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Biomedical subjects

A G Dalgleish

Publications and source records attributed to A G Dalgleish.

At least 109 records · Page 6Linked to original sources
PubMed1995

Primary non-Hodgkin's lymphoma of the thyroid with bone marrow infiltration at presentation.

Primary non-Hodgkin's lymphoma of the thyroid is predominantly a disorder of elderly females. Most patients present with limited disease and receive local irradiation. Presentation with advanced disease is uncommon and, consequently, bone marrow examination is not always done. We report a patient with primary thyroid lymphoma who had bone marrow infiltration at presentation and discuss the importance of this investigation in management.

Aged↗
PubMed1995

The gp120 envelope of HIV-1 binds peptides in a similar manner to human leukocyte antigens.

OBJECTIVE: All the conserved regions of HIV gp120 have at least some partial homology with human leukocyte antigen (HLA) class I or class II. One functional similarity is the ability of gp120 and HLA class II to bind CD4. Given the close association between HIV-induced disease and the amount of immune activation and anergy, features closely associated with chronic allogenic stimulation, we asked whether gp120 shared any other properties of HLA, in this case the ability to bind peptides. DESIGN: T-cell epitope peptides known to bind to soluble HLA class I or class II were photolabelled and made radioactive. Cross-linking of modified peptides to soluble HLA class I, II and gp120 was activated by ultraviolet light and analysed by sodium dodecylsulphate-polyacrylamide gel electrophoresis. RESULTS: A signal peptide binding to HLA class I and a haemagglutinin peptide that binds to HLA class II were found to bind soluble gp120 specifically; binding and cross-linking could be competed out with excess of the unmodified peptides but not unrelated control peptides. Molecular modelling of gp120 suggests shared anchor sites for peptides binding to both HLA and gp120 soluble molecules. CONCLUSIONS: The ability to bind these two peptides suggests that gp120 has a peptide-binding site of broad specificity, which if functional in vivo, could compete with normal peptide loading of major histocompatibility complex (MHC) class I and/or class II peptides, as well as aberrantly stimulate the T-cell receptor (by virtue of its potential to be mistaken for an allogenic MHC/peptide complex), resulting in immune activation, anergy and apoptosis in susceptible hosts.

Amino Acid Sequence↗
PubMed1995

AIDS: clinical and scientific issues past, present and future.

The time from the recognition that AIDS was an infectious disease, to the discovery of HIV as the causative agent and the identification of the first specific antiviral agent that showed some clinical benefit, was impressively short. Over the last few years it would appear that progress against AIDS has slowed down considerably. Neither new treatments nor vaccines have given much grounds for optimism and back to basics has been the main battle cry. However it is easy to overlook the tremendous improvements that have taken place in the management of HIV disease in the absence of a curative treatment. Many of the opportunistic infections that used to kill patients are not only treatable but are able to be treated prophylactically. This has altered the clinical spectrum of disease with many patients surviving several years with virtually no CD4 lymphocytes only to succumb to other HIV related disease such as non Hodgkins lymphoma. This review identifies the major advances that have occurred in our understanding of AIDS and identifies the major problems to be overcome in the next few years at both the clinical and basic levels.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Eosinophilic folliculitis occurring after bone marrow autograft in a patient with non-Hodgkin's lymphoma.

Eosinophilic pustular folliculitis is a rare disorder previously reported predominantly in Japanese people who are otherwise healthy. Recently, the disorder has been noted in patients with acquired immune deficiency syndrome, as has eosinophilic folliculitis, a similar but distinct entity. The authors report a patient with eosinophilic folliculitis who was immunocompromised after high dose chemotherapy and bone marrow autograft for treatment of non-Hodgkin's lymphoma.

Adult↗
PubMed1994

Cancer vaccines.

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Animals↗
PubMed1994

Panel of anti-gp120 monoclonal antibodies reacts with same nuclear proteins in uninfected cells as those recognized by autoantibodies from patients with systemic lupus erythematosus.

