Pristane-Accelerated Autoimmune Disease in (SWR X NZB) F1 Mice Leads to Prominent Tubulointerstitial Inflammation and Human Lupus Nephritis-Like Fibrosis.

Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longitudinal analyses, we characterized a novel accelerated mouse model of lupus using pristane treatment in SNF1 (SWR X NZB F1) lupus prone mice (pristane-SNF1 mice). Pristane treatment in SNF1 mice accelerated the onset and progression of proteinuria, autoantibody production, immune complex deposition and development of renal lesions. At week 14, the pristane-SNF1 model recapitulated kidney disease parameters and molecular signatures seen in spontaneous disease in 36 week-old SNF1 mice and in a traditional IFNα-accelerated NZB X NZW F1 (BWF1) model. Blood transcriptome analysis revealed interferon, plasma cell, neutrophil, T-cell and protein synthesis signatures in the pristane-SNF1 model, all known to be present in the human disease. The pristane-SNF1 model appears to be particularly useful for preclinical research, robustly exhibiting many characteristics reminiscent of human disease. These include i) a stronger upregulation of the cytosolic nucleic acid sensing pathway, which is thought to be key component of the pathogenesis of the human disease, and ii) more prominent kidney interstitial inflammation and fibrosis, which have been both associated with poor prognosis in human LN. To our knowledge, this is the only accelerated model of LN that exhibits a robust tubulointerstitial inflammatory and fibrosis response. Taken together our data show that the pristane-SNF1 model is a novel accelerated model of LN with key features similar to human disease.

Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model.

BACKGROUND: Hyper-IgD and periodic fever syndrome (HIDS) is an hereditary autoinflammatory syndrome, characterised by recurrent inflammatory attacks. Treatment of HIDS is difficult, although simvastatin is beneficial and etanercept might be effective. Studying the treatment of a rare periodic syndrome is complicated by the varying frequency and severity of symptoms and low prevalence. Our aim was to develop a system of clinical observations to evaluate effectiveness of treatment-on-demand. METHODS: Seven fever episodes in three HIDS patients were monitored, with and without administration of etanercept or anakinra. We developed a clinical score, which includes 12 symptoms. In one patient, inflammatory attacks were provoked by vaccination. RESULTS AND CONCLUSIONS: At the onset of an attack, all patients reported a clinical score between 20 and 25. The score was used to quantify severity and define the end of an attack. Reproducible monitoring of inflammatory episodes was difficult, even in this pilot study. The effect of early administration of etanercept was variable. In one patient, a fever episode could be readily provoked within 12 to 24 hours by vaccination. In this patient, the IL-1ra analogue anakinra was more successful in aborting the inflammatory attack than etanercept. We propose that this vaccination model will allow evaluation of treatment-on-demand in a controlled setting.

Immune stimulation by an antisense oligomer complementary to the rev gene of HIV-1.

Mice developed massive splenomegaly and polyclonal hypergammaglobulinemia within 2 days after intravenous injection of a phosphorothioate oligomer that is antisense to a portion of the rev region of the HIV-1 genome. Histologic examination of spleens from injected animals showed marked expansion of a uniform-appearing population of small lymphocytes and many mitoses. Spleen mononuclear cells (SMNCs) from injected animals showed approximately a 10-fold-increased uptake of [3H]thymidine and production of IgM and IgG. Flow cytometry analysis indicated that the responding cells were predominantly B-lymphocytes. The anti-rev oligomer also was mitogenic in vitro and stimulated immunoglobulin production by normal mouse SMNCs and human peripheral blood mononuclear cells. Similar immunologic effects were observed with an anti-rev 21-mer phosphorothioate, truncated at the 3' end, but not with a 20-mer human p53 antisense phosphorothioate or a 28-mer anti-rev phosphodiester. These observations are consistent with the possibility that DNA sequences homologous to the rev gene participate in the regulation of mammalian lymphocyte activation, proliferation and maturation.

