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Biomedical subjects

G L Asherson

Publications and source records attributed to G L Asherson.

At least 55 records · Page 3Linked to original sources
PubMed1986

Nonspecific inhibitor of DNA synthesis elaborated by T-acceptor cells. II. Requirements for its production and action.

The production of a nonspecific inhibitor of DNA synthesis (nsINH) appears to be one of the final events in the T-suppressor cell circuit in mice exposed to contact sensitizers. We report here that: The nsINH suppresses the proliferative response to a polyclonal T-cell mitogen, concanavalin A (Con A), regardless of the dose of Con A used. It also suppresses DNA synthesis in lymphoid cells stimulated with alloantigens. This suppression can be completely eliminated by adding exogenous interleukin 2 (IL-2). DNA synthesis in lymphoid cells exposed to nsINH before the proliferative stimulus is uninfluenced so that activation of the lymphoid cells at the same time as exposure to nsINH seems to be a requirement for its action. Since the activity of nsINH can be absorbed by activated Lyt-1+ or Lyt-2+ lymphocytes, the early activated T cell appears to be a target of the action of nsINH. The production of nsINH is abolished or severely reduced by adult thymectomy. Natural killer (NK) cells are resistant to nsINH action and no interferon (IFN)-like activity can be demonstrated in nsINH preparation using a conventional assay for IFN.

Animals↗
PubMed1986

Recovery of immunoglobulin isotypes following T-cell depleted allogeneic bone marrow transplantation.

After conventional bone marrow transplantation serum IgG, IgM and IgA levels fall from pre-transplant levels and may not return to normal for 3-12 months. In contrast IgE may rise to supranormal levels, an event that may be associated with graft-versus-host disease. We have investigated the recovery of immunoglobulin isotypes in the recipients of allogeneic marrows depleted of T-cells to prevent graft-versus-host disease. We find that pre-transplant IgG, IgM and IgA levels are maintained throughout the post-transplant period but that there is a short-lived rise in IgE about 3 weeks after transplantation: this rise occurs in the absence of clinically detectable graft-versus-host disease. We conclude that specific T-cell depletion does not impair and may actually enhance the functional recovery of B cells after allogeneic BMT.

Adolescent↗
PubMed1986

An overview of T-suppressor cell circuits.

This review gives an overview of two main suppressor circuits. In its complete form, the first circuit form has an early acting Ts-inducer that behaves like a T-helper cell for the production of idiotype-directed Ts-transducer or antigen-directed Ts-effector cells. In this circuit, the T-suppressor effector cell (Ts-eff) produces antigen-specific T-suppressor factor (TsF). This has a mode of action through the T-acceptor cell (T-acc), a cell that requires immunization, but not specific immunization, for its production. This cell, when armed with TsF-eff and then triggered with antigen and I-J, releases nonspecific TsF that blocks the passive transfer of contact sensitivity. It also blocks the production of IL-2. The biological significance of the complexities of this circuit is discussed in relation to the control of unresponsiveness and the handling infection and antigenic variation of microorganisms. The second set of suppressor cells, T suppressor afferent cells, inhibits only when given early in the immune response but differs from the Ts-inducer by lacking an obligatory mode of action through the Ts-eff/T-acc circuit. In general, the antigen-specific T-helper and T-suppressor factors have a two-chain disulfide-bonded structure. One chain carries the antigen-binding site and the other chain MHC-related determinants. Both chains are required for biological activity, and the genetic restriction in this complementation implies that the antigen-binding chain has a recognition site for MHC determinant(s). The generalization can be made that the MHC-related determinants carried by the factors and the genetic restriction in their induction, in their action, and in the interchain complementation between their separated chains all map to the same region of the genome. This is intelligible on the assumption that the T-cell receptor on the cell that produces the factor has a recognition site for antigen and MHC determinants and that the antigen-binding chain of secreted factor has the same properties.

Animals↗
PubMed1985

I-A region genetic restriction in the production and action of an antigen-specific T-helper factor which bears I-A region determinant(s).

Antigen-specific T-helper factor (ThF) augments the contact sensitivity reaction induced by the injection of small numbers of picrylated cells into mice. ThF was produced by injected picrylated spleen cells into the footpads and taking the 24-hr culture supernatant of the regional lymph node cells. Analysis showed that there was a genetic restriction in the induction of ThF, between these picrylated cells and the mouse making the ThF, which maps to the I-A region. This finding suggests that the receptor on the T cell which makes ThF, and by implication ThF itself, bears recognition site(s) for both antigen and I-A. ThF was then prepared from mice painted on the skin with picryl chloride, and the genetic restriction in its action was investigated. There was a requirement for genetic matching between the mouse producing the ThF and the final recipient which mapped to the I-A region. The genotype of the picrylated cell used as a source of antigen was unimportant. This I-A genetic restriction, together with the finding that ThF bears at least some I-A determinants, suggests that ThF may act by binding to the picrylated cells used as a source of antigen through its antigen-binding site and hence provide the I-A determinants needed for the recognition of antigen in the context of self-MHC. The present findings add to the list of antigen-specific factors which have a two-chain structure and show genetic restriction in their induction, action, and in the interaction between their chains which maps to the same region as the MHC-related determinant(s) which they bear.

