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PubMed1995

Immunomodulation of autoimmunity in MRL/lpr mice with syngeneic bone marrow transplantation (SBMT).

MRL-lpr/lpr mice spontaneously develop a severe autoimmune syndrome, characterized by massive generalized lymphadenopathy, arthritis, arteritis, dermatitis and immune complex-mediated glomerulonephritis. Bone marrow transplantation (BMT) from MHC-matched systemic lupus erythematosus (SLE)-resistant donors to susceptible recipients has proved effective in correcting autoimmune manifestations in autoimmune-prone mice. We investigated the effect of syngeneic BMT from MRL/lpr (donor) to immunocompromised MRL/lpr (recipient), after purging the bone marrow inoculum with MoAbs against mature T cells (anti-Thy 1.2). All the untreated mice developed lymphadenopathy and by the age of 36 weeks five of the eight were dead; in contrast, all the mice which underwent syngeneic BMT following acute immunosuppression with total body irradiation (900 cGy) (TBI) remained disease-free. In an additional experiment, it was found that conditioning with cyclophosphamide (CY) before BMT was more effective than TBI in inhibiting delayed-onset autoimmune manifestations (mean survival 350 days in the CY group and 305 days in the TBI group, versus 197 days in untreated controls). Under both immunosuppressive regimens T cell-depleted bone marrow grafts produced far better results than did unmanipulated BMT. Following syngeneic BMT the incidence of proteinuria and the level of serum anti-DNA (dd) antibodies were significantly reduced, compared with that of the age-matched untreated controls. CY was more effective than TBI in reducing the anti-DNA titres. Likewise, T depletion of bone marrow inocula before BMT induced a more drastic drop in autoantibodies, following both CY and TBI conditioning protocols. After syngeneic BMT (either CY or TBI) no signs of lymphadenopathy were observed even at an advanced age. Upon histopathological examination, the BMT-treated mice displayed normal glomeruli with occasional minimal signs of glomerulonephritis. Syngeneic T cell-depleted BMT following acute cytoreduction of anti-self immune lymphocytes may represent a new therapeutic approach for drug-resistant autoimmune diseases.

Animals↗
PubMed1987

Antibodies to penicillin in children receiving long-term secondary prophylaxis for rheumatic fever.

The occurrence of IgE and IgG antibodies to penicillin G and V in children on long-term treatment with penicillin as secondary prophylaxis for rheumatic fever was studied using Phadebas RAST (Pharmacia Diagnostics, Uppsala, Sweden) and ELISA respectively. The duration of the prophylaxis ranged between 1.5 months and 5 years (mean 1.8 years). Of 18 patients who had been given penicillin for more than 1.5 months, two had IgE antibodies and 12 had IgG antibodies to penicillin. Patients with acute rheumatic fever who had not yet received long-term treatment with penicillin had antibodies of the IgG class in two out of 12 cases. The patients gave no history of adverse reactions to the penicillin injections and there were no signs of immune complex-mediated disease. The two children who had IgE antibodies were switched to oral erythromycin instead of the penicillin injections. Penicillin is the drug of choice in the prophylaxis of rheumatic fever and can apparently be safely given as intramuscular injections of depot-penicillin to prevent recurrences of the disease and ensuing cardiac damage.

Child↗
PubMed2004

Successful renal transplantation following prior bone marrow transplantation in pediatric patients.