Characteristics of clometacin-induced hepatitis with special reference to the presence of anti-actin cable antibodies.

The clinical, biochemical, histopathological and immunological features of 30 cases of clometacin-induced hepatitis are described. The age range of the patients was 32-84 years with a notable female predominance of 29:1. The hepatitis was highly cytolytic with high values of transaminases but with little or no cholestasis. Gammaglobulins were higher than 18 g/l in 73% of the cases. 25 liver biopsies were performed and showed acute hepatitis with a predominant centrilobular necrosis in 17; chronic aggressive hepatitis was noted in 8 cases but 1 showed concomitant cirrhotic changes. Anti-tissue antibodies were looked for in all cases. Anti-smooth muscle antibodies of anti-actin cable type (titre 1/80 to 1/2, 560) were detected in 19 cases, anti-nucleus antibodies in 16 cases which were associated to the former in 14 cases. The above findings show that clometacin produces a hepatitis syndrome quite akin to autoimmune chronic active hepatitis (lupoid hepatitis) and to the hepatopathy induced by oxyphenisatin.

Detailed toxicity studies of liposomal gadolinium-DTPA.

Acute, subacute, and delayed toxicity testing was assessed in mice for liposomal gadolinium-DTPA (Gd-DTPA), blank liposomes, and nonliposomal Gd-DTPA. In the subacute experiments mice were injected intravenously (IV) with 0.3 mmol/kg Gd-DTPA per day for 30 days in the form of either free Gd-DTPA, liposomal Gd-DTPA, or an equivalent amount of lipid in blank liposomes without Gd-DTPA. The interpolated acute LD50 of liposomal and nonliposomal Gd-DTPA, estimated as a means of identifying the approximate level, was similar (LD50 = 5.7 mmol/kg Gd-DTPA). In subacute toxicity testing, prolonged high doses of liposomal Gd-DTPA caused splenomegaly, cardiomegaly, lymphocytopenia and hypergammaglobulinemia (P less than .05). Nonliposomal Gd-DTPA caused mild cardiomegaly and altered liver enzymes (P less than .05). Blank liposomes caused relatively mild splenomegaly (P less than .05) but few other changes. Delayed testing three months after the subacute testing showed that most of the changes caused by the liposomal Gd-DTPA were reversible.

Distinctive patterns of autoimmune response induced by different types of mineral oil.

Although mineral oils are generally considered nontoxic and have a long history of use in humans, the mineral oil Bayol F (incomplete Freund's adjuvant, IFA) and certain mineral oil components (squalene and n-hexadecane) induce lupus-related anti-nRNP/Sm or -Su autoantibodies in nonautoimmune mice. In the present study, we investigated whether medicinal mineral oils can induce other types of autoantibodies and whether structural features of hydrocarbons influence autoantibody specificity. Female 3-month-old BALB/c (16-45/group) mice each received an i.p. injection of pristane (C19), squalene (C30), IFA, three medicinal mineral oils (MO-F, MO-HT, MO-S), or PBS. Sera were tested for autoantibodies and immunoglobulin levels. Hydrocarbons were analyzed by gas chromatography/mass spectrometry. IFA contained mainly C15-C25 hydrocarbons, whereas MO-HT and MO-S contained C20-C40, and MO-F contained C15-C40. Pristane and n-hexadecane were found in IFA (0.17% and 0.10% w/v, respectively) and MOs (0.0026-0.027%). At 3 months, pristane and IFA induced mainly IgG2a, squalene IgG1, and MOs IgG3 and IgM in sera. Anti-cytoplasmic antibodies were common in mice treated with MO-F, as well as those treated with pristane, squalene, and IFA. Anti-ssDNA and -chromatin antibodies were higher in MO-F and MO-S than in untreated/PBS, squalene-, or IFA-treated mice, suggesting that there is variability in the induction of anti-nRNP/Sm versus -chromatin/DNA antibodies. The preferential induction of anti-chromatin/ssDNA antibodies without anti-nRNP/Sm/Su by MO-S and MO-F is consistent with the idea that different types of autoantibodies are regulated differently. Induction of autoantibodies by mineral oils considered nontoxic also may have pathogenetic implications in human autoimmune diseases.

