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At least 829 records · Page 46Linked to original sources
PubMed1997

Enteropathy in Zambians with HIV related diarrhoea: regression modelling of potential determinants of mucosal damage.

BACKGROUND: AIDS is characterised by small intestinal mucosal damage, but its aetiopathogenesis is poorly understood. Enteric infections in Africa differ from those in northern countries, where protozoan infections have been associated with severe enteropathy in AIDS patients. AIMS: To characterise enteropathy in Zambian AIDS patients compared with local controls, and to assess relative contributions of enteric infection, nutritional impairment, and immune dysfunction. METHODS: Computer aided mucosal morphometry of small intestinal biopsy specimens from 56 HIV infected Zambians with persistent diarrhoea and 26 diarrhoea free controls, followed by regression modelling. RESULTS: Patients with HIV related diarrhoea had reduced villous height and increased crypt depth compared with controls. There was no difference between HIV positive and negative controls. In regression models applied to AIDS mucosal measurements, villous height and crypt depth were related to nutritional parameters and to serum soluble tumour necrosis factor receptor p55 concentration. Crypt depth was also related to lamina propria plasma cell count. Intestinal infection was found in 79%, which consisted predominantly of microsporidia in 34%, Isospora belli in 24%, and Cryptosporidium parvum in 21%, but detection of these enteropathogens was not related to severity of enteropathy. CONCLUSIONS: Nutritional and immune disturbances were associated with enteropathy, accounting for over one third of the variation in mucosal morphometric parameters.

Adolescent↗
PubMed1997

Review: immunobiology of preeclampsia.

Preeclampsia has been recognized clinically since the time of Hippocrates: however its etiology and pathophysiology remain enigmatic. This pregnancy-specific syndrome typically presents in late pregnancy as hypertension, edema, and proteinuria. Investigations over the past 15 years have revealed that preeclampsia is associated with abnormal placentation, reduced placental perfusion, endothelial cell dysfunction, and systemic vasospasm. Since it occurs more commonly in primigravidae and in women with underlying collagen-vascular diseases, an immunological component has long been suspected. Increased prevalence in high-order and molar pregnancies and those associated with increased placental mass suggests that trophoblastic volume and fetal antigen load are correlated with the syndrome. Epidemiological reports indicate that the prevalence of preeclampsia is decreased in women who received heterologous blood transfusions, practiced oral sex, or when a long period of cohabitation preceded an established pregnancy. Conversely, the use of condoms as a primary mode of contraception is associated with a higher risk of preeclampsia. These studies suggest that prior exposure to foreign or paternal antigens imparts a protection against the likelihood of developing preeclampsia. Clinical evidence of cellular and humoral immune dysfunction is associated with the syndrome. Fibrin and complement deposition and "foam" cells in atherosis lesions resemble the histopathology of renal allograft rejection. Relative T-cell, natural killer cell, and neutrophil activation have been reported in preeclampsia and circulating cytokines and antiphospholipid antibodies are more prevalent in preeclampsia than in normal pregnant women. These abnormalities are consistent with the systemic endothelial cell dysfunction that has been postulated as a pathophysiological feature of preeclampsia. While such associations do not prove causality, they suggest testable hypotheses for continued basic and clinical investigation of this major complication of human pregnancy.

Female↗
PubMed1990

Are pesticides immunotoxic?

