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Results for “Immune dysfunction”

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At least 505 records · Page 28Linked to original sources
PubMed1995

Immunomodulatory activities of extracellular metallothionein. II. Effects on macrophage functions.

Metallothionein (MT) is a thiol-rich protein that is rapidly induced by exposure to heavy metal cations. We have previously demonstrated that exogenous MT stimulates murine splenocytes to proliferate, but inhibits humoral responses to antigen. These observations suggest that metallothionein released from cells has a complex role in heavy metal-mediated immune dysfunction. Here we examine one possible mechanism by which MT mediates suppression of humoral immunity. Exposure of macrophages to 20 microM MT did not affect their ability to engulf opsonized sheep erythrocytes, but in the presence of 20 microM MT, peritoneal macrophages were stimulated to produce increased levels of oxygen radicals. These results correlated with observations that while macrophage phagocytosis of opsonized Candida albicans was unaltered by the presence of exogenous MT, killing of the engulfed yeast cells was dramatically enhanced by 20 microM MT. Amounts of free cadmium and zinc equimolar to that added as Zn,Cd-MT had no effect on candidacidal activity. MT was also found to significantly decrease lymphocyte proliferation mediated by macrophage activity. Biotinylated MT (MT-b) bound specifically to the plasma membranes of these macrophages, suggesting that membrane-associated molecules of the macrophage may transduce a signal mediated by MT binding. These results demonstrate that macrophages are a sensitive target for MT-mediated immunomodulation and that some of the consequences of the MT interaction with macrophages may be alterations in the capacity to produce an effective immune response and increased extracellular exposure to damaging free radicals.

Animals↗
PubMed2001

Injury induces alterations in T-cell NFkappaB and AP-1 activation.

The immune dysfunction that occurs after severe injury involves major changes in T-cell-mediated immunity resulting in suppressed T-helper 1 (Th1) type responses and increased or persistent T-helper 2 (Th2) type cytokine production. Since little is known about what signaling pathways are responsible for this injury-induced phenotypic shift in T-cells, we undertook this study to address the molecular basis for injury effects on T-helper cell subset cytokine expression. Experiments were designed to test whether diminished IL-2 gene expression after thermal injury coincided with changes in the induction of IL-2 gene regulatory transcription factors. Electrophoretic mobility shift assays (EMSA) were used to screen for nuclear expression of changes of the IL-2 gene transcription factors. Our findings revealed that changes in mitogen-stimulated T-cell AP-1 and NFkappaB factor activation correlated directly with defective mitogen-induced IL-2 mRNA expression. We determined that there was a loss of nuclear AP-1 activation and changes in NFkappaB factor activation at 9 days after injury. T-cell nuclear extracts prepared from sham injured mice showed induction of NFkappaB2 (p52) and RelA (p65) containing NFkappaB EMSA complexes, while we detected no RelA or NFkappaB2 in EMSA complexes using T-cell nuclear extracts prepared from burn injured mice. Instead, these NFkappaB EMSA complexes contained mostly NFkappaB1 (p50). Western immunoblot analysis confirmed defective nuclear RelA translocation. Taken together, these results indicate that T-cell NFkappaB and AP-1 activation pathways may be involved in the injury-induced changes in T-cell cytokine production and the immune deviation that occurs after injury.

Animals↗
PubMed2023

Immunogenomics of cholangiocarcinoma.

The development of cholangiocarcinoma spans years, if not decades, during which the immune system becomes corrupted and permissive to primary tumor development and metastasis. This involves subversion of local immunity at tumor sites, as well as systemic immunity and the wider host response. While immune dysfunction is a hallmark of all cholangiocarcinoma, the specific steps of the cancer-immunity cycle that are perturbed differ between patients. Heterogeneous immune functionality impacts the evolutionary development, pathobiological behavior, and therapeutic response of these tumors. Integrative genomic analyses of thousands of primary tumors have supported a biological rationale for immune-based stratification of patients, encompassing immune cell composition and functionality. However, discerning immune alterations responsible for promoting tumor initiation, maintenance, and progression from those present as bystander events remains challenging. Functionally uncoupling the tumor-promoting or tumor-suppressing roles of immune profiles will be critical for identifying new immunomodulatory treatment strategies and associated biomarkers for patient stratification. This review will discuss the immunogenomics of cholangiocarcinoma, including the impact of genomic alterations on immune functionality, subversion of the cancer-immunity cycle, as well as clinical implications for existing and novel treatment strategies.

