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Biomedical subjects

D H Katz

Publications and source records attributed to D H Katz.

At least 37 records · Page 2Linked to original sources
PubMed1991

Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex.

This article reports that 1-docosanol, a 22-carbon-long saturated alcohol, exerts a substantial inhibitory effect on replication of certain viruses (e.g., herpes simplex virus and respiratory syncytial virus) within primary target cells in vitro. To study the basis for its viral inhibitory activity, a suspension of 1-docosanol was formulated in an inert and nontoxic surfactant, Pluronic F-68; this suspension exerted potent inhibitory activity on the ability of susceptible viruses to infect cultured target cells. Susceptible viruses included wild-type herpes simplex viruses 1 and 2 as well as acyclovir-resistant herpes simplex virus 2 and also respiratory syncytial virus--all of which are lipid-enveloped. In contrast, nonenveloped poliovirus was not susceptible to the inhibitory action of 1-docosanol. Although the precise mechanism has yet to be defined, current evidence suggests that 1-docosanol inhibits viral replication by interfering with the early intracellular events surrounding viral entry into target cells. It is possible that interaction between the highly lipophilic compound and components of target cell membranes renders such target cells less susceptible to viral fusion and/or entry. If this mechanism proves to be correct, 1-docosanol may provide a broad spectrum activity against many different viruses, especially those with lipid-containing envelopes.

Acyclovir↗
PubMed1991

The murine epsilon receptor modulating protein: a novel serine protease which modulates CD23 binding of IgE.

In our recent previous studies, we have identified and purified a murine 17-kDa protein which diminishes the avidity of binding between IgE and CD23 (low-affinity Fc receptor for IgE) without decreasing the quantitative expression of the CD23. The protein was thus designated epsilon receptor modulating protein (epsilon RMP). In this study, we have further characterized this protein and have found that (i) epsilon RMP is inactivated by phenylmethylsulfonyl fluoride and decomposes N,alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester, as well as N-succinyl-Ala-Ala-Pro-Phe p-nitroanilide; (ii) epsilon RMP does not work directly on B cells but requires CD4+ T cells to decrease functional expression of CD23 on B cells; and (iii) the partial internal amino acid sequence of epsilon RMP, obtained by using in situ cyanogen bromide cleavage on polyvinylidene difluoride membrane is unique. These data thus clearly demonstrate that epsilon RMP is a novel serine protease controlling the functional expression of CD23 through the participation of CD4+ T cells. Mechanisms of the involvement of CD4+ T cells are discussed.

14-3-3 Proteins↗
PubMed1991

Complete genomic sequence of the murine low affinity Fc receptor for IgE. Demonstration of alternative transcripts and conserved sequence elements.

The complete sequence of the murine low affinity Fc receptor for IgE (Fc epsilon RII), including the 5' and 3' flanking sequences, is reported. The murine Fc epsilon RII gene spans 12.9 kb and includes 12 exons surrounding 11 introns. The composite exon sequence is virtually identical to previously reported murine Fc epsilon RII cDNA sequences. Much of the proximal promoter regions of the mouse and human homologues of Fc epsilon RII show remarkable homology to each other, including three promoter elements previously identified for MHC class II genes. The reported exon/intron structure of the human FC epsilon RII is similar to the murine homologue, except that the latter has an additional exon coding for a fourth amino acid repetitive sequence (vs three in the human gene). RNase protection studies have identified an additional transcript within intron 2 of murine Fc epsilon RIIa, similar to the human Fc epsilon RIIb form but with a different predicted sequence of the first six amino acids. This transcript is present in the mRNA of purified splenic B cells, but not in the mRNA of the Fc epsilon RII+ B lymphoma cell line M12.4.5. The murine Fc epsilon RII gene contains a large intron (4.2 kb) separating the lectin and nonlectin coding regions, and several repetitive sequences are found clustered within this intron. These results emphasize the importance of the demarcation between these domains and allude to their evolutionary and functional significance.

Amino Acid Sequence↗
PubMed1991

Purification of murine suppressive factor of allergy into distinct CD23-modulating and IgE-suppressive proteins.