So far there is little evidence that occupational or environmental exposure to pesticides has led to clinically significant immunosuppression, and hence to an increased risk of developing infection or cancer. In addition, the incidence of hypersensitivity reactions to pesticides is generally low. Experiments have been conducted in experimental models that indicate that certain pesticides are immunosuppressive to animals. The majority of these experiments, however, have used high (frankly toxic) doses of pesticides and immunosuppression has been monitored using in vivo or in vitro immune function tests, the results of which are difficult to interpret in terms of effects on health. One exception is tributyltin oxide which, in the rat, causes immune dysfunction at doses below those that cause general toxicity, and which compromises the ability of the animals to resist bacterial and parasitic infection. Predictive assessment of possible immunotoxicity induced by exposure to a pesticide should be structured within the current framework of acute, subacute and chronic testing procedures used for regulatory purposes. With the exception of predicting some hypersensitivity reactions (respiratory allergy and autoimmunity), which would require the development of novel specialized methods, indications of potential immunotoxicity can be obtained from standard haematological investigations and by evaluation of lymphoid organs and tissues such as the spleen, thymus, lymph nodes, and bone marrow. Pathological and histopathological examination of the lymphoid system is a mandatory requirement of nearly all subchronic testing guidelines for pesticides worldwide. The incorporation of specialized, and in particular in vitro, immune function tests into the routine toxicological assessment of a pesticide is not only time-consuming and potentially wasteful of animals, but is also scientifically unacceptable; the significance of changes in such tests must await further research on the reserve capacity of the immune system.

Animals↗
PubMed2026

Decoding tumor immune microenvironment heterogeneity by single-cell and spatial multi-omics: From immunotherapy resistance to translational biomarkers.

Immune checkpoint blockade has transformed cancer therapy, yet primary and acquired resistance remain major clinical challenges. Increasing evidence indicates that immunotherapy resistance cannot be fully explained by tumor-intrinsic alterations or conventional biomarkers such as PD-L1 expression, tumor mutational burden, or microsatellite instability. Instead, therapeutic response is shaped by the tumor immune microenvironment (TIME) as a heterogeneous, spatially organized, and dynamically evolving ecosystem. Single-cell omics has revealed diverse immune and stromal cell states, including progenitor and terminally exhausted T cells, suppressive myeloid programs, B-cell/TLS-associated immune-reactive states, and CAF-mediated exclusion phenotypes. Spatial transcriptomics, spatial proteomics, and imaging-based approaches further demonstrate that these cell states assemble into distinct immune niches, including immune-inflamed, T-cell-excluded, myeloid-suppressive, metabolic/hypoxic, and TLS-associated niches. These spatial ecosystems determine whether antitumor immune cells can access malignant cells, receive antigen-presenting support, or become restrained by stromal, vascular, metabolic, and myeloid barriers. In this review, we summarize how single-cell and spatial multi-omics redefine TIME heterogeneity in immunotherapy resistance, highlight ligand-receptor communication networks linking cell states to spatial immune dysfunction, and discuss emerging translational biomarkers for patient stratification. We further propose that future immunotherapy biomarkers should evolve from static single-marker assays toward longitudinal, spatially resolved, and interpretable multi-omics models that guide precision combination immunotherapy.

Humans↗
PubMed1996

Understanding clinical immunological testing in alleged chemically induced environmental illnesses.

