Regarding "A moment with endocrinology and metabolism" Maryland Medical Journal November 1993.
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Humans↗
Biomedical subjects
A Friedman
Publications and source records attributed to A Friedman.
Oral tolerance: a biologically relevant pathway to generate peripheral tolerance against external and self antigens.
OT is a relevant biological pathway for generating peripheral tolerance against both self and external antigens with minimal side effects (fig. 3). This route might, therefore, contain promising potential for the treatment of autoimmune and allergic diseases in the human (fig. 3). Thus, oral administration of autoantigens suppresses experimental autoimmune diseases (EAE, EAU, AA, collagen-induced arthritis, NOD diabetes) in a disease- and antigen-specific manner, and oral administration of alloantigens has led to increase of allograft survival. OT might be important in treatment of immune complex diseases and food allergies. OT is mediated by T lymphocytes using at least two nonmutually exclusive mechanisms: suppression and anergy. Suppression can be adoptively transferred by CD8+ T lymphocytes which act by releasing TGF-beta and IL-4 following antigen-specific triggering. Antigen-driven tissue-directed suppression occurs following oral administration of an antigen from the target organ, even if it is not the disease-inducing antigen (bystander suppression). Thus, synthetic peptides can induce OT, and tolerogenic epitopes of antigen may be different from the autoreactive epitope. Due to the promising results in animal models, OT is being tested in clinical trials in multiple sclerosis, rheumatoid arthritis and uveitis [193, 194].
Administration, Oral↗
[Mossbauer spectroscopy of iron in substantia nigra in Parkinson disease and controls].
Mössbauer spectroscopy was used to study iron content, its redox state and binding sites in substantia nigra from parkinsonian and control brains. Measurements performed on fresh frozen samples demonstrated the presence of ferric iron only, both in disease and control. We found no difference in the total amount of iron in substantia nigra between the disease and control. Mössbauer spectra observed at 4.1 K in fresh frozen samples were different from those obtained in formalin fixed samples. In the fresh frozen samples only ferritin like iron was observed, whereas in the formalin fixed samples also non-ferritin iron was detected. It seems that in formalin fixed brains, during years, iron is released from ferritin and bound to an iron chelator or formalin.
Aged↗
Analysis of donor age and cold ischemia time as factors in cadaveric human islet isolation.
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Adult↗
Pituitary-testicular function in nephropathic cystinosis.
OBJECTIVE: To evaluate reproductive function in patients with cystinosis and in renal transplant recipients without cystinosis. DESIGN: Cross-sectional study. SETTING: Clinical Center, National Institutes of Health. PATIENTS: Ten male patients, 15 to 28 years old, with nephropathic cystinosis and renal allografts formed the study group; 11 renal transplant recipients who had a primary renal disorder other than cystinosis and were matched with study patients for age and renal function served as the control group. MEASUREMENTS: Tanner staging, serum gonadotropin determinations, and testosterone and testosterone-binding globulin assessments. Selected patients also had a human chorionic gonadotropin (HCG) stimulation test, a gonadotropin-releasing hormone (GnRH) stimulation test, and serial sampling for luteinizing hormone (LH). MAIN RESULTS: Although testosterone levels were within normal limits in 7 of 10 patients with cystinosis, the mean testosterone level in patients with cystinosis was 11.5 +/- 2.0 nmol/L compared with 24.2 +/- 3.0 nmol/L in control patients (P < 0.005). No patient with cystinosis reached Tanner stage 5 (full pubertal development), whereas 9 of 11 control patients did. Seven of 10 patients with cystinosis had elevations in LH or follicle-stimulating hormone (FSH) levels, suggesting testicular failure. These patients also had normal LH and FSH responses after GnRH stimulation, increased LH pulse frequency, and reduced testosterone response after HCG stimulation. In comparison, only 3 of 11 control patients had minimally elevated gonadotropin levels, and all 11 had normal testosterone levels. Microscopic testicular examination in one patient showed cystine crystals, germinal dysplasia, increased fibrosis, and Leydig cell hyperplasia. CONCLUSIONS: Abnormalities in the pituitary-testicular axis are common in male patients with cystinosis. These changes appear to be related to the disease cystinosis and not to treated renal failure per se.