Humans↗
PubMed1994

Pineal-opioid system interactions in the control of immunoinflammatory responses.

Several studies have demonstrated involvement of the pineal gland in the regulation of neuropeptide secretion and activity. In particular, the existence of links between the pineal gland and the brain opioid system has been documented. Both opioid peptides and melatonin (MLT), the most investigated pineal hormone, play an important role in neuromodulation of the immunity. Moreover, the immune effects of MLT are mediated by endogenous opioid peptides, which may be produced by both the endocrine system and the immune cells. In addition, the immune dysfunctions that characterize some human diseases, such as cancer, depend not only on the immune system per se, but also at least in part, on altered secretion of immunomodulating neurohormones, including MLT and opioid peptides. Therefore, the exogenous administration of neurohormones could potentially improve the immune status in humans. The present study evaluates the effects of MLT on changes in the number of T lymphocytes, natural killer cells, and eosinophils induced by exogenous administration of interleukin-2 (IL-2). Macrophage activity was also evaluated by determining serum levels of its specific marker, neopterin. The study was performed in 90 patients with advanced solid neoplasms, who received IL-2 at a dose of 3 million IU/day subcutaneously for 6 days a week for 4 weeks plus MLT at a daily dose of 40 mg. Both drugs were given in the evening. The results were compared to those in 40 cancer patients treated with IL-2 alone. The mean increase in T lymphocytes, natural killer cells, and eosinophils was significantly higher in patients treated with IL-2 plus MLT than in those who received IL-2 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Lymphocytic interstitial pneumonitis in autoimmune thyroid disease.

Four patients are described who were found to have autoimmune thyroid disease associated with lymphocytic interstitial pneumonitis. The patients were not receiving any medications known to cause lymphocytic interstitial pneumonitis. Their response to steroid therapy and the relapse of their clinical symptoms after steroid withdrawal support an underlying immunologic dysfunction. It is proposed that lymphocytic interstitial pneumonitis may be yet another manifestation of immune dysfunction in autoimmune thyroid disease.

Adult↗
PubMed1996

[Gene therapy for AIDS: current trends].

Genetic manipulation of somatic cells may be of therapeutic value in a variety of infectious diseases, particularly in human immunodeficiency virus (HIV) infection. Stable insertion of "resistance genes" into cells, susceptible to HIV, could reduce the viral burden in infected individuals and potentially retard the characteristic progressive immune dysfunction. Alternatively, ectopic expression of genes that encode viral antigens, might induce potent antiviral immune responses and form the basis for novel prophylactic and therapeutic vaccines. While laboratory studies have proved that the approach works in principle, preclinical and clinical studies will be necessary to evaluate the therapeutic benefits of such gene-based therapies. Currently, more than 400 patients have already been treated by this innovative therapeutic strategy in the US. In Japan, the Expert Committee on Gene therapy was set up in the council on Science and the Public Health and Welfare in 1991. Recently, gene therapy for ADA has been approved. It is thought that the first gene therapy against HIV infection in Japan is not far away.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Immunologic consequences of acute ethanol ingestion in rats.

Acute ethanol (EtOH) intoxication is commonly associated with many medical and surgical problems which primarily or secondarily involve infection. Chronic EtOH ingestion has been associated with immune dysfunction and an increased risk of infection; however, the relationship of acute EtOH exposure and immune function has not been clearly defined. To determine if there is a relationship between acute EtOH intoxication and immune function, the effects of a single EtOH ingestion on immune function were studied in a rat model. Acute intoxication was produced by gavage feeding of 3 g/kg of EtOH, and immune function was evaluated by in vivo chemotaxis to a chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine and responsiveness of splenic lymphocytes to B- and T-cell mitogens. Chemotaxis was significantly suppressed at 4 hr (49.0 +/- 5.1% of control) after EtOH ingestion (P = 0.001), but returned to normal by 24 hr and remained at that level. However, acute EtOH ingestion showed no suppressive effects on lymphocyte responsiveness to either concanavalin A or LPS. These results indicate that a single ingestion of EtOH has the potential to transiently suppress chemotactic function of granulocytes but not affect lymphocyte mitogenic responsiveness in rats. This potential may contribute to increased susceptibility to infection in patients after EtOH ingestion.

