CD45RA) T cells; and (c) a diverse group of related changes including impaired proliferative response, reduced T cells, CD28 and CD25 expression, B cell percentage and lower CD4:CD8 ratios and increased HLA-DR expression. These findings emphasize that several different groups of immune parameters but not 33 independent immune changes, occurred in the aged population.

Toxicologic pathology is crucial in the identification and characterization of health effects following exposure to xenobiotics, mainly in toxicity experiments in rodents. Regarding regulatory toxicology, histopathology of lymphoid organs and tissues is a cornerstone in the identification of immunotoxic compounds. A 2-tier testing system is usually employed in which the first tier is a general screen for (immuno)toxicity and the second tier consists of specific immune function studies, including host resistance tests or mechanistic studies. The role attributed to histopathology of lymphoid organs in the updated Organisation for Economic Cooperation and Development and Food and Drug Administration guidelines requires improvement and standardization of the histopathology procedures. Optimalization and standardization was started in an international collaborative immunotoxicity study (ICICIS). However, several problems were left unaddressed, mostly because of the few compounds tested in this study. Based on the results of the ICICIS study and the morphologic changes induced by immunotoxic/immunomodulatory compounds observed in other investigations, suggestions are given to further improve the identification and (semi)quantification of histopathologic changes in lymphoid organs and tissues.

Multiple organ failure (MOF) may occur early or late after trauma. Besides direct physical injury of organs, compromise of the microcirculation by inflammation plays an important role in the pathogenesis of MOF. Inflammation also induces counterregulatory responses which may end up in immunoparalysis. As a result, infection and sepsis with additional inflammatory damage to the microcirculation ensue thereby contributing to the late development of MOF. In addition to this biphasic model of posttraumatic MOF, there is evidence that inflammation and immunoparalysis do not only occur in sequence to each other but in parallel early after surgical procedures. The aim of the present brief review is to summarize the posttraumatic mechanisms of inflammation and immunoparalysis and to discuss how to differentiate between both pathophysiologic states.

Three categories of immunotoxic effects are identified: direct immunotoxicity, hypersensitivity, and autoimmunity. Direct immunotoxicity consists of immunosuppression and immunostimulation. Total abrogation of the immune response (immunosuppression) results in more frequent, severe, and often atypical and relapsing infections and lymphomas. Immunostimulation is associated with febrile reactions, the induction/facilitation of autoimmune diseases and allergic reactions to unrelated allergens, and impaired hepatic drug biotransformation. Hypersensitivity is manifested by a variety of symptoms involving either antigen-specific or non-antigen-specific humoral and cellular adverse responses. Autoimmune reactions are divided into organ-specific and systemic reactions. Because of the involvement of many redundant mechanisms, it is difficult to predict responses of the immune system to a given immunotoxic injury. In laboratory animals, histologic but also functional changes are necessary to show evidence of and to predict such adverse responses.

The rapid advances in the field of immunology and an understanding of the potential adverse effects of xenobiotics on the immune system have resulted in the development of a discipline in toxicology now referred to as immunotoxicology. This discipline has evolved steadily over the last 2 decades as a result of research in the national and international communities. Various US, European, and Japanese regulatory agencies have recognized a need to promulgate testing guidelines for immunotoxicity in support of the approval process involving toxicological testing. The US Food and Drug Administration "Redbook II" guidelines and some of the research conducted in support of the concepts and testing strategies are presented here. Concerns raised with regard to these guidelines are included, as are on-going initiatives in development of experimental approaches for assessing allergic potential and/or hypersensitivity responses to new foods and food constituents.

Neutrophils have a crucial function in the defense against bacteria and fungi. Indeed, during chronic, severe neutropenia and in case of severe neutrophil dysfunctions, the patients may suffer recurrent and sometimes life-threatening infections. This article describes the clinical symptoms, the theory behind the antimicrobial systems of neutrophils, the methods to diagnose the various aberrations, and the possibilities for treating these patients. A few of the most common causes of neutropenia and neutrophil dysfunctions are described in detail, including recent genetic information regarding the cause of these diseases.

Morphofunctional aspects of the immune system (spleen, Peyer's patches, peripheral blood) were studied in patients with essential hypertension, rheumatic lesions of the heart and rheumatic patients after surgery. Surgical intervention caused considerable immunodepression. The entire system of coordinated functioning of immune organs got impaired. Immunodepressive restructuring of lymphoid organs affects all the structural units. Changes of the vascular-stromal complex are accompanied by changes in the most sensitive and complex mechanisms of the immune system such as vascular endothelium and population of progenitor cells. Metabolic basis transport and synthesis in the endothelium are perversed. In the progenitor cells proliferative activity of lymphocytes was sharply decreased while there was an increase in the function of suppressor T-lymphocytes. It is concluded that desynchronization of enzyme functioning in the vascular component of both the spleen and lymphoid system of the intestine can be regarded as a sign of disintegration of the entire system of immune organs during stress caused by a surgical intervention.