Animals↗
PubMed1985

The role of dendritic cells in the initiation of immune responses to contact sensitizers. I. In vivo exposure to antigen.

Twenty-four hours after skin painting mice with picryl chloride (PIC) there was a four- to fivefold increase in the numbers of dendritic cells (DC) isolated from the lymph nodes. These DC initiated primary proliferative and cytotoxic responses when added to cultures of normal syngeneic lymph node cells. The proliferative response was enhanced when the donors of the responding lymph node cells were sensitized with the same antigen. Contact sensitivity developed in syngeneic mice injected into the footpads with 30,000-50,000 DC from lymph nodes of mice painted with picryl chloride 1 day previously. Thus, 1 day after skin painting mice, there were dendritic cells in the draining lymph nodes which were able both to initiate primary stimulation of lymphocytes in vitro and to sensitize recipient mice to give specific delayed hypersensitivity reactions.

Animals↗
PubMed1985

Two-chain disulphide-bonded structure of antigen-specific T-helper factor: both chains are necessary for activity and their interaction is I-A restricted.

The molecular structure of the antigen-specific T-helper factor (ThF) which augments contact sensitivity in mice was studied. ThF was split into two types of polypeptide chain by mild reduction and alkylation; one antigen binding (which determined the specificity), the other non-antigen binding. The two chains were, by themselves, inactive but complemented each other and reconstituted biological activity. In addition, a genetic restriction was observed in the complementation of the two chains which mapped to the I-A subregion of the H-2 complex.

Animals↗
PubMed1985

The control of the contact sensitivity skin reaction: T-suppressor afferent cell blocks the production of antigen-specific T-helper factor.

Lymph node cells from mice painted with the contact sensitizers picryl chloride or oxazolone produce antigen-specific T-helper factor. This is detected by its ability to increase the contact sensitivity response to the injection of small numbers of haptenized spleen cells into the footpads of naive recipients. The production of this T-helper factor is inhibited by the injection of spleen cells from mice given water-soluble, chemically reactive hapten such as picrylsulphonic (trinitrobenzenesulphonic) acid--an agent which induces unresponsiveness. The cells which inhibit the production of T-helper factor are antigen-specific T-suppressor cells. They are sensitive to cyclophosphamide given before the injection of picrylsulphonic acid, but are unaffected by adult thymectomy. In this respect, they resemble the family of Ts-aff which inhibit the development of contact sensitivity, specific antigen-induced lymph node proliferation and the specific IgG response, and differ from the T-suppressor efferent cell (Ts-eff) which acts at the expression stage of the contact sensitivity reaction. These results are fully compatible with the view that the Ts-aff inhibits the development of contact sensitivity by blocking the production of antigen-specific T-helper factor.

Animals↗
PubMed1985

In vivo activity of interleukin-2: conversion of a stimulus causing unresponsiveness to a stimulus causing contact hypersensitivity by the injection of interleukin-2.

The intravenous injection of hapten-modified (picrylated) cells causes unresponsiveness. When conventional or recombinant interleukin-2 (IL-2) is also injected, strong contact sensitivity occurs. This IL-2 is effective when given 7 hr after the injection of the picrylated cells or 2 days later, but has no effect when given beforehand. It is suggested that picrylated cells given intravenously fail to induce contact sensitivity secondary to a failure of IL-2 production, and that IL-2 may be one of the second signals which converts a 'tolerogenic' stimulus into an immunogenic stimulus.

Animals↗
PubMed1985

A non-specific inhibitor produced by Candida albicans activated T cells impairs cell proliferation by inhibiting interleukin-1 production.

Human T lymphocytes cultured in vitro for 5 days with Candida albicans purified polysaccharide (MPPS) produce and antigen non-specific inhibitor (nsINH) which blocks cell proliferation when added at the beginning of the culture. The antigen presenting function of antigen pulsed adherent cells (macrophages) is significantly impaired by incubation in nsINH. Further analysis shows that nsINH blocks the production of interleukin-1 both from human mononuclear cells stimulated with lipopolysaccharide. Furthermore, the production of interleukin-2 (IL-2) is also suppressed when MPPS stimulated cells are cultured in presence of nsINH. However nsINH does not affect the appearance of IL-2 responsive cells as the addition of gibbon IL-2 to the culture fully reverses the suppressive effect of nsINH on blast transformation.

