PubMed Health⌕ Search

Biomedical subjects

T Lehner

Publications and source records attributed to T Lehner.

At least 91 records · Page 5Linked to original sources
PubMed1995

Induction of IgA and IgG antibodies in vaginal fluid, serum and saliva following immunization of genital and gut associated lymphoid tissue.

Vaginal immunization with the Simian immunodeficiency virus (SIV) was investigated in macaques in order to study genital mucosal antibodies. A combined route of genital- and gut-associated lymphoid tissues was used to stimulate IgA and IgG antibodies in vaginal fluid, serum and saliva. Macaques were immunized with a recombinant, particulate SIV antigen (SIV gag P27), covalently linked to the mucosal adjuvant cholera toxin B subunit (CTB). The animals were immunized sequentially as follows: vaginal (x2) followed by oral (x3), or the reverse sequence of immunization. The results show that both vaginal followed by oral immunization or the reverse sequence induces specific p27 IgA and IgG antibodies in the vaginal fluid and serum. IgA antibodies were also detected in saliva. Vaginal IgA antibodies have the secretory component and J chain suggesting that they are of secretory origin.

Adjuvants, Immunologic↗
PubMed1995

T cell responses in macaques after vaginal immunization with particulate SIV p27 antigen.

Rhesus monkeys were immunized by the vaginal and oral routes using a recombinant particulate simian immunodeficiency virus (SIV) antigen. Augmenting vaginal by oral immunization in macaques elicits proliferative CD4+ T cells in the circulation which are specific to the immunizing p27 antigen. Reconstitution of enriched CD4+ T cells, B cells and macrophages from circulating mononuclear cells help B cells in specific IgA anti-p27 antibody synthesis. The results suggest that augmented vaginal immunization induces systemic CD4+ T and B cell responses which may play a part in the protective immunity against SIV (HIV) infection.

Administration, Intravaginal↗
PubMed1995

Comparative investigation of Langerhans' cells and potential receptors for HIV in oral, genitourinary and rectal epithelia.

Human immunodeficiency virus (HIV) is commonly transmitted, during homosexual and heterosexual intercourse, through the rectal and cervicovaginal mucosa, foreskin and urethral epithelia. However, there is uncertainty about HIV transmission through the oral mucosa by oral sex. We have carried out a comparative immunohistological investigation of primate oral, cervicovaginal, foreskin, urethral and rectal epithelia for potential HIV receptors. We investigated epithelial tissues for CD4 glycoprotein, which is the principal receptor for HIV, Fc receptors of IgG for binding HIV-IgG antibody complexes, and HLA class II, which might enable HIV-bound CD4+ cells to gain access to the epithelial cells. CD4 glycoprotein was not found in oral, foreskin, urethral, vaginal or rectal epithelial cells, although CD4+ mononuclear cells were present in the lamina propria of each epithelium. Fc gamma II and Fc gamma III receptors were found in urethral, endocervical and rectal epithelia, and Fc gamma III and Fc gamma I receptors in the foreskin. However, Fc gamma receptors were not found in oral epithelium (buccal, labial, lingual or palatal) and only Fc gamma III receptors were detected in the gingival epithelial cells. HLA class II antigen was also not detected in foreskin, oral or rectal epithelium, but it was expressed by endocervical cells from most human specimens and in male urethral epithelia of non-human male primates. Langerhans' cells were found in all epithelia except those of the urethra and rectum, and they can express CD4 glycoprotein, Fc gamma receptors and HLA class II antigen. The mean number of Langerhans' cells expressing CD4 in the upper third of oral epithelium was significantly lower compared with vaginal epithelium or foreskin. The HIV-binding V1 domain of CD4 was significantly decreased in Langerhans' cells present in oral compared with vaginal epithelium. The results suggest that the foreskin in uncircumcised men and the cervicovaginal epithelium in females might become infected via the CD4+ Langerhans' cells. However, urethral infection might be mediated by HIV-antibody complexes binding to urethral epithelial Fc gamma receptors. The paucity of Langerhans' cells expressing the V1 domain of CD4, the absence of Fc gamma receptors, and a lack of expression of HLA class II antigens in most oral epithelial cells, argue against transmission of HIV through the normal intact oral mucosa.

Adolescent↗
PubMed1995

Lectin-carbohydrate interactions in disease. T-cell recognition of IgA and IgD; mannose binding protein recognition of IgG0.

