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J Farrant

Publications and source records attributed to J Farrant.

At least 55 records · Page 3Linked to original sources
PubMed1990

Role of interleukin-2 and interleukin-6 in the mitogen responsiveness of T cells from patients with 'common-variable' hypogammaglobulinaemia.

We have assessed the ability of interleukin-2 (IL-2) and interleukin-6 (IL-6) to augment the proliferative response of T lymphocytes from 'common-variable' hypogammaglobulinaemia (CVH) patients and from normal controls, to the mitogens phytohaemagglutinin (PHA) and OKT3. We show that with cells from the control group and from those patients whose T cells respond to PHA within the control range, both IL-2 and IL-6 will significantly augment the response to OKT3. However, in those patients with a T cell defect in which the PHA response is below the control range, neither IL-2 nor IL-6 could restore the PHA or OKT3 response to normal. Responses to IL-2 or IL-6 alone were always in or above the control range.

Agammaglobulinemia↗
PubMed1990

Cellular abnormalities in common variable immunodeficiency.

In most patients with common variable immunodeficiency (CVI) there is evidence for an intrinsic B cell defect, despite an apparently normal cell phenotype. There are at least five separate subgroups of CVI, based on B cell function. These groups may be variations in severity of a single defect, or distinct molecular defects. At least some patients may have an abnormality in the secretory process of the B cell. The existence of patients whose cells can secrete IgM and IgG in vitro and yet are hypogammaglobulinaemic in vivo implies that the architecture of lymphoid organs or the traffic of lymphoid cells may be involved in the pathogenesis of the disease. The data on T cell defects in CVI indicates that, with sensitive assays, many patients have some abnormality. In the face of a much more defined B cell defect it is not yet possible to assess the overall contribution of the T cell defects to the immune failure.

Agammaglobulinemia↗
PubMed1989

B cell function in acquired "common-variable" hypogammaglobulinemia: proliferative responses to lymphokines.

We have compared the proliferative responses of an enriched population of B lymphocytes from patients with acquired (common variable) hypogammaglobulinemia (CVH) with the responses of cells from normal individuals. The uptake of [3H]thymidine into DNA was measured on stimulation with a range of interleukins (IL-2, IL-4, and IL-6) and solid-phase anti-IgM. Flow cytometry using CD19 and surface IgM showed that the "non-T" preparations from the peripheral blood of CVH patients either contained B cells within the normal range (30-40% of the cells) or in a minority group no B cells (less than 3% of the cells). Overall, there were no significant differences between the proliferative responses of patients' cells (in the group where normal numbers of B cells were present) and normal cells with any combination of stimulus used. No IgG was produced by cells from any patient and in only one patient was IgM production observed. This suggests that the primary B lymphocyte defect in CVH is in the differentiation phase in B cell function rather than in the growth phase. However, the presence or absence of B cells suggests that different defects exist in subgroups of patients with this disease.

Agammaglobulinemia↗
PubMed1989

The role of lymphokines in common variable hypogammaglobulinemia.

Common variable (acquired) hypogammaglobulinemia (CVH) is a rare primary immunodeficiency disease of great interest as an immunological model of defects in antibody production. In this article, Gavin Spickett and John Farrant discuss evidence of abnormalities in lymphokine production and responses in the generation of the functional failure. It is not yet clear whether the B cell is intrinsically abnormal or lacks appropriate signals, but the block appears to occur in the differentiation phase of B cells, since membrane (but not secreted) IgG is made. Some T-cell defects also occur in this disease. The cause of CVH is unknown, although a viral aetiology has been suggested. Better understanding of lymphokine networks may allow the provision of specific signals to overcome the block in antibody production.

Agammaglobulinemia↗
PubMed1989

Assessment of responses of normal human B lymphocytes to different isolates of human immunodeficiency virus: role of normal donor and of cell line used to prepare viral isolate.

The effect of different HIV-1 isolates on normal human B lymphocyte function has been studied in vitro. Production of IgM and IgG was measured by ELISA using a "standard" non-T preparation of B cells depleted of macrophages and T cells (but not of low-density accessory cells, LDC). Only one (H9/CBL-4) of five different isolates induced polyclonal production of immunoglobulin. Apart from intrinsic differences between isolates, important inherent variables were shown to affect the response. One was the mix of cell types in the responding preparation of B cells. This was tested by examining the effects of HIV-1 isolates independently on the accessory function of LDC and on B cell function when the LDC were removed. Isolate H9/HTLV-IIIRf was nonstimulatory on a B cell preparation containing LDC and suppressive on LDC accessory function yet could enhance function of B cells when the LDC were depleted. Another variable was the donor of the normal B cells. The B cell response was consistent with each donor but varied greatly with different donors. Thus, no single explanation emerges for the hypergammaglobulinemia in some adult AIDS patients and for the hypogammaglobulinemia in some pediatric cases. Additionally, the cell lines used to propagate the virus particularly affected the assay of B cells depleted of LDC. Uninfected supernatants had different effects on the B cell function, and these host cell effects (perhaps by release of cytokines or other mediators) may be exacerbated in infected cell lines. Our data show the complexity of the abnormal B cell function in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Defective DNA synthesis by T cells in acquired 'common-variable' hypogammaglobulinaemia on stimulation with mitogens.

