Biomedical subjects

G L Asherson

Publications and source records attributed to G L Asherson.

At least 37 records · Page 2Linked to original sources

PubMed1992

A nonspecific inhibitor of contact sensitivity elaborated by macrophages: genetic restriction in its production but not in its action.

It is known that macrophages armed with hapten-specific T suppressor factor (TsF) and then exposed to antigen (haptenized spleen cells) liberate a nonspecific inhibitor of the transfer of contact sensitivity (CS). This is called macrophage suppressor factor (MSF). This paper shows that MSF is only released when the source of the TsF and the haptenized spleen cells share the same I-J subregion. This is based on the comparison of B10.A(3R) and B10.A(5R) mice. In contrast, the action of MSF is antigen nonspecific and genetically unrestricted. In these respects it resembles the antigen-nonspecific inhibitor (nsTsF-1) made by the T acceptor cell when armed with TsF. However, it differs from nsTsF-1 in acting directly on the I-A- population which transfers contact sensitivity and not indirectly via I-A+ T cells. In vitro, MSF fails to inhibit the proliferative response of lymph node cells to specific antigen and their production of IL-3 activity, IFN-tau, and IL-2. This indicates that MSF is not a global inhibitor of T cell activity. The finding that MSF inhibits systemic passive transfer of contact sensitivity, but has no effect on local passive transfer strongly supports the view that MSF affects the arrival of certain cells critical for the development of the reaction to the skin challenge site.

Animals↗

PubMed1992

Chemical inactivation of the Kveim reagent.

In an attempt to identify the nature of the active principle, Kveim reagent was exposed to chemical fractionating agents. Thirty-one patients with sarcoidosis underwent simultaneous intradermal injection with fractionated and unfractionated Kveim material. Kveim reagent was stable in the presence of DNAse, RNAse, pronase, 95% phenol, neutral detergent, and to lipid extraction with chloroform-methanol. Kveim reagent was also stable in the presence of both 8 M urea (8MU) and 2-mercaptoethanol (2ME) when used alone. When both these agents were used together, Kveim reagent was inactivated. Fourteen patients had a positive test to unfractionated Kveim reagent; of these, only 2 gave a positive response to material fractionated by exposure to 8MU and 2ME. Simultaneous exposure to 8MU and 2ME was more likely to inactivate Kveim reagent (10/10 tests) than sequential exposure to 8MU and 2ME (2/4 tests). Chemical analysis of the fractionated material showed that it retained granuloma-generating activity despite the lack of carbohydrates. Protein loss in terms of total and relative amino acid composition was progressive and non-specific throughout processing. These results are consistent with a protein-active principle which is dependent on three-dimensional structure.

Chemical Fractionation↗

PubMed1992

Immune deviation in the mouse: transfer of selective depression of the contact sensitivity and interleukin-2 response with retention of interferon-gamma production requires CD8+ T cells.

Mice were injected intravenously (i.v.) with trinitrophenyl (TNP)-modified spleen cells. They were subsequently immunized by epicutaneous application of 2,4,6-trinitrochlorobenzene (TNCB, picryl chloride) or 'oxazolone'. The intravenous injection of antigen caused immune deviation (split tolerance) with selective loss of contact sensitivity (CS) and antigen-induced interleukin-2 (IL-2) production, and concomitant retention of antigen-induced interferon-gamma (IFN-gamma) production. This phenomenon was antigen specific as the response to oxazolone was unaffected. Moreover, lymph-node cells stimulated with antigen three times in vitro (from 'deviated' mice which had been injected with antigen i.v., and then sensitized with TNCB) showed limited proliferation. The per cent of IL-2R+ cells and the absolute number of V beta 8+ cells dropped. In contrast, lymph-node cells from 'undeviated' mice showed increased proliferation and IL-2 production on repeated stimulation with antigen in vitro and the per cent of IL-2R+ cells and the absolute number of V beta 8+ cells recovered increased. Spleen cells, taken from mice 3-7 days after the injection of antigen i.v., transferred immune deviation to normal recipients i.e. following epicutaneous immunization with TNCB, the recipients showed the same selective unresponsiveness as the donors. Thy-1+ CD4- CD8+ cells were required. These findings indicate that immune deviation can be demonstrated at the level of lymphokine production.

Animals↗

PubMed1991

Functional equivalence of cryptococcal and haptene-specific T suppressor factor (TsF). I. Picryl and oxazolone-specific TsF, which inhibit transfer of contact sensitivity, also inhibit phagocytosis by a subset of macrophages.

Monoclonal and conventional cryptococcal-specific T suppressor factors (TsF) (also called TsFmp) depress phagocytosis by a subset of macrophages, while picryl- and oxazolone-specific TsF depress the passive transfer of contact sensitivity. This paper shows that these haptene-specific TsF also inhibit phagocytosis by a subset of macrophages and, using this assay, that the anti-haptene TsF resemble the anti-cryptococcal TsF in five respects: (i) the need for reexposure to specific antigen to trigger the release of TsF; (ii) genetic restriction in action; (iii) possession of an antigen-binding site; (iv) expression of I-J determinants; and (v) inactivation by reduction and alkylation. Purification of the anti-picryl TsF by sequential affinity chromatography indicates that the inhibition of phagocytosis is due to the TsF itself and not to a TsF-antigen complex. The TsF inhibits phagocytosis by a direct action as macrophages treated with TsF and exposed to antigen do not release a second factor which inhibits phagocytosis. These results and those of the accompanying paper indicate that the anti-cryptococcal and anti-haptene TsF are functionally equivalent, antigen-specific suppressor factors.