Two disease associated lectin-carbohydrate interactions have been studied. (1) A T-cell surface lectin which binds IgA1 and IgD is expressed on CD4+ and CD8+ T-lymphocytes in a number of diseases including systemic lupus erythematosus, rheumatoid arthritis (RA), Behcet's disease and IgA nephropathy. We have demonstrated that calcium independent binding to this receptor is mediated by the O-linked disaccharide Gal beta 3GalNAc which is associated with the hinge regions of both IgA1 and IgD. (2) In rheumatoid arthritis the proportion of IgG0 glycoform populations lacking terminal galactose increases. We have shown that terminal GlcNAc residues on oligosaccharides in the Fc region of IgG0 can bind to the C-type lectin, serum mannose binding protein, and thus activate the classical complement pathway. This provides a mechanism of activation of the complement system not available to the other classes of IgG glycoforms.

Carbohydrate Metabolism↗
PubMed1994

Targeted lymph node immunization with simian immunodeficiency virus p27 antigen to elicit genital, rectal, and urinary immune responses in nonhuman primates.

A s.c. route of immunization was developed in non-human primates, which targets the genitourinary-rectal associated lymphoid tissue. A vaccine consisting of rSIV gag p27, expressed as hybrid Ty virus-like particles (p27: Ty-VLP) was administered in the proximity of the internal iliac lymph nodes. Secretory IgA and IgG Abs to the p27 Ag were elicited in the vaginal, male urethral, rectal and seminal fluids, urine and serum. Two or more immunodominant B cell epitopes were identified within peptides 51-90 and 121-170 of the sequence of p27, using serum or biliary IgA and IgG Abs. CD4+ T cell proliferative responses to p27 were elicited predominantly in the targeted internal iliac, as well as the inferior mesenteric lymph nodes and the spleen, but not in the unrelated lymph nodes. These cells were then studied for helper function in p27 specific B cell Ab synthesis. Specific IgA and IgG Abs were detected in the same lymphoid tissues as those that displayed proliferative responses. However, cross-over reconstitution experiments between splenic and iliac lymph node B and CD4+ T cells suggest that the iliac B cells are essential for specific IgA Ab synthesis, whereas splenic B cells preferentially synthesize IgG Ab. The targeted lymph node (TLN) route of immunization gave comparable B cell, proliferative T cell, and Th cell responses to the vaginal, male genitourinary, and rectal mucosal routes, which were augmented by oral immunization. However, the TLN route induced urinary and seminal fluid sIgA and IgG Abs in addition to genital and rectal Abs. Generating secretory IgA and IgG Abs at the mucosal surfaces, and T and B cell immunity in the regional draining lymph nodes, spleen and circulation by TLN immunization may prevent transmission of virus through the mucosa, dissemination of the virus, and the formation of a latent reservoir of infection.

Animals↗
PubMed1994

Assembly of monoclonal antibodies with IgG1 and IgA heavy chain domains in transgenic tobacco plants.

The genes encoding the heavy and light chains of a murine monoclonal antibody (mAb Guy's 13) have been cloned and expressed in Nicotiana tabacum. Transgenic plants have been regenerated that secrete full-length Guy's 13 antibody. By manipulation of the heavy chain gene sequence, constant region domains from an immunoglobulin alpha heavy chain have been introduced, and plants secreting Guy's 13 mAb with chimeric gamma/alpha heavy chains have also been produced. For each plant antibody, light and heavy chains have been detected by Western blot analysis and the fidelity of assembly confirmed by demonstrating that the antibody is fully functional, by antigen binding studies. Furthermore, the plant antibodies retained the ability to aggregate streptococci, which confirms that the bivalent antigen-binding capacity of the full length antibodies is intact. The results demonstrate that IgA as well as IgG class antibodies can be assembled correctly in tobacco plants and suggest that transgenic plants may be suitable for high-level expression of more complex genetically engineered immunoglobulin molecules. Since mAb Guy's 13 prevents streptococcal colonization in humans, transgenic plant technology may have therapeutic applications.

Antibodies, Bacterial↗
PubMed1994

A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3.

In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p < 0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder.

Adolescent↗
PubMed1994

Automat: a novel software system for the systematic search for protein (or DNA) similarities with a notable application to autoimmune diseases and AIDS.