Viral myocarditis is an important cause of heart failure and dilated cardiomyopathy. T lymphocytes are implicated in myocardial damage in murine models of coxsackievirus B3 (CVB3) myocarditis. We used knockout mice lacking CD4 (CD4(-/-)), CD8 (CD8(-/-)), both coreceptors (CD4(-/-)CD8(-/-)), or the T-cell receptor beta chain (TCRbeta(-/-)) to address the contribution of T-cell subpopulations to host susceptibility to CVB3 myocarditis. Severity of disease was magnified in CD8(-/-) mice but attenuated in CD4(-/-) mice, consistent with a pathogenic role for CD4(+) lymphocytes. Elimination of both CD4 and CD8 molecules from T lymphocytes by genetic knockout better protected mice from myocarditis, demonstrating that both CD4(+) and CD8(+) T cells contribute to host susceptibility. The same benefit occurred in TCRbeta(-/-) mice, with prolonged survival and minimal myocardial disease observed after CVB3 infection. Elevated interferon-gamma and decreased tumor necrosis factor-alpha expression are associated with attenuated myocardial damage in CD4(-/-)CD8(-/-) mice. These results show that the presence of TCRalphabeta(+) T cells enhances host susceptibility to myocarditis. The severity of myocardial damage and associated mortality are dependent on the predominant T-cell type available to respond to CVB3 infection. One mechanism by which CD4(+) and CD8(+) T-cell subsets influence the pathogenesis of myocarditis may involve specific cytokine expression patterns.

In an extended OECD 407 study protocol, including immune parameters, male Riv:Tox Wistar SPF rats were treated for 35 days with benzo[a]pyrene (B[a]p) (3, 10, 30, or 90 mg/kg body weight) by gavage. Oral administration of B[a]p in rats resulted not only in general toxicity, as indicated by the effects on body weight, but also in immunotoxicity, as indicated by the effects on bone marrow, thymus, spleen, and lymph nodes. Oral B[a]p induced a dose-related decrease in thymus weight (at 10, 30, and 90-mg/kg). Lymph node weights (popliteal, mandibular, and mesenteric) were decreased in the 90-mg/kg rats only. Histologically, indications for cortical atrophy were noted in the thymuses of the 30- and 90-mg/kg dose groups, which was confirmed by morphometric analysis. Nucleated spleen and bone marrow cell counts were decreased in the 90-mg/kg group. Both the absolute number (90 mg/kg) and relative number (10, 30, and 90 mg/kg) of B cells in the spleen were decreased. Red blood cell (RBC) and white blood cell (WBC) counts were significantly decreased; for the WBC at 90 mg/kg, and for the RBC at 10, 30, and 90 mg/kg. The absolute number of lymphocytes and eosinophilic granulocytes was decreased in the 90-mg/kg group, while the absolute number of monocytes was increased in the 10- and 30-mg/kg dose groups. Serum immunoglobulin levels showed a decrease of IgM and IgA after treatment of the animals with 30 and 90 mg/kg, respectively. The highest dose of B[a]p treatment (90 mg/kg) resulted in a significant decrease of natural killer (NK)-cell activity in the spleen. Most toxic effects were only observed in the highest-dose group (90 mg/kg), but compared to the general toxicity, some parameters indicating immunotoxic effects were also affected at lower doses (10 and 30 mg/kg). In conclusion, immunotoxicity of B[a]p can be detected using parameters of the immune system such as described in the recently updated OECD 407 guideline. In the present study thymus weight changed and spleen B-cell populations were affected at a dose of 10 mg/kg, a level where no overt general toxicity was noted.

Although the major action of racemic beta(2 )-agonists on the airways is relaxation of airway smooth muscle, these drugs have several other effects mediated through beta(2 )-adrenergic receptors expressed on other cell types. These additional actions of beta(2 )-agonists may contribute to the efficacy of beta(2 )-agonists in relieving asthma symptoms. beta(2 )-agonists inhibit plasma exudation in the airways by acting on beta(2 )-receptors on postcapillary venule cells. They inhibit the secretion of bronchoconstrictor mediators from airway mast cells and inhibit effects on release of mediators from eosinophils, macrophages, T-lymphocytes, and neutrophils. In addition, beta(2 )-agonists may have an inhibitory effect on the release of neuropeptides from sensory nerves. The effect of beta(2 )-agonists on mediator release from structural cells in the airways such as epithelial cells is uncertain. Despite all of these inhibitory effects on inflammatory cells in vitro, beta(2 )-agonists do not appear to reduce the chronic inflammation of asthma. Desensitization is more readily seen in inflammatory cells than in airway smooth muscle cells and may account for this discrepancy. Corticosteroids may increase expression of beta(2 )-receptors in inflammatory cells to overcome the desensitization in response to chronic beta(2 )-agonist exposure.

Haemophilus ducreyi, the causative agent of chancroid, produces a hemolysin, whose role in virulence is not well defined. To assess the possible role of hemolysin in pathogenesis, we evaluated its target cell range by using wild-type H. ducreyi 35000, nonhemolytic mutants with the hemolysin structural gene deleted, and isogenic strains expressing different amounts of hemolytic activity. The cytotoxicity of the various cell types was assessed by quantitating the release of lactate dehydrogenase into culture supernatants as a measure of cell lysis. In these experiments, human foreskin fibroblasts, human foreskin epithelial cells, and, to a lesser extent, HEp-2 cells were lysed by H. ducreyi hemolysin. Hemolysin also lysed human blood mononuclear cells and immune system cell lines including U937 macrophage-like cells, T lymphocytes, and B lymphocytes. In contrast, human polymorphonuclear leukocytes were not sensitive to hemolysin under the conditions tested. We also analyzed the effect of hemolysin on invasion of human epithelial cells and found that H. ducreyi strains expressing cloned hemolysin genes showed a 10-fold increase in invasion compared to the control strain. These data support the hypothesis that the H. ducreyi hemolysin is important in the pathogenesis of chancroid and may contribute to ulcer formation, invasion of epithelial cells, and evasion of the immune response.

