Biomedical subjects
Publications and source records attributed to P Beverley.
Immune responses against foreign antigens are initiated and controlled by dendritic cells (DCs). Accumulating evidence suggests that autoimmunity, involving T cells directed against self, can also be primed by DCs. We propose that DCs could induce autoimmunity following their differentiation by certain cytokines, or because of intrinsic defects in genes controlling DC function. Both processes result in DCs that behave deviantly.
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T cells recognizing poorly displayed self determinants escape tolerance mechanisms and persist in the adult repertoire. The process by which these T cells are primed is not clear, but once activated, they can cause autoimmunity. Here, we show that dendritic cells treated with interleukin 6 (IL-6) process and present determinants from a model native antigen in a qualitatively altered hierarchy, activating T cells in vitro and in vivo against determinants that were previously cryptic because of poor display. IL-6 does not induce conventional maturation of dendritic cells but alters the pH of peripheral, early endosomal compartments and renders the cells more susceptible to killing by chloroquine. Acidification of endosomes by ouabain mimics the effect of IL-6 and allows processing of the same cryptic determinant. These results suggest that cytokines such as IL-6 could initiate and help to propagate an autoimmune disease process by differentiating dendritic cells into a state distinct from that induced by normal maturation.
Much interest is currently being shown in immunotherapy as a treatment for cancer since several tumour-associated antigens have been identified and the genes encoding them cloned. One such molecule is the tumour-associated human MUC1 gene product. In this report we describe tumour rejection studies in a C57B1 murine model system with syngeneic MUC1-expressing tumour cells designed to examine the efficacy of MUC1 cDNA as an immunogen. Intra-muscular immunisation with 100 microgram MUC1 cDNA 3 times at 3-weekly intervals resulted in tumour protection in approximately 80% of mice. Tumour protection was dose-dependent, with 50-100 microgram being the most effective dose. Both humoral and cell-mediated MUC1-specific immune responses were detected. Anti-MUC1 antibodies were detected after immunisation with DNA alone, indicating that the injected DNA was expressed. Humoral immune responses did not correlate with tumour rejection. Tumour challenge with syngeneic tumour cells expressing MUC1 appeared to be a pre-requisite for the generation of MUC1-specific cytotoxic T lymphocytes.
In most individuals, HIV infection is characterized by a progressive decline in the number of peripheral blood CD4+ T lymphocytes, and while the number of CD4+ cells is within the normal range, defects in immune function are detectable. To date neither the decline in function nor the decline in cell number have been satisfactorily explained. Here we describe a mechanism which may contribute to the immunodeficiency and decline in CD4+ cell numbers in HIV-infected individuals. We show that recently activated T cells are susceptible to apoptosis when exposed to HIV gp120 in the presence of anti-gp120 antibody.
Human papilloma virus (HPV) type 16 is found in the majority of cervical cancer patients and the transforming protein E7 is consistently expressed in cancer cells, making it a potential target for immune attack. In this study we have investigated whether E7 gains access to the MHC class I processing pathway and provides cytotoxic T lymphocyte (CTL) stimulating peptide epitopes. CTL were induced in H-2b mice by immunization with recombinant vaccinia virus expressing E7 (Vac-E7). To map CTL recognition, natural peptides were purified from cells expressing either intact or truncated E7 protein. Following peptide separation by HPLC one major CTL epitope was detected and truncated constructs localized this epitope to the C-terminal region. Mapping with synthetic peptides indicated that residues 49-57 (RAHYNIVTF) were recognised by anti-E7 CTL. Synthetic 49-57 peptide was used to induce CTL, which recognized the same HPLC purified natural peptide fractions as anti-E7 CTL. Binding motifs for H-2b class I molecules did not predict residues 49-57 to be a CTL epitope, but instead the sequence 21-28 (DLYCYEQL) which contains a Kb anchor motif. Synthetic 21-28 peptide was found to bind to Kb class I molecules and readily induced CTL, indicating that the T cell repertoire of H-2b mice can recognize this epitope. However, these CTL did not recognize peptides isolated from E7 expressing cells, showing that natural processing did not produce detectable levels of the 21-28 epitope. Together, the data demonstrate that an unexpected E7 peptide can function as a major CTL epitope.
