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J R Lamb

Publications and source records attributed to J R Lamb.

At least 55 records · Page 3Linked to original sources
PubMed1996

Induction of anergy in human T helper 0 cells by stimulation with altered T cell antigen receptor ligands.

CD4+ T cells may become profoundly unresponsive to antigenic restimulation following ligation of TCR by immunogenic peptides bound to MHC class II molecules in the absence of costimulation. Furthermore, it has been reported that anergy can be induced as a consequence of engagement of TCR by analogues of antigenic peptides presented by live APCs. In this study, based on resolution of the crystal structure of an influenza virus hemagglutinin (HA) peptide (HA 306-318) bound to HLA-DRB1*0101, we investigated the potential of analogues with amino acid substitutions at those positions predicted to form interactions with TCR to differentially activate and/or anergize HA-specific human Th0 cells restricted by DR1 class II molecules. For some analogues altering the affinity of peptide/TCR interactions revealed a direct positive correlation between antigenicity and their ability to induce anergy. Nevertheless, certain HA peptide analogues functioned as partial agonists, which although they failed to stimulate clonal expansion, were capable of rendering the Th0 cells unresponsive to immunogenic rechallenge. Furthermore, differences were noticed in the characteristics of the anergic phenotype induced by selected analogues. Restimulation with the native peptide of Th0 cells pre-exposed to the HA analogues in the absence of costimulatory signals failed to uncouple IL-4 and IFN-gamma secretion; however, in some instances, dissociation of proliferation from cytokine production was observed. The ability to differentially signal T cells through changing the affinity of peptide/TCR interactions may have implications in the potential use of altered TCR ligands in immunotherapy.

Amino Acid Sequence↗
PubMed1996

T-cell responses to allergens: epitope-specificity and clinical relevance.

Allergen-specific T cells play an important role in the pathophysiology of atopic allergies. Recently, cDNAs that encode many important allergens have been cloned and their amino acid sequences deduced, thus allowing the elucidation of the epitope-specificity of allergen-specific T cells. Here, Joost van Neerven and colleagues discuss the results of these studies, and the implications for the development of efficient strategies for specific immunotherapy.

Allergens↗
PubMed1996

A T cell clone with three potential TCR alpha chain rearrangements expresses only one receptor combination at the cell surface.

In determining the T cell receptor (TcR) usage of various T cell clones that recognize peptide antigens derived from allergens, a particular clone (AC20) was found, that apparently expressed three different species of mRNA encoding alpha chains. The logical conclusion that the cells were not clonal was refuted by the finding of only a single beta chain rearrangement. One of the alpha chains (V alpha20), was not in frame, but two V alpha8 transcripts of different lengths were both potentially translatable. Sequence analysis suggested that the shorter transcript was generated by a secondary splice event from the longer, through the use of a splice donor sequence encoded by the J alpha38 gene segment. The efficiency of excision of the intervening sequence is such that approximately equal amounts of the long and short transcripts occur in the steady state pool of mRNA. This phenomenon has been reported previously in TcR alpha rearrangements, but it has never been made clear whether these truncated chains can form a functional TcR. Reconstitution of a TcR negative cell line with these transcripts showed that only the full length alpha chain was able to pair efficiently with the beta chain to generate a functional receptor at the cell surface.

Amino Acid Sequence↗
PubMed1996

Peptide-mediated regulation of the allergic immune response.

A major key to successful immunotherapy may depend on altering the qualitative nature of the immune response in allergic patients. In this review we examine how immune responses to environmental allergens are regulated, and the mechanisms used by the immune system to prevent allergic sensitization. We also discuss future prospects of using allergen-derived peptides in immunotherapy and the possibility of 'reprogramming' the immune responses by immunizing under conditions that promote Th1 responses instead of Th2 responses.

Animals↗
PubMed1996

Defective antigen processing associated with familial disseminated mycobacteriosis.

To gain insights into a possible immune defect predisposing to disseminated mycobacteria infection, we studied three of six surviving children with disseminated Mycobacterium avium complex infection, who had no recognized form of immunodeficiency. We used mycobacteria isolated from the patients and diphtheria, tetanus and pertussis vaccine (DTP) to study antigen-specific T lymphocyte responses. We observed that interferon-gamma (IFN-gamma) production by T cells in response to antigens (both mycobacteria and DTP) in these patients with disseminated infection was greatly impaired. This defect did not seem to be the result of T cell unresponsiveness, as phytohaemagglutinin (PHA) stimulation was able to induce high levels of IFN-gamma comparable to those seen in control patients with localized infection. Further experiments showed that peripheral blood mononuclear cells (PBMC) from patients with disseminated infection were able to present influenza haemagglutinin (HA) peptides to specific T cell clones. However, this ability was lost when the whole HA protein was used as source of antigen. Taken together, these observations support the notion that the primary immune defect in these patients with disseminated mycobacterial infection rests in the antigen-processing functions of their antigen-presenting cells (APC). These findings may provide clues to the wider problem of susceptibility to mycobacteria and other intracellular pathogens and have implications in designing therapy for these patients.