In humans and experimental murine models enteroviruses, and in particular coxsackieviruses of group B (CVB), may induce chronic myocarditis associated with a persistent type of heart muscle infection. Persistent myocardial infection has been characterized by restricted viral replication and gene expression, which is capable of sustaining chronic inflammation. Altered replication and transcription of the virus, in addition to an immune response insufficient to recognize and clear infected cells entirely, are essential mechanisms for initiation and maintenance of persistent heart muscle infection. Viral cytotoxicity was found to be crucial for organ pathology both during acute and persistent infection, indicating that enterovirus myocarditis is a virus-induced rather than an immune-mediated disease. Notably, resistance to the development of persistent heart muscle infection is not linked to the H-2 haplotype of the host. In addition to persistently infected myocytes, detection of the replicative minus-strand RNA intermediate provided evidence for virus replication in lymphoid cells of the spleen, predominantly in splenic B lymphocytes, during the course of the disease. Whereas viral RNA was also detected in certain CD4+ helper T cells and Mac1+ macrophages, no enteroviral genomes were identified in CD8+ T cells. Detection of infected activated B lymphocytes both in heart tissue of CVB3-infected immunocompetent mice and syngenic SCID mice receiving splenocytes from CVB3-infected donors support the concept that B cell traffic may contribute to maintenance of chronic disease. Dissection of the diversity of viral and host-specific determinants in susceptible and resistant hosts will allow us to define the protective mechanisms that mediate resistance to the development of life-threatening acute and chronic enterovirus myocarditis.

Psoriasis is an immunologically mediated skin disease linked to several different class I major histocompatibility complex alleles. However, the phenotype of the pathogenic lymphocyte and nature of the T cell activating event which triggers conversion of symptomless (PN) skin into psoriatic plaques (PP skin) is unknown. This study extends our previous observations in which autologous blood-derived immunocytes were injected into PN skin engrafted onto SCID mice to produce full-fledged PP lesions. The first question addressed is whether injected CD4+ T cells or CD8+ T cells were responsible for phenotypic conversion of PN to PP skin. In five different patients only CD4+ but not CD8+ T cell lines produced psoriatic lesions. Next, immunological events occurring within PN skin following injection of CD4+ T cells in grafts that had sufficient tissue available for detailed analysis was examined. In two patients, intraepidermal resident CD8+ T cells were induced to proliferate during lesion development, expressing acute activation markers CD25 and CD69. In another patient, injection of CD4+ T cells revealed CD69 expression by intraepidermal CD4+ as well as CD8+ T cells. To explore the molecular basis for local T cell activation and proliferation, we discovered that intraepidermal immunocytes, including both CD4 and CD8+ T cells, expressed surface receptors (ie, CD94, CD158a, CD158b) typically confined to natural killer cells (ie, natural killer receptors; NKRs) accumulated immediately before onset of acute lesions. The presence of NKR bearing immunocytes was also observed in 10 of 15 different biopsies of chronic plaques taken directly from patients, whereas PN skin (n = 8) or normal skin from healthy donors (n = 8), did not contain such NKR positive immunocytes. Of particular relevance to psoriasis is that these NKRs recognize various class I alleles including those typically inherited by psoriatic family members such as HLA-C and HLA-B allotypes. We conclude that injection of CD4+ T cells into PN skin triggers a series of local immunologically mediated stimulatory events that produce further T cell activation and appearance of both CD4 and CD8+ T cells that express NKRs.

Reports on patients with hemiparalysis indicate the importance of the nervous system for the pathophysiology of rheumatoid arthritis (RA) or osteoarthritis (OA). Norepinephrine (NE) and opioids seem to be more antiinflammatory neurotransmitters whereas substance P is proinflammatory. The study aimed to investigate the direct noradrenergic nerve-immune cell interaction in human synovial membrane. We used a recently developed superfusion technique with electrical stimulation of synovial membrane to elicit local NE from synovial membrane slices. The readout parameter of synovial immune cells was interleukin-6 (IL-6). IL-6 was spontaneously secreted from RA and OA synovial membranes. Electrical field stimulation intensively reduced IL-6 secretion. In patients with OA or RA, this electrically induced reduction of IL-6 secretion was not significantly changed by alpha- or beta-adrenergic antagonists. The study demonstrates that local endogenous NE seem to play a minor role, which may be due to a depletion of NE or loss of noradrenergic fibers during chronic RA and OA.

