Biomedical subjects

T Lehner

Publications and source records attributed to T Lehner.

At least 37 records · Page 2Linked to original sources

PubMed2000

Generation of CD8+ T cell-generated suppressor factor and beta-chemokines by targeted iliac lymph node immunization in rhesus monkeys challenged with SHIV-89.6P by the rectal route.

The targeted lymph node (TLN) immunization strategy was investigated in macaques, in order to determine the efficacy in generating secretory, systemic, and cellular immune responses, CD8+ T cell-generated suppressor factors, and beta-chemokines. TLN immunization of the rectal and genital mucosa-associated iliac lymph nodes (TILNs) was compared with axillary TLN immunization (TAxLN) using HIV-1 MN/LAI gp140env and SIV p27gag in alum. Significantly higher immune responses, as well as CD8+ T cell-generated anti-SIV factors and the beta-chemokines RANTES, MIP-1alpha, and MIP-1beta, were elicited by iliac as compared with axillary TLN immunization. The immune responses induced by TLN immunization were examined for their capacity to prevent rectal mucosal infection by the pathogenic dual-tropic SHIV-89.6P. Despite significant secretory, serum, cellular, and beta-chemokine responses, the macaques were infected by SHIV-89.6P. Whether the lack of protection was associated with the antigenic unrelatedness of SHIV-89.6P to the immunizing HIV-1 MN/LAI gp140 or to the virus utilizing CXCR4 to a much greater extent than CCR5, remains to be determined.

Animals↗

PubMed2000

The role of gammadelta T cells in generating antiviral factors and beta-chemokines in protection against mucosal simian immunodeficiency virus infection.

In view of the role of gammadelta(+) T cells in mucosal protection against infection, the proportion of gamma delta T cells was examined in cells eluted from lymphoid and mucosal tissues of macaques immunized with simian immunodeficiency virus (SIV) gp120 and p27 in alum and challenged with live SIV by the rectal mucosal route. This revealed a significant increase in gammadelta T cells eluted from the rectal mucosa (p < 0.01) and the related iliac lymph nodes (p < 0.0001) in protected as compared with infected macaques. Preferential homing of PKH-26-labeled gammadelta(+) T cells from the primed iliac lymph nodes to the rectal and cervico-vaginal mucosa was demonstrated after targeted iliac lymph node as compared with i. m. immunization. Investigations of the mechanism of protection revealed that gammadelta(+) T cells can generate antiviral factors, RANTES, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta which can prevent SIV infection by binding to the CCR5 coreceptors. Up-regulation of gammadelta(+) T cells was demonstrated by immunization of macaques with heat shock protein (HSP)70 linked to peptides and with granulocyte-macrophage colony-stimulating factor (GM-CSF). This was confirmed by in vitro studies showing that GM-CSF can up-regulate gammadelta(+) T cells from macaques immunized with HSP-linked peptides but not those from naive animals. We suggest that a novel strategy of immunization with HSP70 linked to antigen may generate both cognate immunity to the antigen and innate immunity by virtue of up-regulation of gammadelta(+) T cells. These cells generate antiviral factors and the three beta-chemokines that prevent binding and transmission of SIV or M-tropic HIV by the CCR5 coreceptor.

Animals↗

PubMed2000

Heat shock proteins generate beta-chemokines which function as innate adjuvants enhancing adaptive immunity.

Heat shock proteins (HSP) are widely distributed and highly immunogenic molecules. A novel property reported here is that stimulation with HSP70 of CD8-enriched T cells derived from naive non-human primates caused a dose-dependent increase in concentrations of the beta-chemokines RANTES, macrophage inflammatory protein (MIP)-1alpha or MIP-1beta. However, the concentrations of these beta-chemokines were greatly increased when the CD8 T cells derived from HSP70-immunized non-human primates were stimulated with HSP70. HSP linked to peptides or proteins combined generation of beta-chemokines with an adjuvant function by enhancing specific T cell proliferative responses and IgG and IgA antibodies. The beta-chemokine and adjuvant functions were also elicited by topical mucosal administration of HSP linked to an antigen. We postulate that microbial HSP can stimulate beta-chemokine production which may be responsible for innate adjuvanticity, as was found in cells eluted from normal rectal mucosal tissue, and constitutes a significant component of the mucosal-associated lymphoid system. Furthermore, stimulation of innate immunity may drive adaptive immunity and account for the protective effects of HSP against tumors and viruses.