Toxic shock-like syndrome is a serious complication of invasive streptococcal disease. The syndrome is believed to be the consequence of exposure to exotoxins produced by the infecting organisms which behave as superantigens. We describe two patients who fulfilled clinical criteria for this syndrome, one of whom died. Streptococci isolated from both patients were found to produce a mitogen specific for the V beta 2+ T lymphocyte subset in vitro, which had the characteristics of a superantigen. The phenotype and function of lymphocytes collected from both patients during the acute phase of their illness demonstrated a marked reduction in circulating CD4+ ('helper') and CD45RA+ ('naive') T lymphocytes expressing the V beta 2 chain, and an increase of those expressing CD8, CD45RO and the V beta 2 chain. This effect resolved within 4 weeks in the patient who survived. Proliferation assays demonstrated no T cell anergy in either patient. Stimulation of lymphocytes by superantigen in these clinical situations does not appear to cause permanent deletion of T cell subsets, as has been observed in animal models.
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CD4 and CD8 T lymphocytes can be further subdivided using antibodies to isoforms of CD45 with restricted cellular distributions. These further subsets, detected in man, rodents and sheep, differ in surface phenotypes, rate of cycling, migration and response to recall antigens. Their lineage relationship has still not been fully established.
In vitro studies shows that recombinant tumour necrosis factor (TNF) alpha and beta, and interferon-gamma (IFN-gamma) can enhance HIV replication, and peripheral blood mononuclear cells (PBMC) infected with HIV in vitro secrete high levels of the same cytokines. As T cells secrete all three mediators, the capacity of T cell activation signals to trigger cytokine production in PBMC from HIV-infected individuals was investigated as such patients may be immunocompromised. We demonstrate that asymptomatic seropositives in CDC group II/III as well as patients who have progressed to CDC group IV of the disease proliferate efficiently to anti-CD3 antibody, recombinant interleukin-2 (rIL-2), phytohaemagglutinin (PHA), PHA plus phorbol 12,13 dibutyrate (PMA) but secrete significantly (P less than 0.05) higher amounts of TNF-alpha, TNF-beta and IFN-gamma compared with controls in response to the same stimulants. We also show a difference between group II/III and group IV patients with the latter secreting more TNF-alpha and IFN-gamma. The kinetics of TNF-alpha and -beta, and IFN-gamma production was stimulus dependent with overall levels varying in time for each stimulus. Furthermore, the kinetics of the response to all three stimulants were altered in seropositives; CDC group II/III and group IV patients secreted higher levels of cytokines over several time points compared to controls. The altered production of these mediators by HIV-infected patients may contribute to disease progression and to the pathogenesis of AIDS.
Antigen expression by human small cell lung carcinoma cells in serous effusions was determined by staining smears of cells with a panel of four monoclonal antibodies including UJ13A (cluster 1 antigen) and CAM 5.2 (anti-cytokeratin) using an immunoalkaline phosphatase technique. This was quantified by counting the proportion of stained and unstained tumour cells and was compared with that of small cell lung carcinoma in sections of solid tumour. Differential expression of antigen expression was noted with significantly fewer small cell carcinoma cells in serous effusions staining with UJ13A or CAM 5.2. The reasons for this differential expression are unknown, but may reflect adaptation to a different environment or be a prerequisite for spread to serous space.
UCHT1, a CD3-producing hybridoma, is lysed by cloned human T cells of both CD4 and CD8 phenotypes. The lysis is specific for the CD3 receptor and is mediated by 90% or more of all T cells from blood, without evidence for a subset of CD4 T cells incapable of cytotoxicity. CD4 clones characterized as 'helper' cells by in vitro help for specific antibody production by B cells also lysed CD3 targets. Varicella zoster virus (VZV) super-infected B lymphoblasts were lysed by three of six VZV-specific T-cell clones and 1 Cl-specific T-cell clones lysed 1 Cl hybridoma targets. Resting B cells (from tonsil) coated with CD3 antibody were lysed by CD4 clones. The data suggest that the majority of clonable CD4+ T cells lyse target cells recognized via CD3 or through the antigen receptor.
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The tumor promoter 12-O-tetradecanoylphorbol 13-acetate induces the expression of the interleukin 2 receptor and the disappearance of the T3 complex in a T cell hybridoma, T cell clones, thymic and peripheral T cells and T cell tumors. These changes are accompanied by an increased sensitivity to interleukin 2 and antigen-specific unresponsiveness in T cell clones.