Alcoholic Intoxication↗
PubMed1992

Immune mechanisms in the pathogenesis of viral diseases: a review.

Three immunopathological mechanisms may determine the pathogenesis of viral diseases in animals. (1) A variety of viruses causes transient or prolonged immunosuppression by infecting lymphoreticular tissues and interacting with components of the immune system. (2) In persistent viral infections effective immune responses may result in tissue damage. The mechanisms involved are T-cell-mediated destruction of infected cells and delayed-type hypersensitivity. (3) In a number of viral diseases pathogenic immune complexes are formed when antibodies are produced and react with viral antigen molecules persisting in the host. The selected examples of immune dysfunction are the focus of this review.

Animals↗
PubMed1998

Experimental studies on immunosuppression: how do they predict for man?

The ultimate goal of any animal model in immunotoxicity testing is that it be a sensitive predictor of xenobiotic-induced immune dysfunction in humans. Such models should be capable of identifying the target(s) within the immune system affected by the xenobiotic. In particular the tier testing models have been successfully used to identify and characterize a variety of different immunotoxicants in animals as it pertains to immunosuppression and reduced resistance to infectious diseases. These tier models in mice and rats have been validated in interlaboratory studies. Although these protocols were designed for studies of rats and mice, some have been applied successfully for studying immunotoxicity in other animal species, including non-human primates. A great amount of data has been generated by the application of these models, which demonstrate that xenobiotics alter the immune system of animals. In man, the database on chemical-induced immunosuppression is limited, as the use of markers of immunotoxicity has received little attention in clinical and epidemiological studies. Such studies have not been performed frequently, and their interpretation often does not permit unequivocal conclusions to be drawn, due for instance to the presence of confounding factors and the uncontrolled nature of exposure. Also, testing possibilities in humans are limited and immune function changes by chemical exposure are often subtle. In humans, a number of agents have been shown to have immunosuppressive properties (including PCBs, PCDDs, PCDFs, oxidant gases, and ultraviolet radiation), but the strongest evidence stems from the clinical use of immunosuppressant drugs in transplant patients. These human data do in general terms confirm the data gained with experimental animals. Immunotoxicity assessment in rodents therefore adequately forms the basis for human risk assessment. Knowledge on the predictability of these animal models and immune assays can be further improved by comparison of the human and animal data obtained in the development of drugs.

Animals↗
PubMed2006

Filoviruses and the balance of innate, adaptive, and inflammatory responses.

The Filoviruses Marburg virus and Ebola virus are among the deadliest of human pathogens, causing fulminant hemorrhagic fevers typified by overmatched specific immune responses and profuse inflammatory responses. Keys to both vaccination and treatment may reside, first, in the understanding of immune dysfunctions that parallel Filoviral disease and, second, in devising ways to redirect and restore normal immune function as well as to mitigate inflammation. Here, we describe how Filoviral infections may subvert innate immune responses through perturbances of dendritic cells and neutrophils, with particular emphasis on the downstream effects on adaptive immunity and inflammation. We suggest that pivotal events may be subject to therapeutic intervention as Filoviruses encounter immune processes.

Dendritic Cells↗
PubMed2006

Reserpine-induced model of stress suppresses mucosal immunity.

Stress contributes significantly to the development of many diseases. In clinical studies, a strong correlation between depression and immune dysfunction has been shown. Our previous studies indicated that sympathetic innervation can regulate intestinal mucosal immunity through sympathetic synapses, but the mechanism in stress/depression-induced intestinal immune deficiency was unclear. Using a mouse model in which behavioural stress/depression is chemically induced by reserpine, it is found that there is a substantial deficiency of intestinal local humoral and particularly specific antibody response to the antigen stimulation in reserpine-treated group. No significant difference of CD4+, CD8+ or Mac1+ cells between reserpine-treated and control groups was detected in the intestine. This deficiency is closely correlated with stress/depression. A possible correlation between stress, cytokine secretion and humoral immunity in vivo is postulated.