Alkylation↗

PubMed1991

Functional equivalence of cryptococcal and haptene-specific T suppressor factor (TsF). II. Monoclonal anti-cryptococcal TsF inhibits both phagocytosis by a subset of macrophages and transfer of contact sensitivity.

Monoclonal anti-cryptococcal TsF (which inhibits phagocytosis by macrophages) and anti-picryl TsF use the same two circuits to block the transfer of contact sensitivity (CS). Both arm macrophages which then release a macrophage suppressor factor (MSF) when exposed to antigen. This MSF depresses the transfer of CS. The evidence suggests that a single molecular species of TsF (MW ca. 70 kDa), which bears an antigen-binding site and I-J determinant, is responsible for MSF production and inhibition of phagocytosis. Anti-cryptococcal TsF also arms the T acceptor cell which then releases nsTsF-1 after triggering with a specific antigen (SCPA). This nsTsF-1, which depresses the transfer of contact sensitivity, was authentic, as shown by its I-J positivity (in contrast to MSF) and its role in the production of nsTsF-2. As anti-picryl TsF also inhibits phagocytosis, it was concluded that anti-cryptococcal TsF, originally detected by the inhibition of phagocytosis, and anti-picryl TsF, originally detected by inhibition of CS, are functionally equivalent.

Animals↗

PubMed1990

Major histocompatibility complex regulation of the class of the immune response: the H-2d haplotype determines poor interferon-gamma response to several antigens.

The lymph node cells of CBA (H-2k), but not BALB/c (H-2d) mice, release interferon (IFN)-gamma into the supernatant when immunized with picryl chloride epicutaneously and then exposed to antigen (haptenized cells) in vitro 4 days later. The failure in IFN-gamma production maps to the major histocompatibility complex (MHC; H-2d) in the congenic BALB/c, BALB/k and BALB/b mice. The evidence that this is an MHC regulation of the class of response to a range of antigens and not a classical Ir gene effect is (a) the difference is seen with several antigens including picryl chloride, "oxazolone" and purified protein derivative of tuberculin and (b) BALB/c mice, which fail to produce IFN-gamma, show excellent contact sensitivity to picryl chloride. It was also found that the crosses between responder and nonresponder strains (CBA x BALB/c)F1 respond to antigen on responder cell but not on nonresponder cells. This influence of MHC on the class of the immune response is a possible basis for some of the associations of MHC with disease.

Animals↗

PubMed1988

T suppressor efferent circuit which affects contact sensitivity to picryl chloride: the late-acting, second nonspecific T suppressor factor bears I-A determinants which are responsible for the I-A genetic restriction in its interaction with its target cell.

The T suppressor efferent circuit in the picryl (TNP) system, which inhibits the passive transfer of contact sensitivity, involves at least two antigen-nonspecific factors. The second nonspecific T suppressor factor (ns-2) bears I-A determinants of both the alpha and the beta chain as shown by affinity chromatography on immobilized anti-I-A monoclonal antibodies. Sequential absorption shows that the determinants of the alpha and beta chain occur on the same molecular complex. No absorption was obtained with anti-I-E antibody. There are two genetic restrictions associated with ns-2--the first is in its release from the second T suppressor efferent cell (on exposure to antigen) and the second is in its inhibitory interaction with its target cell. Both are MHC restricted and matching in I-A (but not I-E, or I-J) is sufficient. The question was asked whether the I-A of the ns-2 was directly responsible for the I-A genetic restriction in its action. F1 TsF was made in (H-2k X H-2b)F1 mice by injecting picrylated parental cells intravenously and triggering the release of ns-2 with the corresponding picrylated parental cells. Both I-Ak- and I-Ab-positive ns-2 were produced and were separated by affinity chromatography on immobilized anti-I-A monoclonal antibody. The I-A phenotype of these separated ns-2 of F1 origin determines the genetic restriction in their action; i.e., I-Ak+ ns-2 only inhibits passive transfer by H-2k cells and I-Ab+ ns-2 only acts on H-2b cells. In contrast, the I-A haplotype of the picrylated cell used to induce the Ts cell which makes ns-2 is unimportant. It was concluded that the I-A on the ns-2, and not a possible recognition site for I-A, serves as a restriction element. This finding suggests that ns-2 may act directly on the I-A-restricted T cell which mediates contact sensitivity.

Animals↗

PubMed1988

A alpha and A beta class II I-A determinants of antigen-specific T-helper factor and its antigen-nonbinding chain.