A Trichinella spiralis infection produces an acute inflammatory reaction and tissue damage in the mucosa, and, in addition, functional changes occur in the external muscle layers. The aim of the present study was to characterize structural changes in the musculature that occur during early infection, and to identify relationships between immune cells and muscle cells, as part of an ongoing investigation into the immune modulation of motor function in the gut. Rats were infected with T. spiralis larvae and the gut fixed at 12 h, 24 h, 48 h and 6 days post-infection for electron microscopy of the longitudinal muscle. Macrophages and lymphocytes penetrated the longitudinal musculature 12-24 h post-infection. Distinct contacts were observed between specific cell types; cellular protrusions from macrophages or lymphocytes made close apposition contacts with smooth muscle cells. Resident macrophages in the subserosal space, fibroblast-like cells as well as smooth muscle cells showed marked activation during inflammation. Fibroblast-like cells were frequently seen intercalated between lymphocytes and smooth muscle cells, hence they may mediate communication between immune cells and the musculature.

An adult, castrated male llama was presented for evaluation of a chronic respiratory problem. Complete blood analyses indicated a leukopenia and hypoproteinemia. Radial immunodiffusion, bone marrow core, and lymph node biopsies supported a tentative diagnosis of juvenile llama immunodeficiency syndrome. This diagnosis was confirmed by postmortem findings.

An important observation in elderly subjects is their susceptibility to infection associated with a decline in host immune function. Nutrition is also an important factor that influences host defense against infection. We, therefore, evaluated the relationship between nutritional status in 155 healthy subjects ranging in age from 20 to 99 years and various immunological parameters, including the phagocytic and bactericidal activities of neutrophils and monocytes, superoxide production and chemotaxis of neutrophils, lymphocyte subsets, blastoid transformation and serum immunoglobulins. Aging was associated with increased phagocytic activity of neutrophils but not bactericidal activity, superoxide production or chemotaxis of neutrophils. Aging was also associated with a significant decrease in the number of lymphocytes as well as a decline in mature T cells and helper/inducer T cells but with increased numbers of activated T cells, suppressor T cells and natural killer cells. In addition, blastoid transformation in response to phytohemagglutinin (PHA) and concanavalin A (Con A) was significantly reduced in aged subjects. A poor nutritional status was noted in individuals 60 years of age or older. The nutritional status did not influence neutrophil function but correlated significantly with the number of lymphocytes and degree of blastoid formation with PHA and Con A stimulation. Our results suggest that the cell-mediated immunity in elderly subjects is reduced as a result of malnutrition, and that improvement of the nutritional status may enhance the immune function, likely contributing to their successful aging.

To obtain low and high parasite loads in the acute phase of Chagas' disease, A/J mice were infected with 10(3) or 10(5) Trypanosoma cruzi trypomastigotes of the Y strain and treated on day 6 with benznidazol. One year later, chronically infected mice were screened for subpatent parasitemias, tissue pathology, and immune response. Mice infected with the high parasite inoculum showed higher levels of chronic parasitemias, heart and striated muscle inflammation, and activation of the immune system than did mice infected with the low inoculum. Concerning the activation of the immune system, the main findings for high-dose-infected mice were (i) increased numbers of splenocytes, with preferential expansion of CD8(+) and B220(-) CD5(-) cells, many of them bearing a macrophage phenotype; (ii) higher frequencies of B (B220(+)), CD4(+), and CD8(+) large lymphocytes; (iii) a shift of CD4(+) cells towards a CD45RBLow phenotype; (iv) increased frequencies of both CD45RBLow and CD45RBHigh large CD4(+) cells; (v) augmented numbers of total immunoglobulin (Ig)-secreting cells, with predominance of IgG2a-producing cells; and (vi) increased production of gamma interferon and interleukin 4. In addition, these mice presented lower IgM and higher IgG2a and IgG1 parasite-specific serum antibody levels. Our results indicate that the parasite load at the acute phase of T. cruzi infection influences the activation of the immune system and development of Chagas' disease pathology at the late chronic phase of the disease.

The paper deals with a part of neuroimmunopathology which is concerned with the role of the pathologically altered nervous system in the pathology of the immune system and vice versa and considers disturbances in the interconnection of nervous and immune systems. Antibodies against neuromediators and nervous tissue can produce both pathogenetic and sanogenic effects depending on the neurotransmitter function or the nervous structure which they are specifically directed towards. The effects of systematically administered antibodies against nervous tissue and neuromediators demonstrate that antibodies can penetrate into the central nervous system (CNS). The adoptive transfer of the signs of a pathological condition by immunocytes from CNS abnormalities illustrates the role of the immune system in nervous diseases.

The studies demonstrated that gamma-radiation drastically enhanced destructive processes and suppressed the mitotic activity of lymphocytes in the thymus and spleen. This resulted in the altered morphological picture of immune organs: the inversion of layers occurred in the thymus, the splenic white pulp increased by three times, lymphoid nodules with germinating centers disappeared, the marginal area became thinner. Following gamma-radiation, restorative processes in the thymus and spleen were noticeable just on day 3 and 7, respectively. However, the cell composition of murine immune organs failed to achieve control values by day 60 after exposure. Examining the responses of respiratory and digestive lymphoid tissue to acetaldehyde and drinking water organisms indicated that as the concentration of an acting agent and the time of exposure increased, there was lymphocytopoietic inhibition in the lymphoid formations whereas its small doses activated a local immune response.