Animals↗
PubMed2006

The characterization of the exposure to immune mediated apoptosis and the regulation of immune cytotoxic activity in the environment of a neoplasm and in decidua.

Acquiring the immune-mediated apoptosis and the ability to regulate the cytotoxic immune response are the main phenomena playing fundamental roles in such situations as neoplasm survival and creation of immune tolerance during pregnancy. The aim of this study was to investigate these phenomena through the evaluation of metallothionein and RCAS1 proteins in neoplasm and its healthy environment (clear surgical margin), physiological conditions in placenta and its environment (decidua) and the comparison to non-neoplasmatic lesions originating from the environment (nasal polyps, endometriosis). We have shown that the growth of RCAS1 expression was simultaneous to the infiltration of activated immunological cells of tumor environment as well as decidua. The activity of immunological cells was in our study selectively suppressed. Metallothionein expression growth was also observed in healthy tumors stroma and in decidua probably in response to the growing cytotoxic activity and tumor spread. Alterations in RCAS1 and Metallothionein expression seem to be associated with local immune dysfunction in nasal polyps and endometriosis. In conclusion, the ability to compensate the growing cytotoxic immune response is physiologically observed in decidua, the lost of this ability in tumor environment might participate in the development of tumor spread.

Antigens, Neoplasm↗
PubMed1993

CD8+CD38+ and CD8+DR+ peripheral blood lymphoid subsets of HIV-infected intravenous drug abusers correlate with CD4+ cell counts and proliferation to mitogens.

Twenty-nine intravenous drug abusers (ivda), with asymptomatic HIV infection at entry, were sequentially studied at 4- to 6-month intervals for variable follow-up periods (mean, 19.6 months). Two of them progressed to AIDS and another one fell into the IV-C2 stage of the CDC classification at the end of the study. CD8+ lymphoid subsets (CD57+, CD38+, and HLA-DR+) were sequentially analyzed in peripheral blood samples along the follow-up. Both absolute number and percentage of cells within these subsets were found significantly increased over those observed in normal controls. Minor changes were appreciated throughout the follow-up. CD8+CD38+ and CD8+DR+ cells increased slightly (P < 0.05), but the CD8+CD57+ subset did not change significantly. In order to determine whether abnormalities in these subsets are associated with immune dysfunction, we looked for correlation between the quantification of CD8+ subpopulations and other parameters of cellular immunity. Percentage of CD8+CD38+ or CD8+DR+ cells inversely correlates with absolute number of CD4+ cells (P < 0.0001), and percentage of CD38+ subset also correlates with the proliferative response to mitogens in lymphoid cultures. Thus, the enumeration of these populations of CD8+ cells may provide some additional information about the immune status of HIV-infected ivda.

ADP-ribosyl Cyclase↗
PubMed1999

Immunoregulatory cytokines in bone marrow and peripheral blood stem cell products.

In these studies, we compared the phenotype, function, and expression of type 1, type 2, and monocyte-associated cytokine mRNA transcripts in autologous bone marrow (BM) and growth factor-mobilized peripheral blood stem cell (PSC) products. These studies demonstrate that lymphocytes and monocytes in stem cell products are abnormally activated, expressing significantly higher levels of interleukin (IL)-2, 4 and 10, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha), but not IL-8, as compared to normal peripheral blood mononuclear cells (PBMC). In addition, the levels of IL-2, IL-10 and TNF-alpha are significantly higher in mobilized PSC as compared to BM products. The high cytokine levels are unexpected as T cell function in stem cell products is depressed. PSC products have high levels of T cell inhibitory activity, which directly correlates with IL-10 expression, both of which are mechanisms that might be involved in the immune dysfunction within stem cell products used for autologous stem cell transplantation. These data demonstrate that: (1) immune cells in autologous BM and PSC products are activated with the expression of high levels of type 1 and type 2 cytokines as well as monokines; (2) PSC products contain a high frequency of monocytes which mediate T cell inhibitory activity; and (3) despite the high levels of cytokine expression, T cell function in stem cell products is depressed. The significance of these immune abnormalities within stem cell products for myeloid and lymphoid recovery following autologous stem cell transplantation remains to be determined.

Adjuvants, Immunologic↗
PubMed2000

Neoadjuvant interleukin-12 immunogene therapy protects against cancer recurrence after liver resection in an animal model.