The murine suppressive factor of allergy (SFA) has been purified from a T-cell hybridoma and found to consist of two functionally and biochemically distinct protein molecules. One protein (17 kDa) modulates the low-affinity Fc receptor for IgE on lymphocytes (i.e., CD23); it decreases the binding avidity of IgE to CD23-bearing B cells without affecting quantitative expression of CD23 and is thus designated epsilon-receptor-modulating protein. The second protein (30 kDa) suppresses IgE biosynthesis (i.e., SFA). This purified SFA suppresses interleukin 4-induced IgE and IgG1 synthesis by lipopolysaccharide-activated spleen cells but has no effect on other antibody isotypes; since the activity of SFA is not blocked by anti-interferon gamma monoclonal antibody, it is thus distinct from interferon gamma. The data presented indicate that epsilon-receptor-modulating protein and SFA are protein molecules that are involved in modulating the CD23 molecule and IgE antibody synthesis, respectively.

Animals↗
PubMed1991

Elicitation of antigen-induced primary and secondary murine IgE antibody responses in vitro.

Described herein are methods for eliciting and quantitating primary and secondary murine IgE antibody responses in vitro, and the important role of antigen concentration in determining the level of IgE produced during an immune response. The methods for quantitating IgE antibody levels in culture supernatant fluids and in serum by ELISA are presented in detail. The specificity of such methods was confirmed in that (1) no other isotype of antibody registered in the IgE-ELISA, and (2) parallel determinations of IgE antibody concentrations could be obtained by independent analysis using Fc epsilon RI-dependent basophil degranulation. We examined various parameters of cell donor immunization and lymphoid cell culture which allow for optimal in vitro primary and secondary IgE responses. High relative antigen doses result in diminished IgE antibody responses in experimental animals, a finding confirmed herein. High antigen concentrations in vitro also result in relative suppression of IgE antibody synthesis. This was also true for in vitro production of IgG1 and IgA antibodies. Conversely, IgM and IgG2a responses were elicited at both low and high antigen concentrations; IgG2b and IgG3 were not produced under the conditions of priming and culture used herein. Finally, production of IgE in vitro depended on the presence of carrier-primed CD4+ T cells and hapten-specific B cells. Generation of maximal IgE antibody secretion, and hence elicitation of an allergic reaction, is thus dependent on the amount of antigen acting as stimulant for the immune response.

Animals↗
PubMed1991

Human rib bone marrow mononuclear cells spontaneously synthesize and secrete IgE in vitro.

We have examined spontaneous secretion of IgE by human rib bone marrow mononuclear cells (MNC). Bone marrow MNC from nine out of 12 rib specimens synthesized and secreted substantial amounts of IgE during 14 days of in vitro culture. The 14-day supernatants from these bone marrow MNC contained a mean of 2589 pg/ml of IgE (n = 12) with a maximum production of 15,408 pg/ml of IgE compared with small amounts of IgE (80-200 pg/ml) produced by similarly cultured normal and inflammatory bowel disease intestinal lamina propria MNC. Using two rib specimens, time-course studies revealed spontaneous secretion of IgE to be minimal during the first 2 days of culture (152 pg/ml), followed by a steady increase between days 4 (517 pg/ml) and 14 (3588 pg/ml). The addition of pokeweed mitogen resulted in 72% suppression of spontaneous IgE production by bone marrow MNC. The bone marrow MNC isolated from the ribs consisted of 22% Leu12+ (B) cells of which 3.2% were surface IgE positive. Staining for cytoplasmic immunoglobulin revealed 1% of the bone marrow MNC to be cytoplasmic IgE+. The presence of IgE-bearing and IgE-secreting MNC in human bone marrow is consistent with the observation that allergen-specific IgE-mediated hypersensitivity is adoptively transferred by human bone marrow transplantation and demonstrates the usefulness of human bone marrow MNC for examination of IgE secretory and regulatory events.

Adult↗
PubMed1991

Biology and chemistry of low affinity IgE receptor (Fc epsilon RII/CD23).

Recent studies have established that the low affinity Fc receptor for IgE (Fc epsilon RII/CD23) is a structurally and functionally unique immunoglobulin receptor. DNA sequence analysis predicts that, in contrast to other FcR, Fc epsilon RII is not a member of the immunoglobulin gene superfamily and, indeed, is inserted into the membrane in opposite orientation from most other membrane proteins. While the Fc epsilon RII of macrophages, eosinophils, and platelets mediate IgE-dependent cytotoxicity and promote phagocytosis of IgE-antigen complexes, the function of Fc epsilon RII on B lymphocytes remains unclear. Much effort has been directed toward establishment of its role in IgE regulation, but the plurality of B cell Fc epsilon RII expression, i.e. greater than 90% of the mu + /delta + B lymphocytes, is incongruous with simply a role in regulating only IgE responses. Hence, the discovery that Fc epsilon RII is identical to the B-cell activation antigen, CD23, together with its novel structural features, suggests an additional more important role for this interesting protein and would explain the disparity between a commonly expressed receptor with apparently limited functions.