Antigens, Fungal↗
PubMed1984

Intravenous gammaglobulin treatment in patients with hypogammaglobulinaemia.

Intravenous gammaglobulin was compared with the standard British intramuscular preparation in patients with hypogammaglobulinaemia and chronic bronchitis. Five patients were given six months' treatment with the weekly intramuscular preparation and six months' treatment with intravenous gammaglobulin given once every 18 days. During the trial they recorded symptoms of infection, absence from work, and sputum volume; lung function tests were performed during the intravenous treatment. The half life of the intravenous IgG and changes in serum IgG and C1q concentrations were also measured in seven other patients who received intravenous gammaglobulin every two weeks for 12 weeks. IgG concentrations, sputum volume, and infection scores were significantly better during intravenous treatment and there were no adverse effects from the intravenous gammaglobulin. These five patients were significantly more healthy when they received an intravenous gammaglobulin preparation, probably because the intravenous preparation increased serum IgG concentrations. Although longer studies are needed, intravenous gammaglobulin should be considered for patients with severe chest disease and those who cannot tolerate intramuscular injections.

Agammaglobulinemia↗
PubMed1984

T suppressor factor activity is due to two separate molecules. The Lyt-1(-)2+I-J+ cells of mice primed with antigen make an antigen binding molecule which is only active when complemented by cofactor made by Lyt-1+2(-)I-J+ cells.

Mice primed with picrylsulfonic acid (PSA) and then painted on the skin with picryl chloride produce antigen-specific T suppressor factor (TsF). In contrast unpainted primed mice fail to produce active TsF. This is not due to the absence of the antigen binding part of TsF but to the absence of a cofactor. This cofactor is (a) antigen nonspecific and occurs in potassium chloride extract of normal spleen cells. It also occurs in the 24 hr supernatant of normal cells modified by haptenisation with picryl or the unrelated NP antigen (4-hydroxy-3-nitrophenylacetyl), and in preparations of conventional TsF (PSA/PCl) from painted PSA-primed mice; (b) bears I-J determinants; and (c) is produced by Lyt-1+2(-)I-J+ cells. The antigen binding molecule occurs alone in the supernatant of PSA-primed mice. It lacks I-J determinants and has a molecular weight around 35,000 and 75,000. It is produced by Lyt-1(-)2+I-J+ cells and is only active when complemented by cofactor. However, the complementation is genetically restricted and the restriction maps to the I-J subregion of the MHC.

Animals↗
PubMed1984

Nonspecific inhibitor of contact sensitivity made by T-acceptor cells: triggering of T cells armed with antigen-specific T-suppressor factor (TsF) requires both occupancy of the major histocompatibility complex recognition site by soluble I-J product and cross-linking of the antigen recognition sites of the TsF.

The phenomenon of associative recognition, i.e., the recognition of antigen together with major histocompatibility complex products (MHC) was studied in a model system. T-acceptor cells armed with antigen-specific T-suppressor factor (TsF) released a nonspecific inhibitor of the transfer of contact sensitivity when exposed to antigen together with MHC. The MHC product occurred in a KCl extract of cells and behaved genetically and serologically as I-J. Cells armed with anti-picryl or anti-"oxazolone" TsF could be triggered by the corresponding "bis-picryl-L-lysine" and "bis-oxazolone-L-lysine" together with MHC. This suggested that cross-linking of antigen recognition sites on separate molecules of TsF might be required. To investigate this possibility the bifunctional "mixed" hapten "N alpha-picryl-N epsilon-oxazolone-L-lysine," which is univalent with respect to the picryl and oxazolone haptenic groups, was synthesized. This triggered cells armed with a mixture of anti-picryl and anti-oxazolone TsF but not cells armed with either TsF alone. It was concluded that both occupancy of the I-J recognition site and the cross-linking of separate molecules of TsF was required for triggering. Moreover the hapten and the KCl extract could be given sequentially and in either order. This finding suggested that the triggering of the release of nonspecific inhibitor was due to the separate recognition of I-J and antigen and not to new antigenic determinants produced by their interaction.

Animals↗
PubMed1984

Complement activation by cell-associated immune complexes in contact sensitivity.