The mechanisms that lead to organ injury in hypertension are incompletely understood. In particular, there is a lack of evidence that serves to link the elevation of arterial blood pressure with end organ damage. Experimental models of hypertension have a range of microvascular abnormalities in addition to a shift in blood pressure. There is evidence for an oxidative stress in microvascular endothelium derived from xanthine and NADPH oxidase. Furthermore, there exists an immune suppression accompanied by abnormally elevated circulating leukocyte counts, depression of selectin membrane adhesion to the endothelium and enhanced cell apoptosis. Many of the deficiencies in the spontaneously hypertensive rats can be corrected by adrenalectomy, suggesting a contribution of glucocorticoids to the abnormalities in this model. These observations suggest a significantly enhanced vascular oxidative stress which is accompanied by a frustrated inflammatory response due to a glucocorticoid dependent deficiency of leukocyte adhesion to vascular endothelium.

Apoptosis is a special form of cell death, which can be triggered by a variety of signals and pathophysiological conditions, including oxidative stress. Activation of members of the caspase family of cysteine proteases is a crucial event in the apoptotic death program. Being cysteine proteases, the caspases are sensitive to the redox status of the cell, and their activity is blocked by excessive oxidative stress. Thus, alterations of intracellular redox status may either trigger or block the apoptotic death program, depending on the severity of the oxidative stress.

Background: Regardless of its involvement in either wound healing or excessive fibrosis, the interstitial fibroblast can now be considered an important early participant in inflammatory responses. Although it is recognized that certain immune cells and proinflammatory mediators are intricately linked to fibrotic disease, little is presently known about the manner in which these mediators and cells are orchestrated to a fibrotic finale. Experimental studies have shown that interstitial fibroblasts are capable of participating in an inflammatory response by promoting direct fibroblast-to-immune cell communication and/or modulating the release of soluble mediators that are mutually recognized by both types of cells., Methods: Primary cultures of murine fibroblasts were recovered from either normal tissue or tissue undergoing a cell-mediated inflammatory response. These stromal cells were assessed for the expression of various cytokines and chemokines indicative of a type 1 or type 2 response. In addition, the fibroblasts were co-cultured with mononuclear cells to assess the cell-to-cell communication., Results: Fibroblasts recovered from different cell-mediated inflammatory responses demonstrated a dramatic alteration in their cytokine profile. Fibroblasts recovered from the type 2 immune response produced high levels of monocyte chemotactic protein-1 (MCP-1), as compared to the normal fibroblasts and fibroblasts recovered from the type 1 lesion. Mononuclear cells co-cultured with fibroblasts induced a contact-dependent expression of elevated levels of chemokines, especially the macrophage-derived MIP-1 alpha. Thus, both fibroblasts themselves and fibroblasts co-cultured with immune-inflammatory cells have the ability to participate in the maintenance of an inflammatory response via the expression of chemokines., Conclusions: Our laboratory and others have addressed the role of chemotactic cytokines or chemokines in the fibrotic process, and have demonstrated that fibroblasts are capable of modulating the activation of various immune cells that have been implicated in fibrotic disease. In addition, the interstitial fibroblast is capable of regulating its own behavior within the interstitial environment via the expression of chemokines and chemokine receptors. Thus, novel strategies aimed at preventing fibrotic disease will likely need to address the early engagement of inflammatory cells by fibroblasts, and possibly modulate the ability of fibroblasts to generate and/or recognize profibrotic signals supplied by chemokines.

During the past year several novel reports have added new knowledge to our understanding of the pathogenesis of system lupus erythematosus (a) a novel pathway for the presentation of autoantigens to autoreactive T cells was revealed. Universally binding nucleosomal epitopes are productively recognized by autoreactive T cells by binding to the T-cell receptor-alpha chain; (b) circulating T cells from patients with lupus commonly display a deficiency of the T-cell receptor zeta chain, and upon ligation of their cell-surface antigen receptor overproduce tyrosine phosphorylated proteins; (c) lupus and lupus nephritis are associated with a low-binding FcgammaRIIIA (CD16) polymorphism that crosses ethnic barriers; (d) the pathogenetic role of the cytokine interleukin-10 is expanding, because it is reportedly overproduced not only by cells from lupus patients but also by cells from their healthy relatives, and its overproduction in vitro is correlated with increased apoptotic cell death and with lymphopenia.

The aim of the study was to find out whether an extended subacute toxicity study (additional organ weights, histopathology and immune functional tests), routinely employed in testing of chemicals, would shown indications of (adverse) effects on the immune system below general toxicity. Therefore, a five laboratory ring study on the basis of an oral 28-day repeated dose study in rats (OECD guideline 407) was carried out with 1, 5 and 25 mg/kg of cyclosporin A (CsA) per day by gavage. Besides some toxic effects such as reduced body weight gain and increased kidney calcification in the high-dose group, the results of the additional pathologic examinations revealed that CsA caused a pattern of specific morphological alterations of the lymphoid tissues in mid- and high-dose groups. Selected immune parameters such as immunoglobulin determination, plaque-forming assay, flow cytometry, activation status of macrophages and natural killer cells (NK), and proliferative response of spleenocytes and cells from mesenteric lymph nodes (concanvalin A (ConA) and pokeweed mitogen (PWM) stimulation) were also investigated. Some results compared to the controls revealed alterations down to the low-dose group. The extended methodology consistently indicated the potential detection of effects on the immune system below general systemic toxicity. The study will be continued by investigating a second compound with primarily immunostimulating effects. Results from those studies should further contribute to the current discussion of up-dating of repeated dose toxicity guidelines with respect to immunotoxicity.