Antigens, CD↗
PubMed1990

The binding of IgE to murine Fc epsilon RII is calcium-dependent but not inhibited by carbohydrate.

Despite extensive study, little is known about the functions of the moderate affinity IgE receptors (Fc epsilon RII) on B cells. Recent cDNA and genomic cloning studies have demonstrated that, in contrast to other FcR, Fc epsilon RII is not a member of the Ig gene superfamily. Moreover, it uniquely expresses a region that is highly homologous with a membrane-associated, calcium-dependent binding lectin, the asialoglycoprotein receptor. We now report that the interaction between IgE and the Fc epsilon RII of murine B cells and macrophages requires calcium. Furthermore, as might be expected of asialoglycoprotein lectins, this binding was pH-dependent and resulted in ligand internalization. However, although 125I-Fc epsilon RII bound in a calcium-dependent manner to monosaccharide-agarose beads, high concentrations of mono- and disaccharides did not inhibit the interaction between either 125I-IgE and intact B cells or 125I-Fc epsilon RII (from surface-labeled B cells) and IgE-Sepharose. These results suggest that although murine Fc epsilon RII is a lectin, it is not strictly dependent upon IgE oligosaccharides for its binding to IgE.

Animals↗
PubMed1990

The induction of murine B cell Ia by IgE-antigen complexes is dependent on protein synthesis and preceded by class II mRNA accumulation.

Complexes of murine monoclonal anti-DNP IgE and DNP-OVA interact with murine B cells to stimulate expression of cell surface Ia antigens. Enhanced membrane expression of class II MHC antigens was accompanied by a threefold increase of I-A and I-E transcripts, as measured by Northern blot. Peak accumulation of Ia mRNA were detected after 6 hr of incubation with IgE-antigen complexes and returned to control levels after 12 hr of incubation. Hence, induction of Ia mRNA by IgE-antigen complexes was compatible with cell surface Ia expression, both quantitatively and with regard to the time frame. The Ia-inductive effects of both IL-4 and IgE-antigen complexes were inhibited by cycloheximide and actinomycin-D. However, whereas actinomycin-D and cycloheximide blocked IL-4 induction of Fc epsilon RII expression, inhibition of transcription or protein synthesis did not abrogate the increased expression of Fc epsilon R associated with IgE-antigen complexes. These results suggest that the IgE-antigen-induction of B cell Ia expression follows from activation of transcription and de novo synthesis of Ia antigens.

Animals↗
PubMed1990

Comparison of laboratory test use among three urgent care clinics.

Laboratory test ordering practices among physicians at three walk-in or urgent-care medical facilities were compared to evaluate the relationship between practice type and test ordering patterns. The charts of 221 patients were reviewed for test ordering as an aid for the diagnosis of cough or upper respiratory infection (169 patients) or diarrhea (52 patients). For upper respiratory infections, the free-standing walk-in clinic ordered the greatest number of tests; and for both categories of disease, the urgent care unit of a health maintenance organization (HMO) ordered the fewest tests.

Adult↗
PubMed1989

Fc receptors for IgE (Fc epsilon R) on human lymphoid cells: inducible expression of Fc epsilon RII (CD23) on lymphocytes and detection by monoclonal anti-Fc epsilon RII antibody.