Some believe that an abnormal immunoregulatory response based on environmental damage to T cells is fundamental to the production of symptoms in patients with alleged "multiple chemical sensitivity" and/or "environmental illness." According to this theory stimulation of T cells or T cell phenotypic subsets by environmental chemicals results in release of cytokines that can effect appropriate target cells of multiple organ systems, resulting in a wide range of symptoms. This concept is reinforced by frequent media reporting of pollution incidents and environmental disasters plus continued isolated reports of immunologic abnormalities in patients with various forms of alleged environmental illness, multiple chemical sensitivities, or other related syndromes. These include reports of slight perturbations in quantity and function of immunoglobulins, complement and its components, B cells, natural killer cells, T cells, phenotypic T cell subsets, and helper suppressor T cell ratios. There are also reports of increased or decreased interleukin levels including IL-1 and IL-2 or their receptors (IL-2R) in these patients. Such assays are not infrequently performed even though there is no evidence for their diagnostic efficacy in these alleged conditions. It is reasonable, however, to anticipate that with the wide development of assays for many of the interleukins and their receptors, these assays may become important in the future diagnosis of many autoimmune, allergic, neoplastic, and infectious diseases. At this time, however, the induction of environmental illness or multiple chemical sensitivity by exposure to trace levels of environmental "immunotoxins" is unproven and remains a matter of speculation. The reproducibility of immunologic test abnormalities reported under these conditions has not been documented, and the data have often not been analyzed statistically. Appropriate controls also have not usually been employed, nor have control values been provided in many cases. Without consideration of these factors, a patient might be erroneously diagnosed as having some form of "immune dysregulation," "environmental immune dysfunction," or "immunotoxic" syndrome on the basis of only a single panel of cellular immunologic profiles or related immunologic tests illustrating slight deviations from the norm and in the absence of overt disease on physical examination. Consideration must also be given to an understanding of biologic variability and diurnal variations in lymphoid cell numbers in interpreting cellular immunologic profiles. For example, the necessity for age and sex-matched controls, test reproducibility, quantitative versus functional assays, and the significance of major versus minor deviations from the norm must be appreciated. In addition, many other conditions can effect immunologic tests, such as medications, psychologic factors, cigarette smoking, and the presence of concurrent disease, including minor viral infections. All of these variables should be appreciated in test interpretation. Certain clinical indications for analysis of cellular components of the immune system, using flow cytometry, have been provided as guidelines although they are by no means accepted by all groups due to their current incomplete evaluation by the clinical immunology community. These suggested indications are discussed. In this article, attempts are made to outline the various quantitative and functional tests used to assess the immune system, with emphasis on "biomarker" tests to detect possible immune system "damage." Dangers involved in attempting to make clinical evaluations based on results of isolated in vitro assessment of quantity or function of immune system cellular and humoral components without considering the results of a good medical history and physical examination, the many pitfalls involved in the tests, and the many confounding variables that affect the tests are emphasized, as well as the need for proper controls...

Autoantibodies↗
PubMed2005

Toll-like receptor expression in feline lymphoid tissues.

Toll-like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that activate the innate immune system. While it is clear that TLRs are important in the immune response against pathogens, they may also be exploited by some pathogens. Our objective is to determine whether feline immunodeficiency virus (FIV) infection affects TLR expression or function thereby resulting in innate immune dysfunction. To this end, we cloned partial sequences for feline TLRs 1--3, 5--8, and developed real-time PCR assays to quantify feline TLRs 1--9. TLR expression was quantified in normal cat lymphoid tissues, purified lymphocyte subsets, and FIV-infected cell lines. Different expression patterns of TLRs were found in spleen, mesenteric lymph node, retropharyngeal lymph node, thymus, intestinal intraepithelial lymphocytes, and lamina propria lymphocytes. B lymphocytes, CD4+ T cells, and CD8+ T cells all expressed TLRs 2--5, 7--9; however, the relative levels of expression varied among lymphocyte phenotypes. Infection of cell lines with FIV resulted in altered TLR expression levels that differed depending on cell type. These results demonstrate that tissue distribution of TLRs is associated with the immunological role of a particular tissue, that lymphocytes may also express these 'innate immune' receptors, and that FIV infection can alter TLR expression.

Animals↗
PubMed1998

Nutritional and zinc status of head and neck cancer patients: an interpretive review.

In this review, we provide evidence based on our studies, for zinc deficiency and cell mediated immune disorders, and the effects of protein and zinc status on clinical morbidities in patients with head and neck cancer. We investigated subjects with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx. Patients with metastatic disease and with severe co-morbidity were excluded. Nutritional assessment included dietary history, body composition, and prognostic nutritional index (PNI) determination. Zinc status was determined by zinc assay in plasma, lymphocytes, and granulocytes. Pretreatment zinc status and nutritional status were correlated with clinical outcomes in 47 patients. Assessment of immune functions included production of TH1 and TH2 cytokines, T cell subpopulations and cutaneous delayed hypersensitivity reaction to common antigens. At baseline approximately 50% of our subjects were zinc-deficient based on cellular zinc criteria and had decreased production of TH1 cytokines but not TH2 cytokines, decreased NK cell lytic activity and decreased proportion of CD4+ CD45RA+ cells in the peripheral blood. The tumor size and overall stage of the disease correlated with baseline zinc status but not with PNI, alcohol intake, or smoking. Zinc deficiency was associated with increased unplanned hospitalizations. The disease-free interval was highest for the group which had both zinc sufficient and nutrition sufficient status. Zinc deficiency and cell mediated immune dysfunctions were frequently present in patients with head and neck cancer when seen initially. Zinc deficiency resulted in an imbalance of TH1 and TH2 functions. Zinc deficiency was associated with increased tumor size, overall stage of the cancer and increased unplanned hospitalizations. These observations have broad implications in the management of patients with head and neck cancer.