It was found out, that immunomodulative action of low frequency acoustic oscillations (LFAO) is mediated in mice by enhancement or decreasing of distinct stages of immunogenesis. Exposure to this factor at intensity of 80 dB varied number of cells in lymphoid organs, enhanced cell proliferation, improved cooperative interaction of thymocytes and bone marrow cells in immune response, caused increase of allogenic stem cells inactivation. On the contrary, exposure to LFAO at the acoustic pressure of 130 dB caused alternative effects, as inhibition of immunocompetent cells in interaction.

In experimental autoimmune encephalomyelitis (EAE) inflammatory cells cross the endothelial blood-brain barrier (BBB) and gain access to the central nervous system (CNS). Here we show that E- and P-selectin are not involved in the recruitment of inflammatory cells across the BBB. Neither expression of E- nor P-selectin is induced in BBB-forming endothelium at any time after initiation of EAE. Some of the inflammatory cells present in the CNS during EAE express ligands for E- or P-selectin. However, anti-E- and P-selectin antibodies influence neither immigration of inflammatory cells across the BBB nor the development of EAE. In general, suppression of E- and P-selectin expression on BBB endothelium is dependent on factors derived from the CNS microenvironment, eg, astrocytes. Our results suggest that during EAE suppression of E- and P-selectin expression on the BBB provides a CNS-specific mechanism to reduce leukocyte recruitment into the CNS.

The toxicity and carcinogenicity of hexavalent chromium (Cr) in animal and human models are reviewed. The focus of this review is not on the well-established fact that hexavalent Cr compounds of low and high water solubility can induce respiratory cancers, but rather this review addresses other types of cancers induced by exposure to hexavalent Cr compounds. Additionally, non-cancer endpoints are also discussed with documentation of human and animal studies showing non-cancer health effects of hexavalent Cr exposure on the respiratory system, GI system, immune system, liver, and kidney. There is an emerging understanding that because hexavalent chromate is isostructural with phosphate and sulfate, it is readily taken up by the G.I. tract and penetrates to many tissues and organs throughout the body. This is supported by animal studies and experiments using human volunteers. From the epidemiological studies, there is suggestive evidence that hexavalent Cr causes increased risk of bone, prostate, lymphomas, Hodgkins, leukemia, stomach, genital, renal, and bladder cancer, reflecting the ability of hexavalent chromate to penetrate all tissues in the body. A high accumulation of Cr(III) in all tissues and organs is a strong indication of the wide toxic potential of exposure to soluble hexavalent Cr in the drinking water and in the ambient environment.

The aim of this article is to provide an up-dated overview of the available information on the role played by tachykinins in recruiting/regulating the function of immune/inflammatory cells, an issue which has received considerable input from the recent availability of potent and selective antagonists for tachykinin receptors. It appears that NK1 receptors play a role in mediating the extravascular migration of granulocytes into inflamed tissues in response to various inflammatory stimuli, although this effect may not be due to the expression of NK1 receptors by granulocytes themselves. Several data also imply a role for NK1 and NK2 receptors in regulating immune function. No data are available to suggest the expression of NK3 receptors by inflammatory/immune cells. Mast cell degranulation by substance P appears to be a non-receptor dependent response which may take place in vivo during intense stimulation. An emerging concept in the field relates to the ability of certain immune cell types to synthesize and possibly release tachykinins. Immune cells could represent an additional source of tachykinins in inflamed tissues, providing a non-neurogenic tachykininergic contribution to the local inflammatory process.

Background & Aims: Changes in innervation pattern and neuropeptide content have been shown in chronic pancreatitis (CP), including increased neuronal expression of growth-associated protein 43 (GAP-43). We used GAP-43 as an established marker of neuronal plasticity and correlated histological findings with pain scores of patients with CP., Methods: In tissue samples from 29 patients with CP, the parenchyma-fibrosis ratio, degree of perineural immune cell infiltration, and neuronal GAP-43 immunoreactivity were determined by digitized morphometry and correlated with individual pain scores., Results: In CP, GAP-43 was significantly increased in pancreatic nerve fibers and intrinsic neurons. GAP-43 expression correlated with individual pain scores. The infiltration of pancreatic nerves by immune cells was significantly correlated with the intensity of pain. Pain scores correlated neither with the degree of pancreatic fibrosis nor with the duration of the disease., Conclusions: The results suggest that infiltration of pancreatic nerves by immune cells and neuronal plasticity are pathogenic factors for the generation of pain, whereas the degree of pancreatic fibrosis has no major impact on pain in CP.

Chronic exposure to jet fuel has been shown to have adverse effects on human liver function, to cause emotional dysfunction, to cause abnormal electroencephalograms, to cause shortened attention spans, and to decrease sensorimotor speed (3-5). Due to the decision by the United States Air Force to implement the widespread use of JP-8 jet fuel in its operations, a thorough understanding of its potential effects upon exposed personnel is both critical and necessary. Exposure to potential environmental toxicants such as JP-8 may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.); e.g., the immune system. Significant changes in immune consequences, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long-lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed for 1h/day for 7 days to varying concentrations of aerosolized JP-8 jet fuel to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on their immune systems. It was observed that even at exposure concentrations as low as 100 mg/m3 detrimental effects on the immune system occurred. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in losses of different immune cell subpopulations depending upon the immune organ being examined. Further, JP-8 exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low concentration exposure of mice to JP-8 jet fuel caused significant toxicological effects on the immune system. It appears that the immune system may be the most sensitive indicator of toxicological damage due to JP-8 exposure, as effects were seen at concentrations of jet fuel that did not evidence change in other biological systems. Such changes may have significant effects on the health of the exposed individual.