The studies presented herein describe (1) a sensitive, quantitative, and objective assay for detecting cell membrane-bound form of Fc receptors for IgE displayed on human lymphoid cells based on measuring unlabeled Fc epsilon R-bound IgE by a solid-phase RIA of cell lysate fluids; (2) the development and characterization of an IgM monoclonal antibody, termed 7E4, which is specific for human lymphocyte Fc epsilon RII (CD23) molecules; and (3) a system for reproducibly inducing de novo synthesis and expression of Fc epsilon RII proteins on human lymphocytes following exposure to the mitogenic lectin, pokeweed mitogen. The Fc epsilon RII molecules induced by exposure to PWM were proven to be present on lymphocytes, and not on other cell types in several ways, including (1) documenting sensitivity of such proteins to both acid pH and trypsin treatment, the latter manipulation being ineffective in removing Fc epsilon RII molecules on basophils and mast cells; (2) demonstrating specific reactivity of the expressed Fc epsilon RII molecules with the 7E4 monoclonal antibody, which is specific for human lymphocyte Fc epsilon RII molecules and does not react with Fc epsilon R molecules on other cell types; and (3) observing the required concomitant presence of both T and B lymphocytes during the induction process and proving that the induced Fc epsilon R+ cells are indeed B cells of the Leu-12+ phenotype by fluorescence analysis. The ability to induce expression of Fc epsilon RII molecules on human lymphocytes exposed to a mitogen such as PWM requires special technical attention to the method of preparation and isolation of human lymphoid cells from peripheral blood. This in vitro system for up-regulating Fc epsilon RII expression on human lymphocytes should provide us with an important new tool to analyze the participation of such cells in the regulatory mechanisms controlling the human IgE antibody system.

Animals↗
PubMed1989

The cellular lesion responsible for exaggerated IgE synthesis accompanying allergic breakthrough.

Appropriate levels of IgE are maintained by a cellular and molecular network composed of (1) a suppressive, Ly-1+, CD4+ T cell-dependent arm that is activated by inappropriate high levels of IgE and (2) an enhancing, CD8+ T cell-dependent arm that controls this suppression in a feedback regulatory manner. Ly-1+ T cells also function to counterbalance (inhibit) the activity of these latter CD8+ T cells. It has been previously shown that Ly-1+ T cells can reverse low-dose irradiation-induced enhancement of IgE antibody responses (i.e., allergic breakthrough). We have analyzed lymphocytes isolated from mice subjected to low-dose irradiation to determine which component of this network is defective in such animals. Stimulation of normal lymphocytes with IgE in vitro resulted in the release of lymphokines that suppress IgE antibody responses. In contrast, similar stimulation of lymphocytes from irradiated mice did not elicit secretion of such suppressive lymphokines, unless the cells were depleted of CD8+ T cells or reconstituted with normal Ly-1+ T cells. Because Ly-1+ T cells of irradiated mice could not reconstitute the response, we conclude that this functional subset of CD4+ T cells, which normally controls CD8+ T cell activity in this network, is defective in animals that exhibit irradiation-induced allergic breakthrough.

Animals↗
PubMed1989

Cloning of cDNA coding for low-affinity Fc receptors for IgE on human T lymphocytes.

Using a cDNA probe corresponding to the membrane-bound form of the B cell receptor for IgE, we have isolated, sequenced, and expressed a cDNA clone which codes for a human T lymphocyte Fc epsilon R from HUT-78 cells. This T cell Fc epsilon R cDNA codes for 320 amino acid residues, and shows high homology to the B cell Fc epsilon R sequence. The major differences between this T cell and the B cell Fc epsilon R cDNA sequences are (i) a limited stretch of nucleotides at the 5' segment of the coding region which encodes a putative cytoplasmic region of the Fc epsilon R molecule and the untranslated 5' end; and (ii) an additional 64 bp segment in the untranslated 3' end containing two repeats in tandem with three existing repeats in the same region. The expression of Fc epsilon R on T lymphocytes may reflect involvement of the Fc epsilon R in regulation of IgE-mediated responses. The cytoplasmic difference implies functional activity of the Fc epsilon R in T lymphocytes that is mechanistically different from the Fc epsilon R of B lymphocytes.

Amino Acid Sequence↗
PubMed1988

IgE-antigen complexes enhance Fc epsilon R and Ia expression by murine B lymphocytes.

Murine monoclonal IgE interacts with B cells of BALB/c mouse spleen with greater efficiency in the presence of its specific antigen. Complexes of anti-DNP IgE and DNP-OVA not only resist elution from B lymphocytes by acid but have a substantially longer dissociation half-time when compared with monomeric IgE (440 vs. 8 min, respectively). Further, these IgE-antigen complexes induce Fc epsilon R expression in lymphoid cells more efficiently than IgE alone. Maximum levels of B cell Fc epsilon R were observed after a 24 h incubation with 1 microgram/ml IgE in the presence of 1 microgram/ml DNP-OVA, while 30 micrograms/ml monomeric IgE was needed to elicit a similar increase of Fc epsilon R expression. Most importantly, overnight incubation of B cell-enriched BALB/c spleen cells with IgE-antigen complexes resulted in an augmented membrane expression of class II MHC antigens. B cell surface expression of both I-A and I-E antigens responded to a comparable level after incubation with IgE-antigen complexes but did not occur in response to either IgE or antigen alone. The enhanced sIa expression occurred in parallel to IgE-antigen concentrations that gave rise to Fc epsilon R hyperexpression. Moreover, double staining for Fc epsilon R and surface Ia antigen shows that B cells exhibiting the highest density of Fc epsilon R also demonstrated the most surface I-A, suggesting that B lymphocytes are autonomous in their response to IgE-antigen complexes. Changes in class I MHC or sIgM were not observed after overnight incubation with IgE and antigen. These results demonstrate the importance of IgE-antigen complexes for intercellular signaling and further suggest that the IgE system plays a broader role in immune response than it has generally been credited.