Improving survival rates following pediatric bone marrow transplantation (BMT) will likely result in greater numbers of children progressing to end-stage renal disease (ESRD) because of prior chemotherapy, irradiation, sepsis, and exposure to nephrotoxic agents. Renal transplantation remains the treatment of choice for ESRD; however, the safety of renal transplantation in this unique population is not well established. We report our experience with living related renal transplantation in three pediatric patients with ESRD following prior BMT. Two patients with neuroblastoma and ESRD because of BMT nephropathy, and one patient with Schimke immuno-osseous dysplasia and ESRD because of immune complex mediated glomerulonephritis and nephrotic syndrome. Age at time of BMT ranged from 2 to 7 yr. All patients had stable bone marrow function prior to renal transplantation. Age at renal transplant ranged from 8 to 14 yr. All three patients have been managed with conventional immunosuppression, as no patient received a kidney and BMT from the same donor source. These patients are currently 7 months to 6 yr status post-living related transplant. All have functioning bone marrow and kidney transplants, with serum creatinine levels ranging 0.6-1.2 mg/dL. There have been no episodes of rejection. One patient with a history of grade III skin and grade IV gastrointestinal-graft-vs.-host disease (GI-GVHD) prior to transplantation, had a mild flare of GI-GVHD (grade I) post-renal transplant and is currently asymptomatic. The incidence of opportunistic infection has been comparable with our pediatric renal transplant population without prior BMT. One patient was treated for basal cell carcinoma via wide local excision. Renal transplantation is an excellent option for the treatment of pediatric patients with ESRD following BMT. Short-term results in this small population show promising patient and graft survival, however long-term follow-up is needed. Pre-existing immune system impairment and bone marrow function should be taken into consideration when weighing different immunosuppressive agents for renal transplantation. Patients who have undergone renal transplantation following BMT are at high risk for opportunistic infections and malignancy, and need life-long medical surveillance.

Adolescent↗
PubMed1982

Renal glomerular changes associated with liver cirrhosis.

Renal glomerular changes associated with 79 liver cirrhosis cases were studied by light and electron microscopy, and immunofluorescent methods. The glomerular changes were classified as follows: 1) Mixed membranous and proliferative glomerulonephritis type having subepithelial, subendothelial, mesangial and paramesangial deposits (37 cases), 2) membranous glomerulonephropathy type (6 cases), 3) IgA nephropathy type (3 cases), and 4) glomerulosclerosis types (5 cases). Clinically, the patients with marked renal glomerular changes and proteinuria, hematuria, and retention by the PSP test. It was suggested that the essential renal glomerular changes in liver cirrhosis was immune-complex mediated glomerulonephritis and that glomerular sclerosis was merely a secondary change to glomerulonephritis.

Fluorescent Antibody Technique↗
PubMed1994

Minocycline-induced hemolytic anemia.

A case of drug-induced immune hemolytic anemia is described. A 2 year old boy exhibited sudden anemia and hemoglobinuria after administration of minocycline (MINO). The specific immunoglobulin G antibody against MINO was demonstrated in the patient's serum by western blotting. This is a rare example where anti-minocycline immune complex-mediated hemolysis was responsible for an intravascular hemolytic process.

Anemia↗
PubMed2006

A novel category of enteropathogenic Escherichia coli simultaneously utilizes the Nck and TccP pathways to induce actin remodelling.

Enterohaemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) induce drastic reorganization of the microfilament cytoskeleton. EHEC and EPEC translocate Tir (translocated intimin receptor) which, once inserted into the host plasma membrane, binds the bacterial outer membrane adhesin intimin. Tir(EPEC) then becomes tyrosine phosphorylated facilitating the recruitment and site-specific binding of the eukaryotic adaptor Nck, which in turn binds and activates the Wiskott-Aldrich syndrome protein (N-WASP), leading to actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. In contrast, Tir(EHEC) has no Nck binding site; instead, EHEC utilizes the translocated effector TccP (Tir-cytoskeleton coupling protein) to bind and activate N-WASP. Here we report a novel class of EPEC that translocates both TccP and Tir(EPEC)-like effector molecules. Consistent with these characteristics, we show that both the Tir-Nck and Tir:TccP actin remodelling pathways function simultaneously during infection, making this a novel and versatile EPEC category.

Actins↗
PubMedDate not supplied

Physiological and pathological roles of Apaf1 and the apoptosome.