Carcinoma, Squamous Cell↗
PubMed2000

[Immunomodulator properties of ecstasy (MDMA)].

In vitro exposure to ecstasy (3,4-methylenedioxymethamphetamine, MDMA) alters some immune parameters such as T-cell regulatory function, cytotoxic T-lymphocyte activity, natural killer cell activity and macrophage function. Administration of MDMA in rats produces a suppression of lympho-proliferation response and a decrease in circulating lymphocytes, accompanied by an increase in plasma corticosterone. It was postulated a direct action of MDMA on lymphocytes or rather an indirect action mediated by the hypothalamic pituitary adrenal axis (HPA-AXIS) and/or the sympathetic nervous system (SNS). Acute MDMA treatment effected on healthy-volunteers produces an immune dysfunction associated with pharmaceutical characteristics and so with MDMA plasma concentrations. There is a decrease in CD4+ T-cells and functional responsiveness of lymphocytes, while percentage of natural killer cells increases. A contemporary rise of cortisol plasma concentrations supports the hypothesis of MDMA-induced release of corticotrophin-releasing factor from the hypothalamus and subsequent HPA-axis and SNS activation.

Animals↗
PubMed2004

Increased plasma carnitine concentrations in preeclampsia.

OBJECTIVE: Preeclampsia is associated with abnormal lipid metabolism, including fatty acid metabolism. Carnitine plays an indispensable role in the oxidation of fatty acids. The aim of the study was to evaluate the possible role of abnormal fatty acid oxidation in preeclampsia by comparing plasma carnitine levels between preeclamptic and healthy control pregnant women. METHODS: Plasma concentrations of free carnitine and short-, medium-, and long-chain acylcarnitines were investigated with electrospray tandem mass spectrometry in pregnant women with preeclampsia (n = 33) and in normotensive healthy pregnant control subjects (n = 28). Excluded were multiple pregnancies and women with preexistent hypertension, diabetes, renal dysfunction, immune disease, and intrauterine fetal death. Control subjects were healthy pregnant women without hypertension or proteinuria. RESULTS: The results revealed that, except for the medium-chain plasma acylcarnitines, all plasma carnitines were significantly increased (P <.001) in the preeclamptic group (t test for unpaired samples). Free carnitine and the short- and long-chain acylcarnitine values were increased by approximately 50% compared with the control group. Total and short-chain plasma acylcarnitine levels were significantly correlated to diastolic blood pressure, whereas no relationship could be demonstrated between carnitine concentrations and the variables proteinuria and systolic blood pressure. CONCLUSION: The considerable increased plasma carnitine concentrations, together with the accumulation of lipids, support the role of abnormal lipid metabolism in the pathophysiology of preeclampsia. It is suggested that toxic metabolites resulting from abnormal fatty acid oxidation in the placenta contribute to the endothelial dysfunction of preeclampsia.

Carnitine↗
PubMed1998

Hyporesponsiveness to intradermal administration of hepatitis B vaccine in insulin dependent diabetes mellitus.