Animals↗
PubMed1988

Production of IL-1-mimicking anti-idiotypic antibodies in rabbits in response to IL-1 immunization.

This report describes the characterization of immunoglobulins with interleukin-1 (IL-1)-like activity from the serum of rabbits immunized with partially purified mouse IL-1. Early after immunization, immune sera were found to contain anti-IL-1 antibodies (idiotypes) that inhibited IL-1 bioactivity (augmented-proliferation of PHA-stimulated thymocytes). Later, anti-idiotypic antibodies appeared that mimicked IL-1 activity. These IL-1-like antibodies were affinity purified either on an anti-IL-1-enriched Ig-Sepharose 4B column from an early bleed or sequentially on anti-Ig and Protein A immunoadsorbent columns. By ELISA anti-idiotypic antibodies specifically bound to rabbit anti-IL-1 antibodies. Functionally, IL-1 mimicking antibodies were reproducibly effective in augmenting the in vitro proliferation of PHA-stimulated thymocytes or Con A-stimulated D10 cells. On the other hand, they did not support proliferation of the IL-2-dependent CTLL-2 cells. The ability of IL-1-mimicking antibodies to enhance thymocyte proliferation could be blocked by functional site related anti-IL-1 antibodies. By Western blot, 125I-labeled IL-1 and IL-1-mimicking antibodies bound to a similar 23 Kd mol. wt protein material recovered from the lysate of thymocytes stimulated with PHA for 48 h. That the observed bioactivity could be attributed to antibody molecules and not to contaminant IL-1 was ascertained by several methods, namely (1) SDS-PAGE analysis of 125I-labeled material and (2) resistance to loss of bioactivity by lyophilization. Furthermore, as neither Ig-anti-Ig nor BSA-anti-BSA complexes mimicked IL-1-augmented thymocyte proliferation, a non-specific effect due to immune complexes could be excluded. The occurrence of antibodies mimicking several of the IL-1 functions induced following IL-1 immunization suggests a potential role for the idiotypic network in modulating cytokine activities and a possible link between regulation of the immune system by cytokines and immunoglobulin idiotypes.

Animals↗
PubMed1988

Perturbation of the autoimmune network. I. Immunization with anti-idiotypic antibodies prior to challenge with antigen induces quantitative variations in the autoantibody response.

The effect of immunization with anti-idiotypes on the production of autoantibodies subsequently induced with nominal antigen, thyroglobulin, was investigated in BALB/c mice with three distinct rabbit antibodies and one syngeneic monoclonal antibody (mAb) specific for an idiotype (Id62) borne on a mouse monoclonal autoantibody to thyroglobulin. In these in vivo experiments, dose, route and form of the anti-idiotypic immunization were kept constant, but the time interval between exposure to anti-idiotype and antigen challenge was varied. When the interval was short (two weeks), heterologous anti-Id62 antibodies predisposed to suppression of the autoantibody response in 2/3 instances. Suppression was also obtained in mice immunized with a syngeneic mAb directed against Id62. In each case, a prominent idiotype-positive (Id') response was measured in the serum. Adsorption/elution studies indicated that Id' molecules in suppressed mice were principally non antigen-binding. On the other hand, when the time interval between injections was long (14 weeks), mice preimmunized with one rabbit anti-Id62 antibody showed a markedly increased autoantibody response. The Id' component in enhanced mice was largely enriched for antibodies reacting with the antigen. These findings suggest that the state of activation of autoreactive clones and the type of anti-idiotypes used may be determinant factors in the overall effect of manipulation of autoimmune responses with anti-idiotypic antibodies.

Animals↗