Different cellular pathways can lead to apoptosis. Apaf1 is the molecular core of the apoptosome, a multiproteic complex mediating the so-called mitochondrial pathway of cell death. The importance of this pathway during development has been clearly demonstrated by knocking out key genes. Also, the relevance of Apaf1 dosage during development has been recently underlined. Moreover, a growing body of evidences seems to point out a possible role of the mitochondria-dependent apoptosis in different pathologies. In particular, we discuss here some recent evidences regarding the putative role of the apoptosome in neurodegeneration and cancer.

Animals↗
PubMed1996

High-titer interferon-alpha antibodies in a patient with pemphigus foliaceus.

Among 13 patients with pemphigus or bullous pemphigoid, high titers of anti-interferon-alpha (IFN-alpha) antibodies were present in all serum samples of one patient suffering from pemphigus foliaceus. This patient was characterized by a relatively benign course of the disease. The IFN antibodies were of oligoclonal or polyclonal origin, predominantly of the IgG subtype, and displayed a broad spectrum of specificity including various natural and recombinant IFN-alpha subtypes as well as recombinant IFN-omega 1. In vitro, these antibodies neutralized both the antiviral and antiproliferative activities of the respective IFN types. Recognition of the patient's endogenous IFN-alpha demonstrated their autoantibody nature. The IFN antibodies were present at diagnosis and resistant to continued immunosuppressive treatment. Despite clinical remission, the IFN antibodies persisted, suggesting that they were not pathogenically related to the skin manifestations of the pemphigus. There were no sings of immune complex-mediated organ damage. IFN antibodies constitute a new class of autoantibodies that may occur in conjunction with pemphigus and likely interfere with the endogenous IFN system.

Adult↗
PubMed1996

Melatonin reduces mortality from Aleutian disease in mink (Mustela vison).

Aleutian disease (AD) results from a persistent parvoviral infection that results in marked hypergammaglobulinemia and immune complex mediated lesions of the kidney, liver, lungs and, arteries. Melatonin protected both a wild type or demi strain and a demi/dark crossed strain of mink from AD. The biogenic amine also afforded protection against other non-diagnosed diseases naturally found on mink farms when it was available from a subcutaneously-placed reservoir. Some genetic strains of mink apparently differed in the resistance of mink to the virus and in the protective ability of melatonin. The demi strain was the most resistant followed by pastels, mahogany, darks, and those strains with the double recessive Aleutian gene. The protective action of melatonin appeared to result from melatonin's ability to scavenge free radicals, but it could also be due to the induction of antioxidant enzymes or to the modulation of immunity. Melatonin also protected mink against distemper.

Aleutian Mink Disease↗
PubMed1988

Pathological and immunological effects of surgically induced varicocele in juvenile and adult rats.

The presence of a varicocele in adult men has been correlated with infertility. This study documents the effect of an experimentally induced unilateral varicocele in 21-day-old juvenile prepubertal and 51-day-old adult rats (n = 10 per group) on subsequent adult testicular function. Varicoceles were induced by partial occlusion of the spermatic vein. There were ten sham-operated and five nonoperated control rats in each age group. The rats were sacrificed 1 month after surgery. Intrascrotal temperatures were elevated in both groups with varicoceles. Histologically, the ipsilateral testes of rats in both age groups demonstrated a decrease in the numbers of functioning seminiferous tubules and germ cells, but the decrease was significantly greater in the juveniles than in the adult rats. No changes were seen in the contralateral testes. Significant titers of cytotoxic sperm antibodies were present in all animals with varicoceles, which is in contrast to controls. The juveniles had significantly lower antibody titers (mean log2 +/- SEM; 3.2 +/- 0.09 vs. 8.5 +/- 1.1, P less than 0.001) than the adults. The induction of a unilateral varicocele damaged spermatogenesis and testicular function to a greater extent in juveniles than in adult rats. This damage may be immune complex-mediated.

Age Factors↗
PubMed1989

Collagen induced arthritis as an experimental model for rheumatoid arthritis. Immunogenetics, pathogenesis and autoimmunity.