Mouse monoclonal antibodies (MAbs) directed against the HIV-1 gp120 envelope protein were screened for their reactivity with intracellular antigens expressed in normal uninfected monocytes by indirect immunofluorescence and immunoblotting. Some of these MAbs reacted with the nuclei of normal uninfected cells, producing three main staining patterns by indirect immunofluorescence. Western blot analysis showed that these monoclonal antibodies recognize peptides of various molecular weights present in nuclei preparations of normal monocytes. Reactivity with peptides of similar molecular weight was also detected in sera from both HIV-infected individuals and patients with systemic lupus erythematosus. This evidence for antigenic similarities between HIV-1 gp120 and nuclear antigens represents a novel example of molecular mimicry of self-antigens by HIV envelope proteins, which supports the involvement of mechanisms of autoimmunity in HIV disease pathogenesis through recruitment of autoimmune responses to self-structures by HIV antigens.

Antibodies, Monoclonal↗
PubMed1994

The role of IL-2 in gene therapy.

Interleukin-2 (IL-2) is a growth factor for T-cells which enhances both non-specific immune responses such as natural killer (NK) and lymphokine-activated killer (LAK) cells as well as MHC-restricted cytotoxic T-cell responses. Early studies using IL-2 to treat a number of advanced cancers suggested that it may be active against malignant melanoma and renal cell carcinoma. However, responses were at the expense of considerable morbidity and mortality. Those, and subsequent studies, which aimed at increasing the efficacy and reducing the toxicity of IL-2-based treatments, are briefly reviewed and the current situation in which IL-2 is being used more frequently, in low dose subcutaneously administered regimens (often in combination with other agents such as alpha-interferon) assessed. The ultimate application of IL-2 against human cancer may be when it is secreted either by tumour-infiltrating lymphocytes or the tumour cells themselves. A number of studies using this approach are about to commence or have already started. Tumour cells transduced with IL-2 could effectively act as a therapeutic vaccine against low volume disease.

Animals↗
PubMed1994

Dendritic cells are potent antigen-presenting cells for in vitro induction of primary human CD4+ T-cell lines specific for HIV gp120.

Activation of T helper cells specific for viral antigens is critical for antibody production and for generation of cytotoxic cells during the immune response to HIV. Since T-cell activation depends on antigen-presenting cells (APCs), it is important to define the cells that have a role in presentation of HIV antigens in general and of gp120 in particular. Peripheral blood mononuclear cells (PBMCs), adherent monocytes (AMs), dendritic cells (DCs) and Epstein Barr virus-transformed B-cell lines (LCLs) were tested for the capacity to present gp120 to a specific T-cell clone. DCs proved to be the most effective APC. Primary T-cell lines were generated from uninfected and unprimed individuals by using different APCs in the presence of gp120 or an immunodominant peptide. T-cell lines specific for gp120 were obtained with PBMCs or DCs as APCs, but not with AMs or LCLs. The data showed that (a) DCs are the most effective APCs for presentation of gp120 to specific T cells and (b) DCs are necessary for in vitro induction of primary T-cell lines specific for gp120.

Antigen Presentation↗
PubMed1993

Viral burden in AIDS.

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Acquired Immunodeficiency Syndrome↗
PubMed1993

Role of flanking variable sequences in antigenicity of consensus regions of HIV gp120 for recognition by specific human T helper clones.