Twenty-one patients are described with a proliferation of morphologically mature T lymphocytes. The clinical course was chronic in most, and splenic enlargement the main clinical finding; skin involvement and lymphadenopathy were rare. The mean lymphocyte count at presentation was 8 X 10(9)/1 (range 0.75-24 X 10(9)/1). Nineteen of these patients showed some form of cytopenia (18 neutropenia, two red cell aplasia, eight thrombocytopenia) and one had hypogammaglobulinaemia. Seven patients had long-standing arthropathy serologically proven to be rheumatoid arthritis and these had previously been considered to have Felty's syndrome. Five of the group have died (three with an aggressive course), but most have remained stable for prolonged periods with a slow increase in peripheral lymphocyte count and marrow infiltration. Spontaneous regression was never observed but in two patients a prolonged remission was achieved by chemotherapy. The lymphocytes were morphologically and phenotypically homogeneous at presentation and remained so post-splenectomy; they contained azurophilic granules, stained with acid phosphatase but weakly or not at all with alpha napthyl acetate esterase. Membrane phenotyping shows the majority of the cells to be E+, Fc gamma+, OKT3+, OKT8+. Most cells do not stain with OKT1-like reagents and a significant number express HLA-Dr. From these and other reported cases it is clear that this condition represents a distinct entity resulting from the expansion of a subset of cytotoxic/suppressor T cells--the question of the benign or neoplastic nature of the disease remains open. Using T cell-specific antisera and E-rosetting techniques, a small percentage of CLL cases have been shown to be of T-cell origin (TCLL) (Dickler et al, 1973; Lille et al, 1973). Estimates of the percentage vary but in most series T-CLL has been diagnosed in less than 5% (Brouet & Seligmann, 1981), and this is supported by date from the M.R.C. Leukaemia Unit which found T-CLL in only 1.5% of 600 cases of CLL examined by marker studies (D. Catovsky, unpublished). Amongst the published reports of T-CLL a variety of clinical and morphological entities have been described including T prolymphocytic leukaemia (TPLL) (Brouet et al. 1975) and adult T cell disease in Japanese (Uchiyama et al, 1977) and West Indian Caribbean groups (ATLL) (Catovsky et al, 1982). In the original series of Brouet & Seligmann (1981) the group was defined as presenting in middle age with marked hepatosplenomegaly, some lymphadenopathy, skin involvement and with an aggressive disease course; peripheral blood and marrow lymphocytosis were variable.(ABSTRACT TRUNCATED AT 400 WORDS)
4 patients are described with rheumatoid arthritis, splenomegaly, neutropenia and an unusual proliferation of T cells in the blood and marrow. These patients are clinically similar to patients with classical Felty's syndrome but can be distinguished from them by staining blood and marrow mononuclear cells with a panel of monoclonal anti-T cell antibodies. The T cells from patients with T cell proliferations stain with UCHT1 (OKT3 equivalent) and UCHT4 (OKT8 equivalent but do not stain with a panel of OKT1-like antibodies. In 7 patients with classical Felty's syndrome there was no increase of UCHT4 cells in the blood and the large majority of T cells stained with OKT1-like antibodies. The marrows from the patients with T cell proliferations contain plentiful haemopoietic progenitor cells and it is probable that the T lymphocytes suppress their normal maturation. There was a poor response to splenectomy in 2 patients with T cell proliferations, and single cytotoxic drug therapy may be more appropriate when therapy is required. The literature is reviewed and it is suggested that the T cell proliferations may be secondary to the rheumatoid process.
Influenza virus-specific (A/X31) long-term cultured human T-cell lines belonging to the helper/inducer T-cell set, produce high potency antigen specific helper factors which induce in vitro antibody production to A/X31 by autologous B cells, as well as small and variable amounts of non-specific helper factors. When added to unseparated peripheral blood mononuclear cells, both cultured T cells and their supernatants suppress in vitro antibody synthesis as measured by a solid phase enzyme-linked immunoassay, and T-cell proliferation to antigens and allogeneic cells, but not to mitogens. This phenomenon was further analysed and could be separated into several steps: (i) the production of suppressor inducer factor(s) by the T-cell lines which are distinct from the helper molecules; (ii) activation of T cells belonging to the suppressor/cytotoxic subset as defined by monoclonal antibodies, a process which is antigen-independent and non-genetically restricted, and is optimal with 18 hr incubation; (iii) the activated T cells non-specific suppress antibody production and antigen-induced or allogeneic cell-induced T-cell proliferation. Thus, antigen-specifically activated T-inducer cells exert multiple activities, including specific and non-specific help and non-specific induction of T suppressor cells.