Adolescent↗
Galloway-Mowat syndrome of abnormal gyral patterns and glomerulopathy.
The combination of microcephaly, gyral abnormalities, developmental delay, and a glomerulopathy constitutes a recognizable syndrome. The inheritance is autosomal recessive. Additional abnormalities may include seizures, minor facial anomalies, and hiatal hernia. Onset of proteinuria often occurs in the first 3 months of life, but always before age 3 years. A uniform pattern of renal histologic changes has not been found. There is no effective treatment for the neurologic or renal manifestations of this condition. The prognosis is extremely poor; every patient but one has died before age 5 1/2 years. Antenatal diagnosis may be possible.
Abnormalities, Multiple↗
Targeted delivery of peptide epitopes to class I major histocompatibility molecules by a modified Pseudomonas exotoxin.
Cytotoxic T lymphocytes (CTLs) expressing the CD8 surface marker recognize peptides in association with major histocompatibility complex (MHC) class I molecules. Although most peptides expressed on MHC class I molecules are derived from self- or virally encoded proteins, delivery of exogenous proteins to the cytosol can result in their being processed for presentation to CTLs on MHC class I molecules. We describe two fusion proteins (PEMa and PENP), consisting of the binding and translocating domains of Pseudomonas exotoxin A (PE), fused to peptide epitopes from influenza A matrix protein and nucleoprotein, respectively. These fusion proteins were internalized and processed by MHC class I-positive target cells, resulting in sensitization of target cells for lysis by peptide-specific CTLs. A point mutation known to interfere with intoxication by wild-type PE also reduced the ability of PEMa to sensitize target cells. Fusion of peptide or polypeptide epitopes with PE provides a potential means of eliciting CTLs without the use of self-replicating agents, as well as a useful probe for studying MHC class I-restricted antigen processing.
ADP Ribose Transferases↗
Heterologous protection against influenza by injection of DNA encoding a viral protein.
Cytotoxic T lymphocytes (CTLs) specific for conserved viral antigens can respond to different strains of virus, in contrast to antibodies, which are generally strain-specific. The generation of such CTLs in vivo usually requires endogenous expression of the antigen, as occurs in the case of virus infection. To generate a viral antigen for presentation to the immune system without the limitations of direct peptide delivery or viral vectors, plasmid DNA encoding influenza A nucleoprotein was injected into the quadriceps of BALB/c mice. This resulted in the generation of nucleoprotein-specific CTLs and protection from a subsequent challenge with a heterologous strain of influenza A virus, as measured by decreased viral lung titers, inhibition of mass loss, and increased survival.
Animals↗
Direct evidence for anergy in T lymphocytes tolerized by oral administration of ovalbumin.
The present study investigated bystander suppression, specific suppression and anergy as mechanisms for oral tolerance. Oral tolerance was induced in mice by a single gastric intubation of 20 mg ovalbumin (OVA) and was evaluated in vitro by the absence of T lymphocyte proliferative responses to OVA after priming by OVA-complete Freund's adjuvant (CFA). T lymphocyte unresponsiveness was antigen specific, systemic and was not affected by the vehicle used for immunization. T lymphocytes derived from tolerant popliteal lymph nodes (PLN) responded to an acetone precipitate (AP) of mycobacteria present in CFA; this response was not suppressed by co-culture with OVA, thereby arguing against a mechanism of bystander suppression in our system. Responses of PLN T lymphocytes derived from OVA-CFA primed, non-tolerant mice, or those of an OVA-specific T lymphocyte line, were not suppressed by PLN or spleen cells derived from OVA tolerant mice. These results excluded the possibility that oral tolerance was induced and maintained by a mechanism of specific suppression. At the cellular level, we found that OVA-tolerant T lymphocytes did not produce interleukin-2 (IL-2) nor express IL-2 receptor in response to OVA stimulation in vitro; both observations are indicative of a state of anergy. Incubation of OVA-tolerant PLN T lymphocytes together with murine recombinant IL-2 for 5 days, released anergic T lymphocytes and a concomitant OVA-specific proliferative response of CD4+ T cells was detected. Taken together, our experimental system excludes the involvement of bystander or specific suppression in the induction of oral tolerance to OVA, and provides direct evidence to show that oral tolerance results from specific T lymphocyte anergy.