Antigen Presentation↗
PubMed1996

Reversal of the inhibitory effects of HIV-gp120 on CD4+ T cells by stimulation through the CD28 pathway.

The effects of exposure to HIV-gp120 on proliferation and cytokine production by T cell lines were investigated. T cell lines were generated by stimulation of peripheral blood mononuclear cells from several healthy donors with cross-linked anti-CD3 antibodies and IL-2. These T cell lines exhibited the characteristics of Th1 cells, producing IL-2 and interferon-gamma (IFN-gamma), but not IL-4, on stimulation with anti-CD3 antibodies. In the presence of gp120, stimulation with anti-CD3 antibodies was inhibited in terms of both proliferative responses and the secretion of IL-2 and IFN-gamma. Similar effects were observed when a T cell line was stimulated in the presence of a synthetic peptide representing the CD4-binding region of gp120. Neither gp120 nor the CD4-binding region peptide had any effect on IL-4 production by the T cell lines. Stimulation through the CD28 pathway partially restored both the proliferative effect and cytokine production by T cell lines in response to anti-CD3 antibodies in the presence of gp120. Anti-CD28 antibodies also partially restored cytokine production when purified CD4+ T cells from a T cell line were stimulated with anti-CD3 antibodies in the presence of gp120. Anti-gp120 antibodies partially or completely reversed the inhibitory effects of gp120 on T cell proliferation. These results indicate that stimulation through the CD28 pathway may restore defective CD4+ T cell responses in HIV-infected individuals.

Abatacept↗
PubMed1996

Regulation of house dust mite responses by intranasally administered peptide: transient activation of CD4+ T cells precedes the development of tolerance in vivo.

We have previously demonstrated that intranasal (i.n.) administration of an immunodominant peptide (p1-111-139) derived from the house dust mite (HDM) allergen Der p 1 inhibits antigen-specific CD4+ T cell responses in H-2b mice. Here we report that i.n. peptide induced a rapid but transient activation of MHC class II restricted CD4+ T cells that peaked 4 days after peptide treatment and was of similar magnitude to that induced by parenteral immunization with antigen in adjuvant. During the early phase of the response lymph node and splenic T cells secreted a range of lymphokines when re-stimulated in vitro with p1 111-139; however, by day 14 IL-2 and IFN-gamma secretion by T cells were down-regulated. Mice deficient in CD8+ T cells became tolerant by i.n. treatment with peptide, suggesting that CD8+ T cells are not involved in down-regulating the CD4+ T cell response. Rechallenging mice with a single dose of p1 111-139 21 days after the initial treatment elicited a further transient T cell response, which was subsequently down-regulated over time. Although the i.n. peptide induced a strong transient CD4+ T cell response, only low levels of peptide-specific antibodies were detected either after the initial or subsequent i.n. exposures to p1 111-139. Our findings address the mechanisms underlying peripheral T cell tolerance following i.n. administration of a high dose of immunogenic peptide and have implications for understanding the consequences of peptide immunothearapy.

Animals↗
PubMed1996

Induction of T cell responses to the invariant chain derived peptide CLIP in mice immunized with the group 1 allergen of house dust mite.

In this study we demonstrate that immunization of H-2(b) mice with the allergen Der p 1 induces MHC class II restricted T cells that proliferate to residues 15-29 of Der p 1 (p15-29) and to the murine MHC class II-associated invariant chain derived peptide (CLIP). T cells from naive H-2(b) mice and those immunized with murine CLIP fail to respond to either CLIP or p15-29. T cell lines and clones reactive with p15-29 strongly proliferate in response to splenic antigen-presenting cells (APC) from normal H-2(b) mice but show reduced proliferation to APC from invariant chain deficient mice. Furthermore, T cells isolated from Der p 1 primed mice and expanded on H-2(b) spleen cells in the absence of the p15-29 epitope retained specificity for both p15-29 and CLIP, suggesting that naturally presented self components can act as mimetic peptides and may maintain T cell memory to foreign antigens.

Allergens↗
PubMed1996

Regulation of cytokine and chemokine transcription in a human TH2 type T-cell clone during the induction phase of anergy.

BACKGROUND: Selected cytokines produced by allergen specific CD4+ T cells from atopic individuals contribute to both the specific and non-specific effector mechanisms of the allergic immune response. The chemokine family of cytokines and tumour necrosis factor (TNF)-alpha are leucocyte regulatory and proinflammatory molecules. The chemokines include interleukin (IL)-8 and the RANTES/SIS cytokines. OBJECTIVE: There has been no systematic survey of chemokine production in T-cell subtypes. Because of their wide range of biological properties, it might be expected that they would be closely regulated by T cells. This paper illustrates one way (through the characterization of T-cell clones) these questions might be addressed. METHODS: Northern blot analysis was used to quantitate steady state transcription of selected cytokine genes and enzyme linked immunosorbent assay (ELISA) was used to quantitate soluble product. RESULTS: mRNA expression of the chemokines (IL-8, HuMIP-1 alpha and HuMIP-1 beta) and TNF alpha is upregulated in TH2-like cloned house dust mite reactive human CD4+ T cells under conditions of activation and during the induction phase of anergy. Although the development of anergy superinduces mRNA for both IL-8 and TNF alpha, protein production is low compared with that released during activation. In contrast, RANTES, a chemoattractant for CD4+/CD45RO+ memory T cells, eosinophils and basophils, is constitutively expressed at the RNA level by the T cells and not modulated by signals of activation and anergy induction. The production of IL-2, IL-4 and IL-5 mRNA and proteins during the induction of anergy peaks at 2 h after stimulation, whereas the kinetics following activation of the T cells is delayed in comparison. CONCLUSION: These data show that the induction of the anergic state coincides with post-transcriptional regulation of selected cytokine genes. Further study of these phenomena will impact on our understanding of the mechanisms of induction of anergy and the regulation of allergic immune responses in desensitization.