Drinking water exposure to cadmium, an environmental contaminant, results in the exacerbation of autoimmune disease in the murine model.

Cadmium is a pervasive environmental contaminant. The primary route of exposure to the general population occurs via contaminated drinking water or food supplies. Our hypothesis was that cadmium could be a trigger for inducing autoimmune disease (AD) in genetically predisposed populations. Therefore, New Zealand Black/White F1 (NZBW) mice were exposed to cadmium via drinking water. Mice were exposed to: 0, 3, 30, 3000 or 10000 parts per billion (ppb) of cadmium in tap water for 2, 4, 28, or 31 weeks. After 4 weeks of exposure, in the group of mice exposed to 10000 ppb cadmium, there was an increased incidence of antinuclear antibodies (ANA). There was also deposition of immune complexes in all groups after 4 weeks of exposure. After 31 weeks, there were increases in IgG2a in mice exposed to low doses of cadmium. In an attempt to establish the progression from an autoimmune reaction to the development of AD, the biological marker for AD, proteinuria, was assessed. Onset of proteinuria was exacerbated by 11 weeks in mice exposed to cadmium. This data suggests that short-term exposure may result in a type of autoimmune reaction since the mice are beginning to produce ANA after only 4 weeks of exposure and there is immune-complex deposition in the kidney. Long-term exposure to cadmium appears to result in the exacerbation of AD as indicated by the development of proteinuria and continued presence of immune complexes in the kidney. The mechanism may involve the increased production of IgG2a, which is capable of forming immune complexes and causing autoimmune glomerulonephritis.

A case of angio-immunoblastic lymphadenopathy with dysproteinemia related to allopurinol.

A 63-year-old man developed generalized lymphadenopathy with skin rashes, fever, hepatomegaly and polyclonal hypergammaglobulinemia, twice, in February 1972 and in June 1979, after taking allopurinol for gout. Cervical lymph node biopsy, performed each time, showed the presence of immunoblasts and plasma cells, effaced nodal structure with involvement of the pericapsular tissue, rich vascularity and numerous mitoses, indicative of angio-immunoblastic lymphadenopathy with dysproteinemia (Frizzera, Moran and Rappaport). The existence of hypersensitivity to drugs, in particular, allopurinol in certain patients was emphasized, and induction of immunoblastic lymphadenopathy with various other therapeutic agents was briefly discussed.

[Effect of phenytoin and carbamazepine treatment on nonspecific immunological reactivity in epilepsy]. / Wplyw leczenia fenytonina i karbamazepina na odczynnowosc immunologiczna nieswoista u chorych z padaczka.

Immunological investigations were carried out assessing the humoral and cell-mediated immunity in 22 patients with epilepsy before starting treatment and at least one year after the onset of treatment with phenytoin or carbamazepine. Sixteen patients were treated with phenytoin and 6 with carbamazepine. In the group treated with phenytoin a statistically significant fall was observed in the serum level of IgG and a decrease in the value of blastic transformation of lymphocytes after stimulation with PHA and PPD with a rise in the number of lymphocytes forming total rosettes with sheep erythrocytes. In the group treated with carbamazepine only a statistically significant fall was observed in blastic transformation of lymphocytes stimulated with PHA, and a trend was noticed for increasing serum IgG and IgM levels. The observed changes in immunological reactivity caused by administration of phenytoin and carbamazepine show that these drugs exert an immunomodulating effect, but changes produced by them are slight and caused no immune deficit in the observed group.

[Serum levels of immunoglobulins and C 3 component of complement in persons occupationally exposed to chlorinated pesticides]. / Zawartosc immunoglobulin i skladnika C-3 dopelniacza w surowicy ludzi zawodowo narazonych na dzialanie pestycydów chlorowcopochodnych.