The type II collagen (CII) induced arthritis animal model (CIA) provides opportunities to study the nature of autoimmune reactions leading to arthritis and may be used as a model for rheumatoid arthritis (RA). Thus, in similarity with RA, the CIA model, when induced with autologous CII, shows a chronic and progressive disease course. The susceptibility to both RA and CIA are correlated to the expression of certain MHC class II allotype genes. In both diseases are autoantibodies to CII and rheumatoid factors produced. Immunohistopathology of affected joints show in both diseases a dominance of activated macrophages/fibroblasts with a significant infiltration of activated T cells and an infiltration of granulocytes. We do here suggest that both RA and CIA are dependent on a synergy between delayed type hypersensitivity and immune complex mediated inflammatory mechanisms and that CIA provides opportunities for studies of immunospecific reactions leading to arthritis.

Animals↗
PubMed1983

Anti-idiotypic antibodies and autoantibodies.

In this paper, we have provided experimental evidence that antibodies to autoantigens bear common idiotypes and that this property makes them susceptible to anti-idiotypic regulation. Spontaneously occurring autoantibodies to Tg in rats have been extensively investigated as a model of immune response responsible for the appearance of autoimmune disease. Large idiotypic cross-reactivity was found among autoantibodies of various individual animals. Similarly, a high degree of idiotypic relatedness was found among mouse monoclonal antibodies reacting with a highly conserved antigenic domain of thyroglobulin. Both rat and mice idiotype were found to be present on spontaneous and induced antibodies to rat thyroglobulin from individuals of other species. In vivo experiments showed that anti-idiotypic antibodies can be effective in suppressing autoantibodies formation. In the induced TIN in BN rats, a single injection of anti-idiotypic serum prior to the induction of autoimmune disease was sufficient to generate a significant selective suppression of autoantibodies produced against a pathogenetic chemical form of the autoantigen, that is, the one against which the autoantibodies used to prepare the anti-idiotypic reagent as mostly reactive. Similarly, it was found that repeated injections of anti-idiotype into rats with ongoing spontaneous production of autoantibodies to thyroglobulin were able to significantly decrease the amount of circulating autoantibodies from the pretreatment values. Thus, although the beneficial effect of anti-idiotype observed in these experiments was only partial, indications were obtained that a specific anti-idiotypic immunity can be used to regulate autoantibody production. Finally, evidence has been provided to support the hypothesis that auto-anti-idiotype, as a normal constituent of the immune response, can be responsible for the potentiation of immune complex-mediated tissue injury that is often the hallmark of autoimmune diseases.

Animals↗
PubMed1994

Asbestos-induced nitric oxide production: synergistic effect with interferon-gamma.

This study has shown, for the first time, that in vitro exposure of rat AMs to either crocidolite (amphibole) or chrysotile (serpentine) asbestos fibers induces the synthesis not only of the O2*- anion, but also of the nitrogen radical, NO*. Furthermore, this asbestos-related effect is enhanced in the presence of interferon-gamma. NO* has been implicated in several pathologic reactions, such as inflammation and immune complex-mediated cell injury. Additionally, NO* may interact with secondary amines to generate nitrosamines, which are potent carcinogens. Our findings could represent a novel type of asbestos-mediated injury, and we propose that the injurious effects of asbestos might be mediated via the interaction of NO* with O2*-, with the generation of ONOO- and other potent toxic free radicals.

Animals↗
PubMed1998

Hormones, pregnancy, and autoimmune diseases.

Hormonal factors linked to age, gender, and reproductive status are undoubtedly involved in regulating the onset of numerous autoimmune diseases. For example, systemic lupus erythematosus (SLE), a disease characterized by immune complex-mediated pathology linked to excess Th2 cytokine production (e.g., IL-10) primarily affects women in the reproductive years. Rheumatoid arthritis (RA), a disease characterized primarily by cell-mediated joint immunopathology linked to deficient Th2 cytokine production, is also more common in women, but, in contrast to SLE, the highest incidence is at menopause. Pregnancy-associated changes in these diseases, however, provide the most compelling evidence that hormonal factors play a major role in modulating the expression of these diseases. SLE often flares during pregnancy, whereas RA commonly remits during pregnancy and flares or initially develops in the postpartum period. These observations appear to be explained by the accumulating data indicating that during pregnancy cell-mediated immune function and Th1 cytokine production (e.g., IL-12, interferon-gamma) are suppressed, and humoral immunity and Th2 cytokine production (e.g., IL-4, IL-10) are enhanced. These patterns reverse in the postpartum period. In other words, antithetical Th1/Th2 cytokine profiles appear to characterize pregnancy and the postpartum period. Strong evidence now indicates that changes in the production of cortisol, progesterone, and estrogen play a major role in modulating Th1/Th2 cytokine balance.