Administration, Oral↗
Modification of the immune response by oral tolerance: antigen requirements and interaction with immunogenic stimuli.
The present study was undertaken to define requirements for antigen in induction and maintenance of oral tolerance and to evaluate the interrelationship between simultaneously administered oral tolerogenic and parenteral immunogenic stimuli. Tolerance was induced by a single gastric intubation of OVA and was assessed by absence of OVA-specific T lymphocyte proliferation in vitro. Tolerance was short termed and held for 21 days in the absence of additional antigen; alternatively, antigen persistence enabled prolonged maintenance of tolerance. Since tolerogenic and immunogenic stimuli reflect two distinct pathways of the immune system, we investigated the consequences of their simultaneous administration. When tolerogenic stimuli preceded immunogenic stimuli up to a minimal period of 24 hr, unresponsiveness dominated. Furthermore, tolerogenic stimuli were able to reduce the level of T lymphocyte proliferation when administered at the time of, and after, immunization. The degree of reduction was inversely related to the interval between parenteral immunization and gastric intubation. Repeated tolerogenic stimuli caused a further substantial reduction in residual T lymphocyte responses. These findings indicate that prevalence of tolerance in the immune response requires rapid dissemination and long term persistence of antigen.
Administration, Oral↗
Retinoic acid promotes proliferation and induces expression of retinoic acid receptor-alpha gene in murine T lymphocytes.
We have studied the direct effect of retinoic acid on the antigen-specific proliferative response of a T lymphocyte clone and have investigated the related expression of the retinoic acid receptor-alpha gene (RAR-alpha). Retinoic acid provided direct growth support, in a dose-dependent manner, for hen egg white lysozyme (HEL)-activated T lymphocytes in serum-free medium. The increase of T lymphocyte proliferation supported by retinoic acid was dose dependent, and best effects were achieved at physiological concentrations (10(-9)-10(-7) mol/liter). Expression of RAR-alpha mRNA in antigen-stimulated T lymphocyte cultures was upregulated by retinoic acid in a dose-dependent manner; maximal expression occurred within 6 hr of culture and in response to 10(-9)-10(-7) mol/liter retinoic acid. Lower expression of RAR-alpha was attained by antigen or mitogen (concanavalin A) in the absence of externally added retinoic acid. The inclusion of retinoic acid at the time of HEL processing led to increased T lymphocyte proliferation, provided antigen presenting cell cultures had been maintained for 16 hr. Our results indicate that retinoic acid and RAR-alpha might function in T lymphocytes in a manner similar to that described in other cell systems, namely as ligand-inducible transcriptional enhancer factors.
Animals↗
Heterologous and homologous protection against influenza A by DNA vaccination: optimization of DNA vectors.
We have recently shown that direct injection of DNA can be an effective vaccine strategy eliciting both humoral and cell-mediated immune responses. Vectors were designed specifically for vaccination by direct DNA injection and refined to improve plasmid production in Escherichia coli. The vectors consist of a pUC-19 backbone with the cytomegalovirus (CMV) IE1 enhancer, promoter, and intron A transcription regulatory elements and the BGH polyadenylation sequences driving the expression of the reporter gene CAT or influenza A nucleoprotein (NP) or hemagglutinin (HA). The respective vectors expressed high levels of chloramphenicol acetyltransferase (CAT) and NP in tissue culture, and yielded 14-15 mg of purified plasmid per liter of Escherichia coli culture. Immunization of mice with the NP and HA expression vectors resulted in protection from subsequent lethal challenges of influenza using either heterologous or homologous strains, respectively.