OBJECTIVE: To evaluate the neoadjuvant use of a herpes simplex viral (HSV) amplicon vector expressing the murine interleukin-12 (IL-12) gene. SUMMARY BACKGROUND DATA: Surgery is the most effective therapy for hepatic malignancy. Recurrences, which are common, most often occur in the remnant liver and are due partly to growth of residual microscopic disease in the setting of postoperative host cellular immune dysfunction. The authors hypothesized that engineering tumors to secrete IL-12 in vivo would elicit an immune response directed at residual tumor and would reduce the incidence of recurrence after resection. METHODS: Solitary hepatomas were established in Buffalo rat livers and directly injected with 106 particles of HSV carrying the gene for IL-12, lacZ (beta-galactosidase) or with saline. One week after injection, the animals were challenged with an intraportal injection of 106 tumor cells, with subsequent resection of the hepatic lobe containing the previously established macroscopic tumor nodule, recreating the clinical scenario of residual microscopic cancer. RESULTS: Hepatoma cells transfected with HSV-IL-12 produced high levels of IL-12 in vitro and in vivo. A significant local immune response developed, as evidenced by a progressive increase in the number of CD4(+) and CD8(+) lymphocytes in the tumor. Treatment of established hepatomas with HSV-IL-12 protected against growth of microscopic residual cancer after hepatic resection. Sixty-four percent of the animals treated with HSV-IL-12 had zero or one tumors compared with 30% of HSVlac-treated and 24% of saline-treated animals. CONCLUSIONS: This neoadjuvant immune strategy may prove useful in reducing the incidence of cancer recurrence after hepatic resection.

Animals↗
PubMed1993

Alopecia universalis in an HIV-positive patient: possible insight into pathogenesis.

Alopecia universalis, a variant of alopecia areata, is a disease of unknown etiology, though evidence for an autoimmune etiology continues to mount. We report an HIV-positive patient with altered T-lymphocyte subsets in whom alopecia universalis developed. A skin biopsy of the patient's scalp demonstrated a classic perifollicular lymphocytic infiltrate, and immunophenotyping of the same specimen revealed that the majority of the cells were CD4+ lymphocytes. During the active loss of hair, the patient's CD4/CD8 ratio was decreased. This ratio normalized during the period of regrowth. Our data suggest that systemic immune dysfunction, as seen in HIV infection, may be more important in mediating alopecia areata than localized immune responses. Given the proposed mechanism of alopecia areata developing in this patient, i.e. influx of CD4+ lymphocytes to the perifollicular regions of skin when the CD4/CD8 ratio is low, it is surprising that alopecia areata is not seen more commonly in patients with HIV infection.

Adult↗
PubMed2006

Crohn's disease: innate immunodeficiency?

In the past, Crohn's disease (CD) has been understood primarily as an immunologic disorder characterized by an abnormal T-cell response. Recent in vitro and in vivo data suggests that CD may instead be precipitated by innate immune dysfunction resulting from a combination of genetic and environmental factors. Some reports have demonstrated a defective immune response in a variety of other cellular components, including neutrophils, monocytes and dendritic cells. Recent studies of granulocyte-macrophage colony-stimulating factor (GM-CSF) in CD, aiming to stimulate the innate immune system with the conception that an innate immune defect underlies the development of the disease, have been demonstrated a clinical benefit and reinforce this evolving understanding of the disease.

Crohn Disease↗
PubMed2001

Requirement for leptin in the induction and progression of autoimmune encephalomyelitis.

Recent evidence indicates that leptin modifies T cell immunity, and may provide a key link between nutritional deficiency and immune dysfunction. To study the influence of leptin on autoimmunity, susceptibility to experimental autoimmune encephalomyelitis induced by immunization with a myelin-derived peptide was examined in leptin-deficient, C57BL/6J-ob/ob mice, with or without leptin replacement, and in wild-type controls. Leptin replacement converted disease resistance to susceptibility in the C57BL/6J-ob/ob mice; this was accompanied by a switch from a Th2 to Th1 pattern of cytokine release and consequent reversal of Ig subclass production. Our findings suggest that leptin is required for the induction and maintenance of an effective proinflammatory immune response in the CNS.

Adoptive Transfer↗