Automat is a novel program which finds exhaustively all the oligopeptide segments shared by a given protein of any size with the proteins of a whole databank. It allows the user to collect statistics on the composition of the sequence studied in reference to the databank used. We present here the rationale and the algorithm underlying this powerful software. Besides its immediate interest for identifying efficiently similarities between proteins (or DNAs), biological applications of this software have already been described in the case of HIV-1 viral proteins, and Automat should prove useful also for studying more generally autoimmune diseases.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Heat shock protein peptides reactive in patients with Behçet's disease are uveitogenic in Lewis rats.

Mycobacterial and homologous human heat shock protein T cell peptide epitopes specific for T lymphocytes in Behçet's disease were investigated for their pathogenicity in Lewis rats. The potential pathogenicity of eight peptides and two controls was assessed by administering the peptides in enriched Freund's adjuvant into the footpads of male Lewis rats. Anterior uveitis which is a major manifestation of Behçet's disease was induced with two out of the four mycobacterial and all four homologous human peptides. The most effective peptides inducing iridocyclitis in 64-75% of rats were peptides with amino acids 336-351 and 136-150, derived from the sequence of the human 60-kD heat shock protein. A few of the rats also showed evidence of focal loss of photoreceptors. These results suggest that selected peptides within heat shock protein 60 kD which function as T cell epitopes in Behçet's disease are capable of inducing uveitis in rats. This supports the view that the peptide T cell determinants may be involved in the pathogenesis of Behçet's disease.

Amino Acid Sequence↗
PubMed1994

The expression of carbohydrate antigens in activated T cells and in autoimmune diseases.

Cell surface carbohydrate antigens have been implicated in cell differentiation and maturation and may play a role in immunoregulation. The expression of carbohydrates in peripheral blood lymphocytes (PBL) was studied by double immunofluorescence flow cytometry, using MoAbs CT1 and CT2 but only a small proportion of cells bound these MoAbs. MoAbs CT1, CT2 and the lectin vicia villosa (VV) which share specificity for Gal NAc were then used to examine lymphocytes from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Behcet's disease (BD) and IgA nephropathy. A significant increase in MoAbs CT1 CT2 and VV binding CD4 or CD8 cells was found only with lymphocytes from patients with SLE. However, MoAbs CT or VV binding lymphocytes from healthy subjects were significantly up-regulated by activation with a mitogen (PHA), cross-linked anti-CD3 MoAb or a common antigen (65kDa heat shock protein), suggesting that an increased proportion of T cells expressing these carbohydrates results from any of the three types of lymphocyte activating agents. Inhibition studies were then carried out to determine the relationship between the MoAbs CT1 and CT2, VV and GalNAc. Indeed, VV binding to T cells was significantly inhibited by either MoAbs CT1 or CT2, or GalNAc but not GlucNAc, suggesting that VV shares a common binding site with MoAb CT and that GalNAc may constitute one of the sugar receptors. Investigations of lymphocytes from adult peripheral blood in health and disease suggest that carbohydrate antigens may play a role in activation and immunoregulation.

Adult↗
PubMed1994

Mucosal model of genital immunization in male rhesus macaques with a recombinant simian immunodeficiency virus p27 antigen.

Human immunodeficiency virus (HIV) can be transmitted through infected seminal fluid or vaginal or rectal secretions during heterosexual or homosexual intercourse. To prevent mucosal transmission and spread to the regional lymph nodes, an effective vaccine may need to stimulate immune responses at the genitourinary mucosa. In this study, we have developed a mucosal model of genital immunization in male rhesus macaques, by topical urethral immunization with recombinant simian immunodeficiency virus p27gag, expressed as a hybrid Ty virus-like particle (Ty-VLP) and covalently linked to cholera toxin B subunit. This treatment was augmented by oral immunization with the same vaccine but with added killed cholera vibrios. Polymeric secretory immunoglobulin A (sIgA) and IgG antibodies to p27 were induced in urethral secretions, urine, and seminal fluid. This raises the possibility that the antibodies may function as a primary mucosal defense barrier against SIV (HIV) infection. The regional lymph nodes which constitute the genital-associated lymphoid tissue contained p27-specific CD4+ proliferative and helper T cells for antibody synthesis by B cells, which may function as a secondary immune barrier to infection. Blood and splenic lymphocytes also showed p27-sensitized CD4+ T cells and B cells in addition to serum IgG and IgA p27-specific antibodies; this constitutes a third level of immunity against dissemination of the virus. A comparison of genito-oral with recto-oral and intramuscular routes of immunization suggests that only genito-oral immunization elicits specific sIgA and IgG antibodies in the urine, urethra, and seminal fluid. Both genito-oral and recto-oral immunizations induced T-cell and B-cell immune responses in regional lymph nodes, with preferential IgA antibody synthesis. The mucosal route of immunization may prevent not only virus transmission through the genital mucosa but also dissemination and latency of the virus in the draining lymph nodes.