The immune response to intradermal or intramuscular hepatitis B vaccine in 18 children with insulin dependent diabetes mellitus (IDDM) compared with 24 healthy children was studied. Patients were divided into responders, hyporesponders, and non-responders according to their antihepatitis B serum concentrations after hepatitis B vaccination. We also studied HLA class II antigen distribution and did delayed type hypersensitivity (DTH) tests on children with IDDM and controls. No difference in the immune response (antihepatitis B surface antigen antibody titres) was found with intramuscular administration, whereas with intradermal administration a statistically lower immune response (p < 0.001) was observed in children with IDDM v controls. This hyporesponsiveness cannot be attributed to HLA class II antigen distribution because their frequency was the same in both groups of children with IDDM. It is suggested that the poor immune response to intradermal hepatitis B vaccine may be due to impaired macrophage activity resulting in failure of antigen presentation, which may be of importance in the immune dysfunction in children with IDDM. This hypothesis is suggested by a significantly lower score on a DTH test to a battery of antigens in the IDDM group when compared with controls. It is therefore suggested that when the hepatitis B vaccination is offered to children with IDDM it may be preferable to give it intramuscularly.

Adolescent↗
PubMed1994

Eosinophilic pustular follicular reaction: a paradigm of immune dysregulation.

BACKGROUND: We encountered 10 patients whose biopsies showed an eosinophilic pustular follicular reaction, a histomorphology alleged to be pathognomonic of eosinophilic folliculitis (EF). Only seven of these patients fell within the clinical spectrum of EF. Seven patients had conditions associated with immune dysfunction, including three patients with an atopic history. Potential antigenic stimuli could be elicited in six cases. METHODS: Formalin-fixed biopsy specimens from all 10 patients were available for examination. Hematoxylin and eosin-, alcian blue-periodic acid-Schiff (PAS)- and PAS-diastase-stained sections cut from paraffin-embedded tissue were examined by light microscopy. Immunoperoxidase preparations with antibody to IgE were performed on paraffin sections and the number of IgE-decorated cells quantitated in each case. Four patients also had biopsy material submitted in Michel's medium, on which direct immunofluorescent studies were conducted. RESULTS: IgE-coated mononuclear cells were present in patients whose lesions would logically be expected to derive from dominant type I hypersensitivity mechanisms and absent or minimal in biopsies from those patients in whom the pathogenetic basis of lesions derived principally from cell-mediated immunity. CONCLUSIONS: The eosinophilic pustular follicular reaction, while characteristic of EF, is not exclusive to that entity. It represents an expression of an excessive immediate or delayed-type hypersensitivity reaction to various auto-, epicutaneous, or ingested stimuli. A background of immune dysregulation may be contributory.

Adolescent↗
PubMed1999

Primary chemically induced tumors induce profound immunosuppression concomitant with apoptosis and alterations in signal transduction in T cells and NK cells.

Whereas transplantable tumors can be readily cured with immunotherapeutic approaches, similar therapies in cancer patients have been less effective. This difference may be explained by an immunosuppression resulting from the presence of a slowly growing primary tumor in the patient, whereas the immune system in a mouse with a rapidly proliferating transplantable tumor would be less affected. As a more appropriate model to the immune dysfunction in patients, slowly progressing primary tumors were induced by the carcinogen methylcholanthrene (MC) in mice. Their ability to induce immunosuppression in T cells and natural killer (NK) cells was compared to that of rapidly growing transplanted MC-induced tumors. The results demonstrate that mice bearing primary MC tumors had significantly diminished T-cell and NK-cell functions, impaired capacity to produce Th1 cytokines, and markedly reduced levels of the signal-transducing zeta chain in T cells and NK cells, similar to that described in cancer patients. Moreover, a substantial number of CD8+ T cells in mice with large primary MC tumors were undergoing apoptosis, correlating with alterations in CD4/CD8 ratios. In contrast, T cells and NK cells from mice bearing rapidly growing transplanted tumors were only marginally affected. These findings could explain the apparent discrepancy between the consistent findings of a diminished immune response and alterations in signal transduction in cancer patients as compared to the less reproducible observations in murine transplantable tumors. In addition, they could explain the differences in the high efficacy of immunotherapy in mice with transplantable tumors and the low therapeutic results in cancer patients.

Animals↗
PubMed2003

A role for CD1d-restricted NKT cells in injury-associated T cell suppression.