Serum concentrations of IgA, M, G and C-3 complement have been compared between 51 men occupationally exposed to chlorinated pesticides and 28 men of the control group. IgG has been found to be statistically significantly increased, whereas the concentration of IgM and C-3 complement--lower in the whole test group, as compared to the control group. These protein changes have been particularly strongly marked in the subgroup exposed to polycyclic chlorinated hydrocarbons. In the authors' opinion, the elevated IgG concentration in the occupationally exposed subgroup may result from immunostimulating effects of chlorinated pesticides, thus the decreased C-3 component of the complement in the serum in the test groups seems to be indicative of immune-complexes contribution to the pathogenesis of diseases resulting from the occupational exposure concerned. Furthermore, the authors suggest that the cyclic conformation of chlorinated pesticides may affect the pathomechanism of those diseases.

[Immunoelectrophorogram and serum levels of immunoglobulins G, A and M in automobile tire factory workers]. / Immunoelektroforogram oraz stezenia immunoglobulin G, A i M w surowicy krwi pracowników zakladow opon samochodowych.

Electrophoresis and immunoelectrophoresis of serum proteins and concentrations of IgG, IgA and IgM in serum were estimated in 87 rubber tire workers producing rubber mixtures (44 males) and tubes (25 males and 18 females). The total serum protein concentration, as compared with controls, was not changed, however the percentage of gamma globulins was elevated and that of albumins and alpha and beta globulins reduced. The immunoelectrophoretic distribution frequently showed a rise of acute phase proteins and immunoglobulins, most frequently those of IgG and IgA. Quantitative determinations showed a significant rise of serum IgG and IgA and in workers employed at the production of rubber mixtures also a fall of IgM concentrations, as compared to control groups.

[Immunoelectrophoretic data and serum immunoglobulin G, A and M levels in workers engaged in the production of organophosphate pesticides]. / Immunoelektroforogram oraz stezenie immunoglobulin G, A I M w surowicy krwi pracowników zatrudnionych przy produkcji pestycydów fosforoorganicznych.

Immunoelectrophoresis of serum proteins and concentrations of IgG, IgA and IgM in serum were estimated in 83 workers employed at the production of organic phosphorus insecticides. In 56.6% of immunoelectrophorograms deviations from normal were found, most frequently a rise of acute phase proteins and IgG. Quantitative determinations showed a rise of serum IgG and IgA and a fall of IgM concentrations as compared to a control group of nonexposed persons.

[Immunological effects of captopril and ramipril in patients with hypertension]. / Immunologicheskii éffekt kaptoprila i ramiprila u bol'nykh gipertonicheskoi bolezn'iu.

Fifteen patients with essential hypertension underwent treatment with captopril (7 patients) and ramipril (8 patients). The drugs belong to angiotensin-converting enzyme (ACE) inhibitors. Pretreatment immunological examination and that after a 10-15-week course of the above therapy involved measurements of IgG, IgA, IgE and beta 2-microglobulin. The analysis of the trend in the immunological indices demonstrated that captopril, distinct from ramipril by the presence of a sulfhydryl group, caused a decrease in immunological parameters suggesting a potential role of culfhydryl groups in mediating ACE inhibitor action on the immune system. The immunological properties of captopril may appear useful in various systemic diseases.

[Immunologic status of children living in a region with an increased level of nitrates in the drinking water]. / Immunnyi status detei, prozhivaiushchikh v raione s povyshennym soderzhaniem nitratov v pit'evoi vode.

Practically healthy schoolchildren living in the district with a high content of nitrates in drinking water experienced distinct quantitative and functional changes of immune indicators: violation of the ratio of immunoregulatory lymphocyte subpopulations, the high level of spontaneous T-lymphocyte blastogenesis, IgE-hyperglobulinemia. The above changes of the immune system could indicate both body sensitization and its desadaptation under unfavourable conditions.