Animals↗
PubMed1994

An examination of linkage of schizophrenia and schizoaffective disorder to the pseudoautosomal region (Xp22.3)

We investigated linkage between schizophrenia and the loci DXYS14, DXYS17, and MIC2 within the pseudoautosomal region in 85 families with two or more siblings suffering from schizophrenia or schizoaffective disorder. A maximum lod score of 2.44 was reached at MIC2, with a dominant model of inheritance at a recombination fraction of 0.367 in females and 0.046 in males (a F:M sex ratio > 1, i.e. opposite to that expected with a pseudoautosomal locus). Evidence consistent with linkage (P = 0.01) was also obtained with a sibling pair analysis at the MIC2 locus. These data do not support (although they do not definitively exclude) a locus within the pseudoautosomal region; they are consistent with the presence of a gene that predisposes to schizophrenia in the sex-specific regions of the X and Y chromosomes.

Adult↗
PubMed1994

A human T-cell receptor recognizes 'O'-linked sugars from the hinge region of human IgA1 and IgD.

A receptor which binds secretory IgA (sIgA) is expressed on human T cells from patients with systemic lupus erythematosus, rheumatoid arthritis, Behcet's syndrome and IgA nephropathy and on normal T cells following phytohaemagglutinin (PHA) stimulation. The specificity of this receptor was initially probed with a panel of normal serum immunoglobulins in competitive inhibition assays with sIgA using two-colour immunofluorescence. While the receptor showed the strongest affinity for IgA1 (IC(50)10(-6) M), IgD which has a similarly glycosylated hinge region to IgA1, also bound to the receptor (IC50 10(-5) M). IgA2, which lacks the 'O'-glycosylated hinge region, did not significantly inhibit the binding at these concentrations suggesting that the IgA determinants for this receptor might be the oligosaccharides present in the hinge region of IgA1. IgA1 has up to 10 'O'-linked oligosaccharides and four N-linked oligosaccharides per molecule. In order to probe the role of the 'O'-linked hinge sugars in the binding event, a sugar library was prepared from IgA1 by a procedure designed to release 'O'-linked oligosaccharides preferentially, and to retain them in the natural closed ring formation. The sugars were released by hydrazinolysis at 65 degrees and the resulting oligosaccharide library analysed by high voltage paper electrophoresis (HVE) and P4 gel permeation chromatography. Competitive inhibition studies demonstrated that both the library and the individual 'O'-linked sugars associated with IgA1 were implicated in the binding of IgA1 to this receptor (IC50 between 1 x 10(-5) M and 6 x 10(-5) M). Within this range the individual sugars showed small differences in their affinity for the receptor in the following order: Gal beta 3GalNAc = NeuNAc2 alpha 3(6)Gal beta 3GalNAc > NeuNAc2 alpha 3(6)Gal beta 3[NeuNAc2 alpha 6]GalNAc > or = GalNAc.

Binding, Competitive↗
PubMed1994

Antibodies to human and non-human primate cellular and culture medium components in macaques vaccinated with the simian immunodeficiency virus.

Inactivated simian immunodeficiency virus (SIV) grown in a human T-cell line induces protection from infection by the virus in macaques. However, observations that immunization with uninfected human T cells or with SIV-1 prepared in human T cells can also induce protection, has raised the possibility that protective antigens could be of human cellular origin. Sera from animals immunized with fixed infected and uninfected human T cells, as well as from animals immunized with partially purified cell-free SIV have been examined for their ability to bind to human and macaque peripheral blood mononuclear cells (PBMC) and to-components present in fetal calf serum (FCS) in which the cells were grown. Analysis by flow cytometry suggests that antibodies to human cell surface antigens can be elicited with both inactivated SIV grown in human T cells and by uninfected T cells. There was a significant association between the presence of anti-cell antibodies and protection from infection. However, anti-cell surface antibodies were not detected with macaque mononuclear cells by flow cytometry or by immunoprecipitation, unless these cells were first treated with FCS or activated by a mitogen. Immunoprecipitation of resting human PBMC with sera from immunized animals suggests the presence of antibodies to class I heavy and light chains [beta 2-microglobulin (beta 2 m)] and to bovine beta 2m, which may originate in FCS used to grow the cell line. Antibodies to CD4 were also found in sera from animals immunized with SIV grown in human T cells. We suggest that human cellular components augmented by FCS elicit anti-class I heavy chain, beta 2m, CD4 and FCS antibodies which may be responsible for protection against SIV infection in macaques.