The lymphoid organs/tissues are widely distributed throughout the body. However, a study of the primary and secondary lymphoid organs provides an adequate assessment of immune status. A histopathological approach to investigate immunotoxicity of various agents is described. The advantages and limitations of this approach are discussed. The usefulness of immunocytochemistry as an aid to study the various sub-populations of lymphocytes are stressed. Histopathological assessments are useful in evaluating immunosuppressive responses. Their value is somewhat less obvious in studying the potentials of test compounds for allergic and hypersensitive reactions. Variable factors affecting the structure and function of lymphoid organs such as stress, nutrition and age are discussed. Pathological lesions produced by various agents in lymphoid organs such as thymus, bone marrow, spleen, and lymph nodes are described.

Bovine leukemia virus (BLV) is a retrovirus which seems to affect both the humoral and the cellular immune response. Cows affected by enzootic bovine leukemia (EBL) showed a reduction of IgM-producing cells in the spleen and lymph nodes. Experimentally infected calves had lower levels of secretory IgM and a decrease in T lymphocytes in the peripheral blood. The reduction in the amount of T cells was noticed mainly in cells bearing the CD4 markers. BLV-infected animals showed diminished responsiveness to newly encountered antigens. Cows naturally infected by BLV produced Igs with impaired structural or biological reactivity. The primary immune response was shown to be deficient in BLV-infected cows following vaccination with synthetic antigen. A marked shift in the proportion of PBL, especially of the CD5+ subset, was noticed. Peripheral blood mononuclear cells from BLV-infected cows secrete elevated levels of certain cytokines and contain increased levels of cytokine mRNA. High levels of cytokines are also found in the sera of BLV-infected cows compared to non-infected animals. A correlation was found between BLV infection and lack of spontaneous recovery from Trichophyton verrucosum infection. Moreover, some studies ascertained a significant association between the herd BLV infection status and disease incidence. The culling rate was higher and milk production lower in BLV-infected vs. BLV-free herds. It seems that BLV infection affects the immune system of a cow to such an extent that it ceases to be productive enough to be kept and, in most cases, the animal is culled before any symptoms of illness associated with persistent immunodeficiency become apparent.

We prospectively studied immune reconstitution in 102 children who underwent T-lymphocyte depleted bone marrow transplants using either closely matched unrelated donors or partially matched familial donors by assaying total lymphocyte counts (TLC), T-cell subsets, B cells, and natural killer cells. TLC, CD3+, and CD4+ T-cell counts remained depressed until 2 to 3 years posttransplant, whereas CD8+ T-cell counts normalized by 18 months, resulting in an inverted CD4:CD8 ratio until 12 months posttransplant. Although the percentage of NK cells was elevated early posttransplant, their absolute numbers remained normal. CD20+ B cells were depressed until 12 to 18 months posttransplant. Factors affecting immunophenotypic recovery were analyzed by nonparametric statistics. Younger patients tended to have higher TLC posttransplant. Higher marrow cell doses were not associated with hastened immunophenotypic recovery. Graft-versus-host disease (GVHD) and/or its treatment significantly delayed the immune reconstitution of CD3+, CD4+, and CD20+ cells. The presence of cytomegalovirus was associated with increased CD8+ counts and a decrease in the percentages of CD4+ and CD20+ cells.

Corneal alkali burns are characterized by persistent inflammatory response and recurrent epithelial erosions. We examine whether immune cell types, i.e., T-cells and B-cells, play a role in this devastating process. Rabbit alkali-burned corneas that healed for 1-49 days were subjected to immunostaining with monoclonal antibodies (mAb) L11/135 (anti-T-cells), and 2C4 (anti-MHC II DQ). Serum was collected weekly and subjected to Western blot immunostaining to detect antibodies against denatured corneal proteins. Our observations demonstrated that all injured corneas reepithelialized within 3 days but then developed recurrent erosions. Immunohistochemical studies revealed that PMN, monocytes, and B-cells labeled by 2C4 mAb and T-cells labeled by L11/135 mAb appeared in the periphery to the cornea at 1 day after alkali burn. Many of these myeloid and lymphoid cells invaded the central stroma after 2 weeks of injuries when the alkali-burned corneas were heavily vascularized. In addition, some fibroblastic cells also expressed the MHC II DQ molecules in the alkali-burned corneas that had healed for > 2 weeks. Plasma cells appeared in granulation tissue of injured corneas that had healed for > 3 weeks. Western blot analysis demonstrated a production of heterogeneous antibodies in a majority of the rabbits (11 of 14) to various denatured corneal proteins (between 80 kDa and 25 kDa) at 5 weeks of alkali burn. Inflammatory cell types, i.e., PMN, macrophages could be found underneath the detached epithelium. These observations are consistent with the notion that the myeloid and lymphoid cells may participate in and complicate the healing of corneal alkali burns.