Natural killer T (NKT) cells are known to modulate T cell responses during autoimmunity, tolerance, and antitumor immunity; however, their potential role in regulating the immune response to injury has not been reported. Using a murine model of burn injury, we investigated whether CD1d-restricted NKT cells played a role in the T cell suppression that occurs early after injury. A functional role for CD1d stimulation of NKT cells in the injury-related immune suppression was demonstrated by experiments in which the suppression of antigen (Ag)-specific delayed-type hypersensitivity and in vitro T cell-proliferative responses were prevented if mice were given anti-CD1d monoclonal antibody (mAb) systemically just before injury. The CD1d-NKT cell-dependent suppression of the T cell response after injury occurred in the absence of quantitative changes in NKT cells themselves or CD1d(+) Ag-presenting cells. We observed that elevated production of the immunosuppressive cytokine interleukin (IL)-4 correlated with burn-induced immune dysfunction, and we found that NKT cells but not conventional T cells were the source of IL-4 early after injury. Lastly, we observed that the injury-induced production of NKT cell-derived IL-4 could be blocked by systemic treatment of burn-injured mice with anti-CD1d mAb. Together, our results reveal a novel mechanism involving CD1d stimulation of NKT cells in the onset of T cell suppression that occurs subsequent to injury.

Animals↗
PubMed2006

Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination.

Ectodermal dysplasia with immune deficiency (EDI) is caused by alterations in NEMO (nuclear factor [NF]-kappaB essential modulator). Most genetic mutations are located in exon 10 and affect the C-terminal zinc finger domain. However, the biochemical mechanism by which they cause immune dysfunction remains undetermined. In this report, we investigated the effect of a cysteine-to-arginine mutation (C417R) found in the NEMO zinc finger domain on dendritic cell (DC) function. Following CD40 stimulation of DCs prepared from 2 unrelated patients with the NEMO C417R mutation, we found NEMO ubiquitination was absent, and this was associated with preserved RelA but absent c-Rel activity. As a consequence, CD40 stimulated EDI DCs failed to synthesize the c-Rel-dependent cytokine interleukin-12, had impaired up-regulation of costimulatory molecules, and failed to support allogeneic lymphocyte proliferation in vitro. In contrast, EDI DCs stimulated with the TLR4 ligand lipopolysaccharide (LPS) showed normal downstream NF-kappaB activity, DC maturation, and NEMO ubiquitination. These findings show for the first time how mutations in the zinc finger domain of NEMO can lead to pathway specific defects in NEMO ubiquitination and thus immune deficiency.

Arginine↗
PubMed1994

Association of IgA-anti-Fab autoantibodies with disease stage in head-and-neck cancer.

Patients with head-and-neck cancer commonly have immune defects. It was reported that these patients have raised serum IgA levels. We investigated whether IgA-anti-Fab autoantibodies, which occur in association with immune dysfunction, are present in patients with head-and-neck cancer. Sera of 101 patients with squamous-cell carcinoma (SCCHN) and 8 patients with adenoid cystic carcinoma (ACCHN) of the head and neck were tested in ELISA for IgA-anti-Fab autoantibody activity. IgA-anti-Fab serum activity was significantly higher in both SCCHN and ACCHN patients than in healthy controls. In patients with SCCHN, an association between disease stage and IgA-anti-Fab activity was established. Stage-IV patients had significantly higher IgA-anti-Fab than stage-I patients or healthy controls. Stage-II and stage-III patients had intermediate levels. Extremely high IgA-anti-Fab activity was observed in 7 patients who died within 6 months following testing, suggesting a relationship of autoimmunity with terminal disintegration of physiological body functions. IgA-anti-Fab autoantibodies may explain the occurrence of immune defects in patients with head-and-neck cancer.

Adult↗
PubMed2004

Autoantibody repertoires to brain tissue in autism nuclear families.