Animals↗
PubMed1993

T- and B-cell functions and epitope expression in nonhuman primates immunized with simian immunodeficiency virus antigen by the rectal route.

Transmission of human immunodeficiency virus (HIV) in North America and Europe occurs most commonly through the rectal mucosa during homosexual intercourse. The simian immunodeficiency virus (SIV) macaque model has been used to investigate rectal immunization. The vaccine used was a recombinant SIV gag p27 expressed as hybrid Ty virus-like particles (Ty-VLP). Sequential ororectal (OR) mucosal immunization was compared with i.m. immunization. Whereas both routes of immunization induced serum IgA and IgG p27 antibodies, only OR immunization induced rectal secretory IgA antibodies. Specific CD4+ T-cell proliferative responses to stimulation with p27 were found after i.m. immunization only in the blood and spleen, but after OR immunization they were found in the internal iliac and inferior mesenteric lymph nodes in addition to the blood and spleen. T-cell epitope mapping of the proliferative responses of short-term cell lines (STCLs) grown from peripheral blood or lymphoid cells revealed a major epitope within the polypeptide 121-150 after either route of immunization. Two minor T-cell epitopes were found within peptide 41-80 in STCLs from splenic and circulating cells. B-cell epitope mapping of serum or biliary IgA and IgG antibodies revealed two overlapping or adjacent immunodominant epitopes to the T-cell epitopes within the polypeptides 121-170 and 51-90. The results suggest that rectal augmented by oral immunization with a recombinant particulate antigen in nonhuman primates elicits secretory IgA and to a lesser extent IgG responses in the draining lymph nodes and the rectal mucosa, whereas systemic immunization targets predominantly splenic and circulating T- and B-cell responses. These findings may have important implications in the strategy of designing vaccines in prevention of homosexual transmission of HIV infection.

Administration, Rectal↗
PubMed1993

T cell epitope expression of mycobacterial and homologous human 65-kilodalton heat shock protein peptides in short term cell lines from patients with Behçet's disease.

T cell epitopes of the 65-kDa heat shock protein (HSP) were mapped in patients with Behçet's disease (BD), by stimulating T cells with the overlapping synthetic peptides derived from the sequences of the Mycobacterium tuberculosis 65-kDa HSP. Significant lymphoproliferative responses were stimulated with four HSP peptides in BD, as compared with the related disease (recurrent oral ulcers), unrelated disease, and healthy controls (p < 0.05 to 0.005). In order to assess the relative frequency of sensitized lymphocytes by these peptides, 7353 short term cell lines were generated from the lymphocytes of patients and controls. Peptides 111-125, 154-172, and 311-325 (p < 0.001) and peptide 219-233 (p < 0.02) yielded significantly greater frequency of STCL in BD than in healthy and disease controls. All but peptide 154-172 stimulated only the CD4+ subset of T cells, although there was no evidence that reactivity to the selected peptides is restricted by DR2 to DR7 Ag. HLA-B51 is significantly associated with BD, but there was no evidence that B51 was a restricting element, when B51+ patients were compared with B51- patients with BD, and with B51+ healthy control subjects. A comparative investigation was then carried out between the corresponding mycobacterial and human HSP peptides. Similar or higher lympho-proliferative responses were stimulated by the human peptides compared with the mycobacterial peptides. These results suggest that the four peptide determinants within the 65-kDa HSP might be involved in the pathogenesis of BD. Whereas the high microbial load and associated stress proteins found in oral ulceration of BD may initiate an immune response to these conserved epitopes, expression of autoreactive T cell clones might be stimulated by immunodominant T cell epitopes of endogenous HSP which may induce immunopathologic changes.

Adult↗