Animals↗
PubMed1996

Human CD4+ T-cell recognition of influenza A virus hemagglutinin after subunit vaccination.

We have examined human CD4+ T-cell recognition of influenza A/Beijing/32/92 (H3N2) virus hemagglutinin following influenza virus HANA subunit vaccination. CD4+ T-cell repertoires were dominated by recognition of epitopes located in conserved regions of the molecule, in a major histocompatibility complex class II haplotype-dependent manner, analogous to that observed following natural infection.

Adult↗
PubMed1995

Mapping T cell recognition: the identification of a T cell receptor residue critical to the specific interaction with an influenza hemagglutinin peptide.

The fine specificity of T cell receptor (TCR) interaction with the influenza hemagglutinin peptide HA 307-319 in the context of the DR1 (DRA, DRB1 0101) and DR4 (DRA, DRB1 0404) was studied in two human T cell clones (HA1.7 and Cl-1) derived from different individuals. Sequencing of amplified TCR transcripts revealed that these two clones express highly related TCR alpha chains, with a conserved junctional motif, but very different TCR beta chains. Modeling studies led to the prediction that the conserved glutamic acid residue in the TCR alpha chain could interact with the lysine at position 316 in the peptide, a known TCR contact residue. HA1.7 TCR-CD3 zeta chimeric constructs were expressed in the rat basophil line (RBL) and shown to confer specific antigen recognition. In two TCR alpha chain mutants, with the conserved glutamic acid residue altered to alanine and lysine, respectively, peptide recognition was lost. Specific recognition was not rescued by altered peptide ligands. Furthermore, Jurkat derivatives expressing the related Jurkat TCR alpha chain paired with the HA 1.7 TCR beta chain did not recognize the HA 307-319/DR1 complex. These data provide evidence for the critical interaction of a TCR residue with antigenic peptide.

Amino Acid Sequence↗
PubMed1995

Differential induction of the NF-AT complex during restimulation and the induction of T-cell anergy.

Stimulation of human CD4+ T-cell clones through the T-cell receptor (TcR) by high doses of specific peptide results in the induction of a long-lived state of nonresponsiveness that has been called anergy. During the induction of anergy, T cells are phenotypically similar to cells responding to an immunogenic stimulus. The amount of TcR at the cell surface is downmodulated, whereas the CD2 and CD25 receptors are increased. When restimulated, however, anergic T cells fail to up-regulate transcription of the IL-2 gene and in consequence do not produce IL-2. In this study, we have compared the ability of various transcription factors to bind to their appropriate site on DNA. Factors were isolated from the nuclei of T cells that were in the induction phase of anergy or were undergoing activation. The pattern of binding activity in restimulated T cells is consistent with the pattern that has previously been shown to regulate T-cell-specific expression of the IL-2 and the beta chain of the TcR genes. The measured binding to a TCF-1 site is the same in the nuclei of resting, activated, and anergized cells. The inducible factors NK-kappa B, beta E2, CD28RC, and AP-1 are not expressed in resting cells and are twofold lower in anergized as compared with activated cells. In contrast, anergic T cells express approximately eightfold lower amounts of NF-AT, a member of the class of inducible factors that regulates IL-2 gene transcription.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1995

Peptide modulation of allergen-specific immune responses.

In vitro peptide stimulation of allergen-reactive T-helper type 1 and type 0 cells, in the absence of costimulatory signals, induces anergy that is accompanied by the modulation of cell surface phenotype and changes in cytokine production. In experimental animal models, the administration of allergen-derived peptides may result in the downregulation of cytokine and antibody production, which is preceded by transient activation of CD4+ T cells, without the induction of effector immunity. Preliminary results of clinical trials using allergen-derived peptides for desensitization are becoming available and should provide some insight into the efficacy of peptide therapy in man.

Antigenic Modulation↗
PubMed1995

Manipulating the immune response in allergic disease: targeting CD4+ T cells.

CD4+ T lymphocytes play an important role in the induction and maintenance of inflammatory responses in allergic diseases. In this review, we examine some of the recent developments that have expanded our knowledge of how T cells recognize and respond to common environmental allergens. In addition, we discuss the role of allergen-derived peptides and their derivatives in the modulation of the immunological activity of allergen-specific T cells, and their potential application for immune intervention. It appears that the ability to redress the balance between qualitatively different subsets of functional components of the immune system may guide the development of therapy.

Animals↗