The hypothesis of an immune dysfunction in autism spectrum disorders has previously been put forward without, however, compelling evidence of a direct relation to its etiology or pathogenesis. To further understand if autoimmunity could play a significant role in autism, we analyzed autoantibody repertoires to brain tissue extract in the plasma of 171 autism children, their parents, and 54 controls, by quantitative immunoblotting. Multiparametric analysis revealed significant differences between patients and controls, and showed that one single reactivity in Section 32 of the blot had the most power to discriminate between these samples. Family correlation coefficients and heritability estimates did not provide any evidence that this reactivity was genetically determined. While the molecular weight of the target protein suggested that it might be an isoform of Myelin Basic Protein (MBP), inhibition assays with human MBP argued against this hypothesis. The study evidences the widespread occurrence of autoreactivities to brain tissue in autism patients, which may represent the immune system's neuroprotective response to a previous brain injury occurred during neurodevelopment. The molecular identification of the target protein in Section 32 will contribute to the understanding of the role of immune responses against brain antigens in autistic patients.

Adolescent↗
PubMed1995

An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes.

The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its high expression in the thymus and spleen and the presence of DNA binding sites for Fli-1 in a number of lymphoid cell-specific gene suggest that Fli-1 is involved in the regulation of lymphopoiesis. Activation of the Fli-1 gene by either chromosomal translocation or viral insertion leads to Ewing's sarcoma in humans and erythroleukemia in mice, respectively. Thus, Fli-1 is normally involved in pathways involved in the regulation of cell growth and differentiation. We have generated H-2Kk-Fli-1 transgenic mice that overexpress Fli-1 in various mouse tissues, with the highest levels of Fli-1 protein in the thymus and spleen. These Fli-1 transgenic mice developed a high incidence of a progressive immunological renal disease and ultimately died of renal failure caused by tubulointerstitial nephritis and immune-complex glomerulonephritis. The incidences of renal disease correlated with the levels of Fli-1 protein in lymphoid tissues of transgenic lines. The hypergammaglobulinemia, splenomegaly, B-cell hyperplasia, accumulation of abnormal CD3+ B220+ T lymphoid cells and CD5+ B220+ B cells in peripheral lymphoid tissues, and detection of various autoantibodies in the sera of diseased Fli-1 transgenic mice suggested the involvement of an immune dysfunction in the pathogenesis of the renal disease. In addition, splenic B cells from transgenic mice exhibited increased proliferation and prolonged survival in vitro in response to mitogens. Taken together, these data suggest that overexpression or ectopic expression of Fli-1 perturbs normal lymphoid cell function and programmed cell death. Thus, H-2Kk-Fli-1 transgenic mice may serve as a murine model for autoimmune disease in humans, such as systemic lupus erythematosus.

Animals↗
PubMedDate not supplied

An animal model of Kaposi's sarcoma. I. Immune status of CD1 mice undergoing dimethyl hydrazine treatment to induce angiosarcomas and other malignancies.

Dimethylhydrazine (DMH) induces colonic cancer and angiosarcomas in mice. In order to determine pertinence of mouse angiosarcoma as a model to AIDS associated Kaposi's sarcoma (KS), we investigated if immune dysfunction occurred during tumor development by DMH. Outbred CD1 male mice received once weekly DMH a 20 mg/kg body weight dose s.c. for 33 weeks. Every two weeks initially and then every week groups of DMH-treated and control animals were sacrificed to determine a) peripheral blood and splenic T cell subset ratio b) 4-day plaque forming cell (PFC) response to i.p. sheep red blood cells (SRBC) and c) mitogenic response of spleen cells to Concanavalin A (Con A) and lipopolysaccharide (LPS). No change in T helper/T suppressor + cytotoxic T cell (Th/Tsupp. + CTL) and mitogenic response to spleen cells to Con A was noted whereas PFC response of animals to SRBC and mitogenic response of spleen cells to LPS decreased. These data suggest that either infection with T cell depleting virus such as LP:BM5 or immunosuppressive drugs affecting T cell function, such as steroids may be required to bring the immune status of DMH treated animals closer to that of AIDS associated KS bearing human subjects.

Acquired Immunodeficiency Syndrome↗