We have studied T cell defects in acquired 'common-variable' hypogammaglobulinaemia (CVH) by measuring the synthesis of DNA, RNA and protein in vitro in response to mitogens and to interleukin 2 (IL-2). We have confirmed that some patients have defective DNA synthesis in response to PHA and shown that this extends to responses to cell-derived B cell growth factor (c-BCGF) which is also mitogenic to T cells. DNA synthesis induced by IL-2 was not defective in these patients suggesting IL2-receptor induction is normal. The mitogen-related defect in DNA synthesis was not accompanied by any reduction in synthesis of RNA or of protein. Levels of the rate limiting enzyme (thymidylate synthetase EC 2.1.1.45) responsible for de novo DNA synthesis in the absence of endogenous thymidine were measured following PHA stimulation and found to be in the normal range. In the CVH patients (but not in normal individuals) the relationship between the levels of thymidylate synthetase and DNA synthesis in response to PHA approached significance, suggesting that this pathway becomes more important in CVH patients than in normal individuals perhaps because of defects in the thymidine 'salvage' pathway.

Agammaglobulinemia↗
PubMed1989

Accessory and T cell defects in acquired and inherited hypogammaglobulinaemia.

Cellular defects in patients with common variable hypogammaglobulinaemia (CVH) and X-linked agammaglobulinaemia (XLA) have been studied in vitro, using a mitogen-driven system of immunoglobulin production. We have confirmed our previous finding of impaired low-density (dendritic) accessory cell function in CVH and now show that accessory cell function is normal in XLA. We demonstrate that macrophage accessory function is normal in CVH. T cell help for IgM production is also deficient in CVH, and T cell help in XLA is also abnormal for both IgG and IgM. Some XLA patients have excessive T suppressor activity. The contribution of these defects to the clinical states is discussed.

Agammaglobulinemia↗
PubMed1988

Induction of autoimmunity with dendritic cells: studies on thyroiditis in mice.

The initiation and maintenance of thyroid autoimmunity by professional antigen-presenting cells were assessed by observing thyroiditis and induction of IgG antibodies to thyroglobulin (Tg). Dendritic cells (DC) were purified from spleens of CBA mice and T cells removed with anti-Thy 1 and complement. Some DC were pulsed with 25-500 micrograms/ml of mouse Tg in vitro and normal syngeneic mice received injections of 10(5) cells intravenously. In untreated animals only 1 thyroid out of 40 showed a lymphocyte infiltrate and antibody to Tg was rarely seen. In animals receiving normal DC without Tg, lymphocyte infiltration was seen 2-6 weeks later in 5 out of 33 thyroids and some animals produced low levels of antibody to thyroglobulin (8 of 33 animals). DC pulsed with 500 micrograms Tg/ml in vitro caused thyroid infiltration in 6 out of 15 animals but did not increase the incidence of anti-Tg antibodies. Lower doses had no effect. When 10(5) DC were given from animals with experimental allergic thyroiditis (EAT, induced with Tg in complete Freund's adjuvant, CFA) more than half of the recipient animals showed thyroiditis (8 out of 15) and autoantibody production (12 of 15 animals). DC may therefore play a role in the initiation and maintenance of autoimmunity by providing a stimulus for antigen-specific T cells.

Animals↗
PubMed1988

Viruses and antibody deficiency syndromes.

Viral infections that occur in patients with primary immunodeficiencies are summarized. These viral infections include: Echovirus, poliovirus, varicella zoster, non-A non-B hepatitis and hepatitis B. Cases of X-linked lymphoproliferative syndrome associated with Epstein-Barr virus infection and congenital rubella syndrome are also reviewed. In the second part of the paper, retrovirus (HIV) isolations from blood mononuclear cells of 3 out of 31 patients with common variable hypogammaglobulinemia are reported. This supports the concept that some of the non-familial "primary" immunodeficiencies may be due to retrovirus infections.

Agammaglobulinemia↗
PubMed1988

Peripheral blood dendritic cells in persons with AIDS and AIDS related complex: loss of high intensity class II antigen expression and function.

The antigen-specific immune response in HIV sero-positive individuals is depressed or absent. This may be due in part to abnormal co-operation between T lymphocytes and antigen presenting cells (APC). We have isolated from the peripheral blood of healthy heterosexuals and patients with persistent generalized lymphadenopathy (PGL) and AIDS, cells of low density (LDC) with dendritic morphology. These cells are known to be potent APC. The expression of two cell surface antigens on these cells, namely 63D3 (a monocyte related antigen) and Class II antigens was examined. LDC from controls and patients with benign, non-progressive PGL (type A) were found to show biphasic expression of Class II antigens. By contrast, the high intensity Class II expression seen on a small proportion of 63D3 negative cells from controls and patients with PGL type A was absent in patients with PGL type B (showing subtle signs of progressive immunodeficiency) and AIDS. The loss of this population of dendritic cells was reflected in the absence of stimulator activity in autologous and heterologous mixed lymphocyte reactions. Thus, it is possible that the loss of these dendritic cells may contribute to the profound immunological abnormalities seen in AIDS.