Previous studies showed that levels of some glycosphingolipids (GSLs) expressed in solid brain tumors grown in vivo were reduced or undetectable in cultured cells prepared from the tumors. This phenomenon has been attributed either to suppressed glycolipid synthesis from unknown forces of the tissue culture environment or to the absence of host cells that normally infiltrate the solid tumors growing in vivo. To test further the host cell hypothesis, we examined host cell markers in two experimental mouse brain tumors, the ependymoblastoma and the CT-2A, that were grown as subcutaneous solid tumors in the flank of C57BL/6J (B6) mice or as cultured cells in vitro. The markers included ganglioside N-glycolylneuraminic acid (NeuGc), GA1 (asialo-GM1), and Fc receptor-bearing cells. NeuGc-containing gangliosides, GA1, and Fc receptors are expressed by macrophages and lymphoid-type cells of the mouse host immune system but are not normally expressed by mouse neural cells. Differences in the relative content of Fc receptor-bearing cells in ependymoblastoma and CT-2A tumors grown in vivo (8.3 and 16.8%, respectively) were proportional to differences in the relative content of NeuGc-containing gangliosides (25.5 and 45.1%) and GA1 (8.5 and 13.8%), respectively. Neither cultured tumor cell line expressed Fc receptors, GA1, or NeuGc-containing gangliosides. These findings suggest that non-neoplastic host infiltrating cells (macrophages) contribute significantly to the GSL composition of solid tumors growing in vivo.

Quantitative and morphological changes in the immune system (CBA x C57BL/6)F1 mice after their enteral (group 1) and intraperitoneal (group 2) inoculation with Salmonella typhimurium in a dose of 2 x (10)6 microbial cells per mouse were studied. The study revealed that on day 28 after inoculation the death rate of the animals was 12.5 +/- 6.75% in group 1 and 57.84 +/- 4.89% in group 2. The same type of changes in the organs of the immune system was observed in both groups of mice, but in the animals of group 2 these changes were more pronounced. This was manifested by leukocytosis, exhaustion of thymic cells, hyperplasia, hypertrophy of the spleen and an increase in the proliferative activity in its B-zone, a decrease in the number of myelokaryocytes. Such changes are indicative of their importance in the resistance of the body to Salmonella infection.

Infiltration of specific immunocytes and stimulation of abnormal gastrointestinal motor activity during ileal inflammation induced by mucosal exposure to ethanol and acetic acid were investigated in 17 dogs. Ileal inflammation significantly increased the frequency of giant migrating contractions (GMCs) and decreased the frequency of migrating motor complexes (MMCs). The frequency of retrograde giant contractions (RGCs) increased only on the day of ethanol and acetic acid treatment. Diarrhea, urgency of defecation, and apparent abdominal discomfort were related to the increased frequency of GMCs. Ileal inflammation also prolonged the duration of postprandial MMC disruption. Histological and immunohistochemical findings indicated transmural inflammation with marked increase in polymorphonuclear cells in the lamina propria and muscularis externa layers. Myeloperoxidase activity increased severalfold in both layers. Cells containing interleukin-2 receptor (IL-2R) increased in the lamina propria. Other immunocytes, such as B and T lymphocytes, dendritic cells, and human leukocyte antigen DR-1 (HLADR)-positive cells, did not exhibit a significant increase in the inflamed ileum compared with the normal proximal jejunum. We conclude that stimulation of GMCs may be the major motility marker of intestinal inflammation.

The immune system is a complex interactive network. Defects in its function can be characterized broadly as being the result of actual deficiencies in the network or misdirection of normal immunologic functions. The assays that are available to detect deficiencies in the immunologic network barely scrape the surface of the possibilities. These assays primarily evaluate humoral immune function, but undetected defects in innate and cellular immunity are sure to exist. Although assays of humoral immunity have allowed the characterization of a number of immunodeficiency syndromes in horses, closer evaluation of the equine immune system using newer assays described in this text, as well as future assays yet to be developed are sure to determine new syndromes. Assays of misdirected immunologic functions have been limited to detection of misdirected antibody responses, but the dependence of antibody production on help from T cells could reflect an underlying defect of cellular immunity. Similar to immunodeficiency syndromes, misdirected responses of the innate and adaptive arms of immunity are sure to occur but will only be detected by more diligent surveillance of diseased horses and application of new immunodiagnostic technologies.

The most striking arguments in favor of a T cell dependent nature of RA are the strong association of the disease with selected class II HLA haplotypes (the "shared epitope" hypothesis) and the fact that, in experimental animal models such as adjuvant arthritis, the disease can be transferred by isolated T cell lines. It is true that T cell activation at the site of inflammation is not excessive. However, there is now unequivocal evidence for focal synthesis of IL-2 and IFN-gamma in the RA synovial membrane and one may realise that a limited but specific T cell activation may be sufficient to induce or perpetuate the immune process. This same argument may explain the lack of clear TCR restriction at the sites of inflammation. Until now, no antigen has been demonstrated to initiate and/or perpetuate RA. Different antigens though have been incriminated in the pathogenesis of RA, including cartilage antigens (collagen, proteoglycans, chondrocyte antigens), heat shock proteins or exogenous (viral/bacterial) antigens. Unless one can pick up the right antigen and clone the relevant T cells, it will be very hard to directly prove a T cell-dependent nature of the disease.