Adjuvants, Immunologic↗

PubMed2000

Premorbid performance IQ deficit in schizophrenia.

OBJECTIVE: Performance IQ (PIQ) is often lower than verbal IQ (VIQ) in schizophrenic patients. Whether PIQ < VIQ precedes psychotic symptoms in schizophrenia remains uncertain. METHOD: We investigated premorbid IQ scores in 63 subjects assessed at a child and adolescent psychiatric unit (mean age 13.1 years, SD 3.2), who at follow-up in adulthood (mean age 30.9 years, SD 3.9) received a lifetime RDC diagnosis of schizophrenia-related psychosis, affective disorder, or no psychiatric disorder. RESULTS: Premorbid PIQ < VIQ significantly differentiated the groups with schizophrenia-related psychosis and no psychiatric disorder. Subjects with schizophrenia-related psychosis had a significantly lower mean value for premorbid PIQ, but not VIQ, compared to subjects who developed affective disorder or subjects without psychiatric disorder. CONCLUSION: Our results emphasize premorbid intellectual deficits in schizophrenia. Those deficits might largely be in consequence of an impairment on the PIQ scale.

Adolescent↗

PubMed2000

Up-regulation of beta-chemokines and down-modulation of CCR5 co-receptors inhibit simian immunodeficiency virus transmission in non-human primates.

A non-cognate mechanism of protection against human immunodeficiency virus-1 (HIV-1) infection involves up-regulation of beta-chemokines, which bind and may down-modulate the CCR5 co-receptors, thereby preventing transmission of M-tropic HIV-1. The objective of this investigation was to evaluate this mechanism in vivo in non-human primates. Rhesus macaques were immunized by a modified targeted lymph nodes (TLN) route with recombinant simian immunodeficiency virus (SIV) glycoprotein 120 (gp120) and p27 in alum, and adsorbed recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) with either interleukin (IL)-2 or IL-4. Immunization induced significant increases in the concentrations of CD8 cell-derived suppressor factor (CD8-SF), regulated on activation normal T cells expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, and down-modulation of the proportion of cells expressing CCR5 (r = 0.737, P<0.05). The macaques were then challenged with SIVmac 220 by the rectal mucosal route. The plasma SIVmac RNA showed a significant inverse correlation with the CD8-SF or the concentration of the three beta-chemokines (r = 0.831 and 0.824, P<0.01), but a positive correlation between the proportion of CCR5+ cells and SIVmac RNA (r = 0.613, P = 0.05). These results demonstrate for the first time in vivo that immunization up-regulates beta-chemokines, which may down-modulate CCR5 co-receptors, and both functions are significantly correlated with the viral load. Hence, the non-cognate beta-chemokine-CCR5 mechanism should be considered as complementary to specific immunity in vaccination against HIV.

Animals↗

PubMed2000

Stabilization of the kerr effect by self-induced ionization: formation of optical light spatially localized structures

The nonlinear propagation of ultrashort laser pulses launched into the air is investigated. The formation of optical light "bullets," or spatially localized structures, has been experimentally observed recently. Their stability is shown as due to the occurrence of a dynamical balance between two opposite nonlinear effects: an optical focusing Kerr effect balanced by a defocusing self-induced multiphoton partial ionization of the neutral gas. Characteristics of the "bullets" are predicted analytically and confirmed numerically. They are found to be in agreement with observations.

Journal Article↗

PubMed2000

T cell responses to 60/65 kDa heat shock protein derived peptides in Turkish patients with Behçet's disease.

OBJECTIVE: Sequence homology and cross reactivity between microbial and human heat shock proteins (HSP) led to the concept that HSP might be involved in the etiopathogenesis of Behçet's disease (BD). We investigated T cell responses to 8 synthetic peptides derived from the mycobacterial 65 kDa and homologous human 60 kDa HSP in patients with BD. METHODS: T cell proliferative responses to synthetic peptides were studied in 49 patients with BD and 46 disease (DC) and 34 healthy controls (HC) with 3H-thymidine uptake test. RESULTS: Positive T cell responses to one or more of the mycobacterial peptides were observed in 52% (12/23) of patients with BD compared with 17% (3/18) of DC (p = 0.02) and to homologous human peptides in 57% (13/23) of BD and 11% (2/18) of DC (p < 0.01). Responses to the mixtures of 4 mycobacterial peptides were also significantly higher in BD compared with controls (stimulation index in BD 4.7 +/- 3.5 vs DC 2.0 +/- 1.2, HC 1.6 +/- 0.4; BD vs DC and HC, p < 0.001). Similar elevated responses to the mixture of 4 human peptides was also observed in patients with BD (BD 3.4 +/- 2.3; DC 1.9 +/- 0.8; HC 1.4 +/- 0.6; BD vs DC, p < 0.01; BD vs HC, p < 0.001). CONCLUSION: These results suggest that cellular immunity against the 65 kDa mycobacterial and 60 kDa human HSP derived peptides is significantly increased in Turkish patients with BD compared to controls, as observed in the UK and Japan.