AIDS-Related Complex↗
PubMed1986

Thyroglobulin-treated blood dendritic cells induce IgG anti-thyroglobulin antibody in vitro in Hashimoto's thyroiditis.

Nonadherent, low density cells of dendritic morphology from the blood of patients with Hashimoto's thyroiditis were treated with human thyroglobulin (Tg) in vitro and cultured under serum-free conditions with autologous patient B cells and irradiated T cells. The patients were selected for high serum levels of IgG antithyroglobulin antibody (anti-Tg IgG). In 2 out of 12 patients the Tg-treatment induced production of anti-Tg IgG in excess of that secreted spontaneously. The amount of antibody produced in vitro (whether increased by Tg or not) correlated with the serum levels of antibody. In 5 patients (including the 2 who responded to Tg) the ratio of supernatant IgG anti-Tg antibody to total IgG was reduced when polyclonal stimulation was done with BCGF (10%). Antibody production was absent in cultures of cells from 2 patients with Graves disease and 4 normal individuals. Thus, in some patients with Hashimoto's thyroiditis, an extrinsically added autoantigen (Tg) on blood-derived dendritic cells can induce IgG anti-Tg antibody in vitro. These data suggest that "professional" antigen-presenting cells may play a role in autoimmune thyroid disease.

Aged↗
PubMed1986

The effect of breast-feeding on proliferation by infant lymphocytes in vitro.

The effect of breast-feeding on the development of lymphocyte responsiveness in infants has been studied. Peripheral blood mononuclear cells from 15 breast- and 15 bottle-fed infants were obtained sequentially between 6 days and 9 months of age. A number of agents were used to stimulate the cells in vitro and the resulting proliferative responses were compared between the two feeding groups. A hanging drop microculture system using serum-free medium, enabled spontaneous proliferation and proliferative responses to several stimuli (T and B cell mitogens, allogeneic lymphocytes, and antigen) to be studied at a range of cell concentrations and days of culture. Significant age-related differences were found between the responses of cells from the two feeding groups. Spontaneous proliferation and proliferative responses to the T cell mitogen phytohaemagglutinin and the antigen tetanus toxoid were significantly greater in the breast-fed group at the two earliest ages studied (6 days and 6 wk). Responses to mitogens which predominantly affect B cells, such as pokeweed mitogen and Staphylococcus aureus (Cowan), were similar in both feeding groups at this age. In contrast, from 3 to 9 months of age, responses of cells from bottle-fed infants were significantly greater to all stimuli than responses from breast-fed infants. One possible explanation for the higher level of proliferation by cells from newborn breast-fed infants, is that these infants may absorb the cell-growth factors and lymphokines known to be present in human colostrum and milk. These factors may stimulate T cells and/or their precursors in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Feeding↗
PubMed1986

Non-adherent, low-density cells from human peripheral blood contain dendritic cells and monocytes, both with veiled morphology.

Dendritic cells (DC) from human peripheral blood, known to adhere transiently and to become non-adherent by 16 hr, can be separated in the low-density interface on hypertonic Metrizamide gradients. Many more low-density cells (5.8% of the mononuclear cells separated on Ficoll) were obtained from the population that was non-adherent after only 90 min. Over 95% of these low-density cells had veiled morphology. A proportion were monocytes by phenotypic and phagocytic properties. One-third of the cells (on average) were DC on the basis of lack of monocyte phenotype and of potency as stimulators in the mixed lymphocyte reaction. Including both the 16 hr and 90 min non-adherent cells, over 2% of the mononuclear cells isolated from human peripheral blood may be DC.

5'-Nucleotidase↗
PubMed1985

Defective low-density cells of dendritic morphology from the blood of patients with common variable hypogammaglobulinaemia: low immunoglobulin production on stimulation of normal B cells.

Low-density cells (LDC) of dendritic morphology from the blood of patients with common variable (late-onset) hypogammaglobulinaemia (CVH) did not induce allogeneic immunoglobulin production by normal B cells unlike LDC from normal blood. When LDC from patients were treated with pokeweed mitogen (PWM), a lower allogeneic secretion of IgM and IgG was induced in normal B cells than that induced by allogeneic normal LDC treated with PWM. B cells from hypogammaglobulinaemic patients were non-responsive to both normal and patient LDC treated with PWM under all conditions tested.

Agammaglobulinemia↗
PubMed1984

Production of antibody by human B cells under serum-free conditions.

A method is described for growing human B cells in 20 microliter hanging drops in Terasaki plates under serum-free conditions. B cell proliferation and differentiation has a critical dependence for added soybean lipid, while T cell proliferation does not. In this medium, pokeweed mitogen stimulation of separated human B cells induces high levels of immunoglobulin in a T dependent manner. Cells from donors vaccinated with tetanus toxoid and shown to be responders by a conventional culture system, produce high levels of IgG anti-tetanus antibody after antigen stimulation in these serum-free microcultures. The serum free culture system has the novel features of high sensitivity to dose of mitogen or antigen, low background responses and high antibody production with low cell numbers.

Antibodies, Bacterial↗