Animals↗
Adjuvant arthritis is associated with changes in the glycosylation of serum IgG1 and IgG2b.
The increased amounts of agalactosyl IgG (N-linked oligosaccharides terminating with N-acetylglucosamine (GlcNAc) in the serum of patients with rheumatoid arthritis (RA) and other chronic inflammatory diseases have suggested that agalactosyl IgG may be involved in the pathogenesis of RA. We have now evaluated the incidence of agalactosyl IgG in the Lewis rat during the course of adjuvant arthritis (AA). The modification in glycosylation of IgG was measured by means of polyclonal and monoclonal anti GlcNAc antibodies as well as by the lectin concanavalin A (Con A). The results show that Lewis rats undergo a change in serum IgG glycosylation during the course of AA. As in human RA patients, rats with AA lack terminal galactose on IgG heavy chain oligosaccharides, and the terminal GlcNAc or mannose residues are thus exposed. The degree of agalactosyl IgG was positively correlated with the incidence of disease, peaked 20 days after disease induction, and the IgG gradually reverted to the fully glycosylated form thereafter. The post-arthritic glycosylation profile was very similar to that characteristic of the naive animal. Purified IgG was shown to contain two IgG subclasses, IgG1 and IgG2b, which underwent changes in glycosylation. Western blot analysis revealed that IgG1 expressed a higher degree of terminal mannose, whereas IgG2b expressed a higher degree of terminal GlcNAc. These findings raise the question of the possible involvement of agalactosyl IgG in immune complex-mediated inflammation.
Acetylglucosamine↗
Stepwise repolarization from Ca2+ plateaus in neocortical pyramidal cells: evidence for nonhomogeneous distribution of HVA Ca2+ channels in dendrites.
Although cortical dendrites have classically been thought of as passive structures, recent evidence suggests that active conductances, including Ca2+ conductance, are also present in the dendritic membrane. To investigate this, we have recorded intracellularly in slices of rat neocortex bathed in 24 mM tetraethylammonium chloride and 1 microM TTX. Under these conditions, pyramidal neurons generated prolonged Ca2+ spikes. In computer simulations, the breakpoint voltage from which the plateau level began to repolarize was closely related to a specific region on the voltage/activation curve of the high-voltage-activated Ca2+ conductance underlying the spike. This modeling result was supported by the experimental observation that substituting Ba2+ for Ca2+ caused a hyperpolarizing shift in breakpoint voltage by 8-10 mV. Often there was stepwise repolarization from the Ca2+ spike to one or more additional plateau levels. In compartmental computer models, this could be simulated by two different mechanisms: (1) the presence of multiple, electrotonically separated sites of Ca2+ spike electrogenesis in the dendritic tree, and (2) the presence of Ca2+ channels with different voltage dependencies in the same compartment. In experiments, brief hyperpolarizing pulses could cut short the high-amplitude plateau without terminating the smaller "steps." This result could be simulated by both computer models. However, only the multicompartmental model could simulate effects of prolonged depolarizing and hyperpolarizing currents on the breakpoint. Thus, the more depolarized the breakpoint, and hence the closer the spike initiation zone to the recording site, the less it was affected by the injected current. In experiments, the ratio of the breakpoint voltages for the different plateau levels was equal to the ratio of the highest repolarization rates. These data indicate that the breakpoint voltage and the time course of repolarization were the same at all the sites of Ca2+ electrogenesis. Our findings provide strong evidence that Ca2+ spike initiation occurs at electrotonically separated "hot spots" in the dendrites, and that voltage dependence of the Ca2+ channels that underlie the spikes is the same at all sites.
Animals↗
Pore formation and mitogenicity in blood cells by the class 2 protein of Neisseria meningitidis.