Adult↗

PubMed1999

Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in familial spina bifida.

Spina bifida cystica (SB) is one of the most common and disabling of birth defects. Folic acid supplementation in mothers during the periconceptional period has been shown to prevent more than 70% of neural tube defects (NTD) including SB. However, the mechanism is unknown. We tested a series of multicase SB families in which 224 individuals were genotyped and a group of 215 unrelated unaffected (external) control individuals for association of SB with the T allele of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism that produces a heat-labile enzyme protein. The data were analyzed using first the transmission/disequilibrium test (TDT) and second a modified case-control study design with Monte Carlo sampling methods. No association of SB with the MTHFR T allele was found by either method. Presently, association between SB and the T allele has been found in four studies, a Dutch study, an Irish study, a North American study, and an Italian study. But no association was found in four other studies, a British study, a French study, a Turkish study, and a German study. A California population-based study found only modestly increased risk of SB with this allele that was not significant at the P < 0.05 level. The present study finds no evidence of the association. Only one other study, the German study, has used TDT analysis. The present study is the first to use a modified case-control study design with Monte Carlo sampling methods to test this association. Thus, it appears that the MTHFR T allele is a risk factor for SB in some populations but not others. Major genetic risk factors for folate-related SB remain to be found.

Alleles↗

PubMed1999

The effect of immunization on chemokines and CCR5 and CXCR4 coreceptor functions in SIV binding and chemotaxis.

The replication of simian immunodeficiency virus (SIV) in acutely infected CD4+ cells can be inhibited in vitro by CD8-suppressor factors (SF) and beta-chemokines induced by immunization of macaques with SIV gp120 and p27 in Alum. A comparison between intradermal, naso-rectal-i.m. and targeted iliac lymph node (TILN) routes showed that immunization by the TILN route elicited the most significant increase in CD8-SF and the beta-chemokines RANTES, MIP-1alpha and MIP-1beta. Increased CD8-SF and beta-chemokines were induced not only in PBMC but also in iliac lymph nodes and spleen of the TILN immunized macaques. Furthermore, CD8-SF and the concentrations of RANTES, MIP-1alpha and MIP-1beta increased with secondary immunizations, suggesting that memory CD8+ cells are involved. Treatment of CD8+ cell culture supernatant with antibodies to RANTES, MIP-1alpha and MIP-1beta neutralized the CD8-SF activity, indicating that blocking the CCR5 by these ligands played an important part in the CD8-SF activity elicited by TILN immunization. Indeed, blocking CCR5 with monoclonal antibodies inhibited SIV replications and MIP-1beta mediated chemotaxis. In contrast, SDF-1 or MAb to CXCR4 failed to suppress SIV replication. However, SDF-1 was able to induce simian PBMC chemotaxis and MAb to CXCR4 inhibited SDF-1 mediated chemotaxis. These results suggest that immunization in macaques induces CD8-SF and beta-chemokines which may prevent SIV infection by blocking the CCR5 coreceptors both in circulating cells and in the rectal and genital draining lymph node cells.

Animals↗

PubMed1999

Induction of inhibitory antibodies to the CCR5 chemokine receptor and their complementary role in preventing SIV infection in macaques.

The seven-transmembrane G-protein-linked CCR5 molecule functions as a major coreceptor for HIV or simian immunodeficiency virus (SIV) infection. Antibodies to CCR5 were studied in rhesus macaques immunized with SIV grown in human CD4(+) T cells. These macaques were completely protected against i.v. challenge with live SIV. Sera from the protected macaques showed significantly greater inhibition of SIV replication (p < 0.001) and macrophage inflammatory protein-1beta-generated CCR5-dependent chemotaxis (p < 0.01) than sera from unprotected macaques, in the absence of significant neutralizing antibodies to SIV. These two functional assays demonstrate serum antibodies to the CCR5 receptors which were specifically inhibited by CCR5-transfected HEK-293 cells. We postulate that anti-CCR5 antibodies may be complementary to beta-chemokines in blocking CCR5 coreceptors to HIV or SIV binding and fusion of CD4(+) cells.