Lymph node cells collected 4 days after painting the skin with picryl chloride activate the first components of the classical pathway of complement cascade, as shown by consumption of C4 of rabbit complement with total sparing of C5 and factor B activity. In contrast, lymph node cells collected 1 or 6 days after sensitization fail to do so. The ability of "4-day" cells to activate complement is inhibited by treating the cells with specific low-molecular-weight hapten, which is known to dissociate the immune complex present on the cell surface. When mouse serum was used as source of complement, a different behavior in complement activation between CBA/J and B10.D2-New/SnJ serum was observed: "4-day" cells failed to consume CBA/J serum whereas a normal complement activation was detected when B10.D2-New/SnJ serum was used. Using these two sera which differ in the level of C4, an inverse relationship between the ability of "4-day" cells to activate complement and their capacity to induce contact sensitivity when injected into the footpad of normal recipients was reported. Experiments performed using sera from C5 genetically deficient mice demonstrate that only the early complement components are involved, suggesting that membrane immune complexes are solubilized as a result of complement activation; on the other hand, membrane bound activated complement components could alter the immunizing potential of "4-day" cells.

Animals↗
PubMed1984

Two-chain structure of T-suppressor factor: antigen-specific T-suppressor factor occurs as a single molecule and as separate antigen-binding and I-J+ parts, both of which are required for biological activity.

Antigen-specific T-suppressor factor (TsF), which acts at the expression stage of the contract sensitivity reaction, was produced by culturing the lymphoid cells of mice injected with picryl-sulphonic (trinitrobenzenesulphonic) acid and then painted with picryl chloride. Supernatant activity was found around 50-60 and 90 kDa on Sephadex gel filtration. The activity at 50-60 kDa was due to two separate (or readily separable) molecules, one antigen binding and the other bearing I-J determinants as shown by affinity chromatography on insolubilized antigen and anti-I-J. These two separate molecules were inactive alone but complemented each other and may be designated as the variable chain of TsF (TsFv) and the I-J+ chain. The use of gel filtration and sequential absorption of individual pools on anti-I-J antibody followed by antigen, together with a complementation assay, also showed a TSFv chain at 30-40 kDa and an I-J+ chain at 20-30 kDa. The higher-molecular-weight activity around 90 kDa was due to a single molecule which was both antigen binding and I-J+. This molecule dissociated on treatment with the reducing agent dithioerythritol followed by alkylation into two separate chains, one antigen binding and the other I-J+, both of which were required for activity. There was a requirement for genetic matching between the antigen-binding chain (TsFv) and the I-J+ chain for biological activity. These data support a two-chain model of TsF in which TsFv and the I-J+ chain occur as a single disulphide-bonded molecule around 90 kDa, or as two separate (or readily separable) chains of lower molecular weight which were inactive alone but complemented each other.

Animals↗
PubMed1984

T helper factor in contact sensitivity: antigen-specific I-A+ helper factor is made by an Lyt-1+2-, I-A+, I-J- T cell.

Antigen-specific T helper factor appears in the 24 hr supernatant of lymph node cells taken 4 days after immunization with contact sensitizer. The factor is assayed by its ability to augment the contact sensitivity response induced by haptenized spleen cells. In practice, picrylated or oxazolonated spleen cells are treated with the factor for 1 hr at 4 degrees and 4 x 10(6) cells are injected into the footpads of recipient mice. Contact sensitivity is assessed 5 days later. The factor first appears 3 days after immunization and its production depends on an Lyt-1+2-, I-A+, I-J- T cell. It is antigen-specific in its action in a criss-cross experiment, and can be absorbed with and eluted from haptenized beads. It bears I-A determinant(s) and the I-A determinant and the antigen binding site(s) occur on the same molecule. The molecular weight is around 60,000. The possible role of T helper factors in the activation of the antigen-presenting cell in the induction stage of the immune response is discussed.

Animals↗
PubMed1984

Non-specific inhibitor made by T acceptor cells inhibits both the afferent and efferent stage of the contact sensitivity reaction.

In the T suppressor circuit which affects contact sensitivity, the T acceptor cell (Tacc) armed with T suppressor factor (TsF) and then triggered by antigen and major histocompatibility complex products (I-J) releases non-specific inhibitor (nsINH). These non-specific inhibitor(s) affect both the efferent and afferent stage of the contact sensitivity reaction and were originally detected by the inhibition of the passive transfer of contact sensitivity. The nsINH also blocks the induction of contact sensitivity when given intravenously at the time of immunization but has no effect when given at the time of challenge. Similarly, it blocks proliferation in the regional lymph nodes induced by contact sensitizer in a dose-dependent fashion; it acts when given at the time of immunization but not 1 day later. This effect is antigen non-specific and H-2 unrestricted. The nsINH bears I-J determinants as shown by affinity chromatography on monoclonal antibody. The nsINH comes from the Tacc and is not a breakdown product of the TsF. This is shown by the fact that, when the Tacc and TsF have I-J of different genotypes, the genotype of the nsINH corresponds to that of the Tacc. Parallel measurements of inhibition of lymphoproliferation and of passive transfer show that the nsINH has a molecular weight of 50-60 Kd and a pI around 6.8 and suggest that similar or identical molecules block both the afferent and efferent stage of the contact sensitivity reaction.

Animals↗