The class 2 outer membrane protein (MIEP) of Neisseria meningitidis has recently been shown to be mitogenic for lymphocytes (Liu, M.A., Friedman, A., Tai, J., Martinez, D., Deck, R. R., Hawe, L. A., Shieh, J. T.-C., Jenkins, T. D., Donnelly, J. J., and Oliff, A. I. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 4633-4637. In this study, a possible connection between MIEP's mitogenicity and its possible action as a porin was investigated. MIEP, purified from the bacterial outer membrane protein complex under denaturing conditions, caused a modest but specific release of ions (86Rb) from both erythrocytes and lymphocytes, ultimately resulting in cell lysis. The dose-response of MIEP on erythrocyte lysis was qualitatively similar to a known porin (protein I from Neisseria gonorrhoeae) but was much less efficient. Induction or preservation of native structure in MIEP increased pore formation, resulting in levels comparable to that of the protein I porin. These observations suggest that native MIEP, free of the other outer membrane proteins of Neisseria meningitidis, can efficiently form pores in cells, but that denatured MIEP is variably and marginally effective. However, pore formation by MIEP was not related to its mitogenicity in lymphocytes, based on: (i) native MIEP was not mitogenic; (ii) denatured MIEP was highly mitogenic; and (iii) denatured MIEP was mitogenic at concentrations below the threshold level for pore formation. Therefore, mitogenicity is dependent upon MIEP being in a denatured, monomeric state and is masked by native conformation.
Bacterial Outer Membrane Proteins↗
Aspiration of ectopic pregnancy under guidance of vaginal ultrasonography.
This case report describes the treatment of tubal pregnancy by aspiration of the gestational sac content and injection of methotrexate by transvaginal sonographic guidance. The confirmation of the embryo aspiration as indicated by disappearance of the embryo with its heart beat and the resulting 46,XY karyotype, raises the question whether methotrexate injection is necessary.
Abortion, Therapeutic↗
A vaccine carrier derived from Neisseria meningitidis with mitogenic activity for lymphocytes.
Protein carriers vary in their ability to increase the immunogenicity of poorly immunogenic or T-lymphocyte-independent antigens. We examined one such carrier, the outer membrane protein complex derived from Neisseria meningitidis serogroup B strain B11, in an attempt to determine why this outer membrane protein complex was more immunogenic in young infants and in relevant animal models than two other carriers used in conjugates made with Haemophilus influenzae type b polysaccharide, a T-cell-independent antigen. A single protein of the outer membrane protein complex, the class 2 porin protein, was purified and shown to function as a T-helper lymphocyte carrier protein. Unexpectedly, it was also found to have mitogenic activity for lymphocytes that was not due to lipopolysaccharide. This mitogenic activity appears to date to be unique to this carrier protein of the carrier proteins tested and may contribute to the ability of the H. influenzae type b conjugate vaccine made with the outer membrane protein complex to generate IgG anti-polysaccharide antibody responses in mice and infant monkeys and protective immune responses in infants less than 6 months of age.
Animals↗
Slow depolarizing afterpotentials in neocortical neurons are sodium and calcium dependent.
Depolarizing afterpotentials (DAPs) were studied in intracellular recordings from neocortical slices bathed in tetrodotoxin (TTX) (1 microM) and tetraethylammonium chloride (TEA) (24 mM), to block voltage-dependent Na+ currents and most K+ currents. The DAP was Ca(2+)-dependent, in that its magnitude varied as a function of the duration of the preceding Ca2+ plateau. It had an apparent reversal potential of between -40 and -5 mV. The DAP was blocked when choline replaced all extracellular Na+; there was a hyperpolarizing shift in apparent reversal potential when extracellular Na+ was lowered. The DAP was blocked by amiloride (1 mM), which also decreased the preceding Ca2+ plateau. The data are consistent with the hypothesis that the DAP is due to electrogenic Na+/Ca2+ exchange.
Animals↗