Animals↗

PubMed1999

CD8-suppressor factor and beta-chemokine function as a complementary mechanism to cognate immunity.

Protection against SIV or HIV infection requires specific antibodies and T-cell immune responses. However, a complementary mechanism may be involved, in which CD8-suppressor factors (CD8-SF) and the constitutive beta-chemokines may prevent the virus binding and replicating. Indeed, there is evidence that targeted iliac lymph node (TILN) immunisation with SIVgp120 and p27 or xenoimmunisation with SIV grown in human T-cells generates CD8-SF, RANTES, MIP-1alpha and MIP-1beta which are significantly correlated with protection from SIV infection by the rectal mucosal or intravenous route, respectively. Inhibition of SIV replication in vitro is dependent on the concentration of beta-chemokines generated by immunisation. The critical level for inhibition of SIV replication appears to be higher for rectal mucosal than intravenous challenge by SIV. The mechanism of protection in vivo has not been elucidated but it is likely that the beta-chemokines bind to CCR5 coreceptors which are internalised. Thus, CCR5 coreceptors are either blocked or not expressed on the cell surface for SIV to bind and infect.

Animals↗

PubMed1999

HIV-1 vaccine-induced immune responses which correlate with protection from SHIV infection: compiled preclinical efficacy data from trials with ten different HIV-1 vaccine candidates.

The specific immune mechanisms necessary and/or sufficient to elicit HIV-vaccine protection remain undefined. Utilising the SHIV rhesus macaque model the immunogenicity as well as the efficacy of ten different HIV-1 vaccine candidates was evaluated. Comparison of the immune responses induced, with the ability of the vaccine to protect from SHIV infection provided a means to determine which type of immune responses were necessary for protection. Vaccine candidates included VLPs, DNA, subunit protein with novel adjuvant formulations, ISCOMs and pox-virus vectors. Protection from SHIV infection was achieved in approximately half of the animals which received a primary intravenous cell-free challenge. The presence of CTL in the absence of other effector responses did not correlate with protection from this route and type of challenge. Virus neutralising antibodies (Nab) appeared to be necessary but alone were insufficient for protection. If Ag-specific IFN-gamma and/or IL-4 as well as lymphoproliferative (LP) responses were found with the lack of a detectable IL-2 response, then protection was not observed. Immunity correlated with the magnitude of Nab responses, beta-chemokines and as well as balanced, qualitative T-helper responses.

AIDS Vaccines↗

PubMed1999

Allo-immunization elicits CD8+ T cell-derived chemokines, HIV suppressor factors and resistance to HIV infection in women.

We assessed the potential for an allogeneic-based vaccine against HIV infection in women who were allo-immunized with their partners' mononuclear leucocytes to prevent spontaneous recurrent abortion. Within 1 month of allo-immunization, there was significant upregulation in the concentrations of CD8 cell-derived suppressor factor activity, RANTES, and macrophage inflammatory proteins 1alpha and 1beta. Allo-immunization also downregulated the proportion of cells with CCR5 and CXCR4 receptors. We also found a dose-dependent decrease in HIV infectivity of CD4+ cells in vitro after allo-immunization with both primary and T-cell line adapted HIV-1. This study provides a rational basis for an alternative or complementary strategy of allo-immunization against HIV infection.

Abortion, Habitual↗

PubMed1999

A synthetic peptide adhesion epitope as a novel antimicrobial agent.

The earliest step in microbial infection is adherence by specific microbial adhesins to the mucosa of the oro-intestinal, nasorespiratory, or genitourinary tract. We inhibited binding of a cell surface adhesin of Streptococcus mutans to salivary receptors in vitro, as measured by surface plasmon resonance, using a synthetic peptide (p1025) corresponding to residues 1025-1044 of the adhesin. Two residues within p1025 that contribute to binding (Q1025, E1037) were identified by site-directed mutagenesis. In an in vivo human streptococcal adhesion model, direct application of p1025 to the teeth prevented recolonization of S. mutans but not Actinomyces, as compared with a control peptide or saline. This novel antimicrobial strategy, applying competitive peptide inhibitors of adhesion, may be used against other microorganisms in which adhesins mediate colonization of mucosal surfaces.

Actinomyces↗

PubMed1999

Mucosal Th1- versus Th2-type responses for antibody- or cell-mediated immunity to simian immunodeficiency virus in rhesus macaques.