Human T helper cells can discriminate among strain variants of HIV gp120 because of T cell clones recognizing non-conserved regions, as demonstrated with T cells from HIV-infected individuals and vaccinated volunteers and with primary T cell lines and clones obtained by in vitro immunization. To obtain a better definition of cross-reactions among T cell determinants within HIV gp120 variants, we used a panel of analog peptides within residues 236-251 from the BRU, MN, SF2 and RF strain sequences to induce primary human T cell lines and clones. Different patterns of response were obtained using each of the analog peptides, although they all share the consensus sequence 246-251. Clones recognizing this sequence were generated by priming with the BRU and RF analog peptides, but not with the SF2 analog peptide. SF2 did not induce any 242-245-specific clones, but only T cells recognizing the 236-240 sequence. A preferential response to residues 236-240 was obtained by priming with the BRU and SF2 peptides, but not with the MN and RF peptides. These results suggest that although the analog peptides exhibit a high degree of homology and share a consensus of the C-terminal sequence (246-251), the T cell response to the conserved sequence 246-251 is controlled by flanking sequences. Therefore the presence of a shared sequence per se does not imply in vitro expansion of clones with that fine specificity, even though such clones are available within the naive repertoire and can be triggered by an analog peptide.

Amino Acid Sequence↗
PubMed1993

Alloactivated cytotoxic T cells recognize the carboxy-terminal domain of human immunodeficiency virus-1 gp120 envelope glycoprotein.

Infection with the human immunodeficiency virus (HIV) virus leads to clinical disease in humans but not in chimpanzees. Progression to disease is associated with activation of the immune system followed by loss of T helper cell function and a slow decline in CD4-positive lymphocytes. The presence of autoreactive and cytotoxic cells in humans but not chimpanzees suggests that mechanisms other than, or in addition to, direct virus-induced cell killing, are required for disease to develop. The observed changes are similar to those seen in chronic allogeneic disease. Here we show that a peptide from the carboxy terminus of gp120, predicted to have a structure similar to the major alpha-helices of major histocompatibility complex (MHC) class I and class II, acts as a cytolytic target when presented on syngeneic cells for alloactivated cytotoxic T effector cells. These data add further evidence to the hypothesis that HIV can act as an allostimulant due to its dual properties of CD4 binding and MHC mimicry. The ability to signal nonspecifically through the T cell receptor could explain the initially paradoxical responses of proliferation, anergy and apoptosis.

Amino Acid Sequence↗
PubMed1993

Immunobiological aspects of HIV treatment.

Recent information on the efficacy of anti-retroviral therapy and vaccination strategies has been disappointing as well as confusing. The recently announced Concorde study suggested that there is no advantage to early treatment of asymptomatic HIV infection with azidothymidine alone, even though the levels of CD4+ cells in the treated group were consistently higher than in the untreated group. This will lead to increasing attention being paid to the mechanisms whereby HIV causes AIDS, which have sadly been sidelined in the rush to produce classically based therapies and vaccines. Over the last year many different theories on how HIV kills CD4+ cells and leads to AIDS have been discussed and tentatively explored.

AIDS Vaccines↗
PubMed1993

Dendritic cells infected in vitro with human T cell leukaemia/lymphoma virus type-1 (HTLV-1); enhanced lymphocytic proliferation and tropical spastic paraparesis.

Evidence supporting a role of the dendritic cell (DC) in stimulating autologous T cell activity in tropical spastic paraparesis (TSP) was sought by studies of cells taken from healthy volunteers and exposed to HTLV-1 in vitro. DC were co-cultured with an HTLV-1-producing cell line (MT-2) at 1:1 or 10:1 ratios. These DC stimulated high levels of proliferation in autologous T cells. This was similar to that seen in an autologous mixed leucocyte reaction (AMLR) using cells from TSP patients. The requirement for both DC and virus was confirmed, since neither DC co-cultured with uninfected MT-2 cells nor addition of infected MT-2 cells directly to T cells caused significant stimulation. DC exposed to the highest dose of HTLV-1 (1:1) for 24 h before addition of T cells caused strong stimulation that increased after 8 h but almost disappeared by 72 h. In situ hybridization showed that approximately 25% of DC became infected in cultured cells after preincubation for 24 h, and over 50% were infected with a 72-h preincubation. We suggest that infection of DC by HTLV-1 may be an initial step in altering the immune system in seronegative patients, and that persistent T cell stimulation in those with genetic susceptibility may underlie the production of neurological disease.

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