Animals↗
PubMed2003

Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity.

Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the roles that specific genes play in lupus, we have examined the disease profiles in mice with single-gene deletions. In total, some 17 genes have been studied. Absence of certain genes, such as CD40L, CD28, or Igh6, abrogated induction of autoimmunity. Other genes, such as Igh5, IL-4, or ICAM-1, had little effect on the development of disease. Intermediate effects were observed in IL-6-deficient mice, while absence of beta2-microglobulin resulted in loss of hypergammaglobulinemia and IgG1 autoantibodies, but produced little change in anti-chromatin antibodies or glomerular deposits. The most interesting observations were obtained with genes related to the expression or function of interferon-gamma (IFN-gamma). Reductions in IFN-gamma levels in murine lupus are associated with reductions in both autoantibody levels and immune-complex- mediated pathology. Genes involved in up-regulation of IFN-gamma expression, such as IL-12, STAT-4, or ICE, did not significantly influence autoimmunity, whereas absence of IFN-gamma or IFN-gamma receptor led to greatly reduced autoantibody response and immunopathology. Absence of IRF-1, a gene ex-pressed in response to IFN-gamma, resulted in selective retention of anti-chromatin antibodies but little glomerular pathology. These studies suggest that the presence of a baseline level of IFN-gamma, rather than increased expression, is important for autoimmunity. Furthermore, as the IRF-1 knockout demonstrates, specific defects in signaling pathways and gene expression subsequent to IFN-gamma/IFN-gamma receptor interaction may influence only certain disease parameters. It has not escaped our attention that IFN-gamma influences the expression and function of other immunologically relevant genes, such as IL-4, IL-6, and beta2-microglobulin. Thus, these genes may be part of the downstream events following IFN-gamma/IFN-gamma receptor interaction that promote the development of autoimmunity.

Animals↗
PubMed1985

Effects of acute and chronic treatment on the pro- and anti-convulsant actions of CL 218, 872, PK 8165 and PK 9084, putative ligands for the benzodiazepine receptor.

CL 218,872 is a triazolopyridazine that acts at the benzodiazepine binding site. At low doses (0.5-7.5 mg kg-1) it is proconvulsant when combined with subconvulsant doses of picrotoxin but not when combined with pentetrazol (leptazol, pentylenetetrazol). At high doses (20-60 mg kg-1) CL 218,872 counteracted seizures caused by pentetrazol but not those caused by picrotoxin. There was tolerance to the proconvulsant effects after five days of treatment and to the anticonvulsant effects after 15-20 days. Two phenylquinolines, PK 8165 and PK 9084, that also act at the GABA-benzodiazepine receptor complex have proconvulsant actions in combination with picrotoxin. Significant tolerance to these effects had not developed even after 20 days of treatment. It is concluded that three different sites on the GABA-benzodiazepine complex mediate the pro- and anti-convulsant actions of CL 218,872 and the proconvulsant actions of PK 8165 and PK 9084.

Animals↗
PubMed1969

The effect of membrane polarization on the time course of the end-plate current in frog sartorius muscle.

1. Intracellular recordings of the end-plate current at different membrane potentials were made, using a voltage-clamp technique.2. When the membrane potential is varied between about +40 and -120 mV, the half-decline time of the end-plate current increases from about 0.6 msec to about 1.6 msec.3. It is suggested that the stability of receptor-mediator complex is affected by the membrane potential.

Animals↗