Simian immunodeficiency virus (SIV)-specific B cell responses and the Th1- or Th2-type profiles of cytokine expression were determined for rhesus macaques immunized with SIV antigens via the iliac lymph nodes (by use of a targeted lymph node [TLN] procedure) or orally with SIV p55gag plus cholera toxin (CT) as a mucosal adjuvant. Analysis of CD4+ T cells purified from SIV-stimulated peripheral blood mononuclear cells of immunized macaques revealed that Th2 cytokine production gradually increased after the second and third TLN immunization. Analysis of SIV-specific B cell responses revealed that peak SIV-specific IgA B cell responses followed the third TLN immunization and occurred during peak Th2-type T cell responses. Oral immunization of macaques with p55gag plus CT induced interferon-gamma-secreting Th1-type and select Th2-type cytokine-producing CD4+ T helper cells, which most likely accounted for the induction of p55-specific systemic IgG and mucosal IgA responses.

Animals↗

PubMed1999

The effect of route of immunization on mucosal immunity and protection.

In macaques, the route of immunization has a profound effect on the immune response. Augmenting rectal or vaginal immunization with oral or nasal immunization enhanced the secretory IgA, serum IgG, and T cell responses. However, targeted iliac lymph node (TILN) immunization with recombinant simian immunodeficiency virus (SIV) gp120 and p27 elicited the most consistent mucosal antibody responses in the rectum, vagina, urine, seminal fluid, and blood. Both mucosal and TILN immunization induced specific CD4+ T cell proliferative responses in the iliac lymph nodes, which drain these mucosal surfaces, and in the splenic and circulating T cells. Rectal mucosal challenge with cell-free SIV induced total protection in 4 of 7 macaques that were immunized by the TILN route, and, compared with unimmunized macaques or those immunized by the mucosal route (P<.001), it induced a >90% decrease in virus load in 3 of them. Protection from mucosal rectal infection with SIV was significantly associated with an increase in the CD8 suppressor factor (which was generated by the iliac lymph node), RANTES, and MIP-1beta (P<.01).

Animals↗

PubMed1999

Beta-chemokine production in macaques vaccinated with live attenuated virus correlates with protection against simian immunodeficiency virus (SIVsm) challenge.

Simian immunodeficiency virus (SIV) uses the CCR5 chemokine receptor as the main co-receptor to enter CD4+ cells. RANTES, MIP-1alpha and MIP-1beta have been suggested as the major human immunodeficiency virus-suppressor factors produced by CD8+ T-cells. The aim of this study was to investigate the CD8+ T-cell production of anti-viral factors and of beta-chemokines in six cynomolgus macaques vaccinated with live attenuated SIVmacC8 in relation to protection against infectious intrarectal SIVsm challenge. Three of the vaccinated animals were completely protected and one was partially protected against the challenge virus. Interestingly, these monkeys showed higher in vitro anti-viral CD8+ cell suppressor activity and beta-chemokine production both before and after vaccination as compared to the infected monkeys. The results indicate that beta-chemokines may play a role in protective immunity but also that genetic and/or environmental factors may influence their production.

Animals↗

PubMed1999

A rational basis for mucosal vaccination against HIV infection.

The lack of success in the development of an effective conventional vaccine against HIV has focused attention on mucosal immunity. This is a rational move, since HIV is transmitted mostly by the mucosal route. The mucosal strategy is based on the concept that: a) HIV/SIV has to cross the mucosal-regional lymph node-blood barriers, each of which can prevent viral transmission or decrease the viral load. b) Immunization has to target directly the mucosal tissues or indirectly the regional lymph nodes, in order to prevent or control viral replication. This strategy is consistent with antigen localization and effective entry into the lymph nodes, driving the immune response. c) A dual immune mechanism may be necessary for effective mucosal protection, mediated by specific CD4 and CD8 T-cell and antibody responses to the immunizing antigens, and innate antiviral factors and beta-chemokines which down-modulate CCR5 co-receptors. Targeted iliac lymph node immunization with SIVgp120 and p27 in alum prevents SIV infection or significantly decreases the viral load when challenged by the rectal route. Indeed, in addition to specific immunity, including significant sIgA antibody-forming cells in the iliac lymph nodes, CD8-suppressor factor and the three beta-chemokines (RANTES, macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta) are significantly associated with protection against rectal mucosal SIV infection.

AIDS Vaccines↗