Antigen-specific T-helper factor (ThF) of CBA (H-2k) origin in the picryl (TNP) contact sensitivity system (Mr 60-70 kDa) was reduced with dithiothreitol under mild conditions. Affinity chromatography on antigen yielded an antigen-binding chain (Mr 20-30 kDa) and an antigen-nonbinding chain (Mr 40-50 kDa). Both chains were glycoproteins and were bound by lentil lectin. Affinity chromatography on anti-I-A monoclonal antibodies showed that I-A determinants occurred on the complete molecule and on the antigen-nonbinding, but not on the antigen-binding, chain. In contrast, five different monoclonal antibodies to I-E alpha failed to absorb ThF. Moreover, the complete molecule and the I-A+ antigen-nonbinding chains had determinants of the alpha and beta chains of I-A and conformational determinants which are based on both chains. Sequential absorption and elution showed that A alpha and A beta determinants occurred on the same molecular complex. These data suggest a minimal model of ThF as a two-chain disulfide-bonded structure with an antigen-binding chain and a separate I-A+ antigen-nonbinding chain which behaves as a single unit in phosphate-buffered saline and has elements of both A alpha and A beta.

Animals↗

PubMed1988

IL-2 influences the balance between immunity and unresponsiveness in the picryl (TNP) contact sensitivity system by blocking the development or action of an Lyt-2+, I-J+ T suppressor cell.

Mice injected with antigen (picrylated spleen cells) intravenously fail to develop contact sensitivity. However, contact sensitivity occurs if these mice are injected with IL-2. This effect of IL-2 was reproduced in vitro by taking spleen cells 2 days after injecting antigen intravenously and culturing them with either 150 u/ml recombinant IL-2 for 2 days or by pulsing with 600-1200 u/ml IL-2 at 4 degrees C for 1 hr. After 2 days in culture these antigen-exposed cells transfer contact sensitivity to naive recipients in a 24-hr experiment. However, the ability of antigen-exposed cells, pulsed with IL-2, to transfer contact sensitivity is abolished when they are incubated with unpulsed antigen-exposed cells and as few as 1/16 of their number have a significant effect. This phenomenon is specific, as normal cell or cells from mice injected with oxazolonated cells intravenously have no effect. The suppressor cells were Thy-1+, Lyt-1-, 2+, I-J+ T cells. It was concluded that IL-2 prevents the development/action of antigen-specific T suppressor cells.

Animals↗

PubMed1988

Recombinant interleukin-2 limits the replication of Mycobacterium lepraemurium and Mycobacterium bovis BCG in mice.

BALB/c mice were infected with Mycobacterium lepraemurium in the footpad or with Mycobacterium bovis BCG intravenously with 5 x 10(7) bacilli. Recombinant interleukin-2 (IL-2) was injected intraperitoneally as a single dose (20,000 U), as a single course of five injections (400 U each), or as a 6-month course starting 3 days after the M. lepraemurium infection. BCG-infected mice received a single dose (1,000 U) or five daily injections of 100 or 1,000 U each. IL-2 significantly reduced the total bacterial counts in the footpad, lymph nodes, and liver of M. lepraemurium-infected mice (50 to 85%) by 6 months and viable counts in the spleen (30 to 50%) by 60 days after BCG infection. The courses of IL-2 started at 60 days were more effective than those started at 3 days after M. lepraemurium infection (P less than 0.05 to 0.001), and for BCG, 100 U of IL-2 was better than 1,000 U (P less than 0.05 to 0.01). These results indicate that IL-2 limits mycobacterial infections in mice and raise the question of its possible use in humans.

Animals↗

PubMed1988

Antigen-specific T-helper and -suppressor factors in the control of the immune response.

Antigen-specific T-helper and -suppressor molecules usually have a two-moiety, disulphide-bonded structure. One chain binds antigen, while the other chain bears I-A in the case of helper factor and I-J in the case of suppressor factor. Their genetic restriction, when it exists, parallels the 'MHC' determinants that they carry and probably reflects the fact that helper cells are activated by antigen in the context of I-A, while suppressor cells are activated by antigen in the context of I-J. T-helper factor probably augments the induction of contact sensitivity by approximating antigen with its own I-A determinants. Different factors act at the induction and the effector stage and they may be antigen or idiotype directed. The antigen-specific factors characteristically are part of complex circuits involving both antigen-specific and non-specific cells and factors and often have a mode of action through the macrophage.

Animals↗

PubMed1988

Recombinant interleukin-2 limits the replication of Mycobacterium lepraemurium and Mycobacterium bovis BCG in mice.

BALB/c mice were infected with Mycobacterium lepraemurium (MLM) in the foot pad or with M. bovis BCG intravenously with 5 x 10(7) bacilli. Recombinant interleukin-2 (IL-2) was injected intraperitoneally as a single dose (20,000 u), single course of 5 injections (400 u each) or 6 monthly courses starting 3 days or 60 days after the MLM infection. BCG infected mice received a single dose (1000 u) or 5 daily injections of 100 or 1000 u each. IL-2 significantly reduced the total bacterial counts in the footpad, lymph node and liver of MLM infected mice (50-85%) by 6 months and viable counts in the spleen (30-50%) by 60 days after BCG infection. The courses of IL-2 started at 60 days were more effective than at 3 days after MLM infection (P less than 0.05-0.001) and in the case of BCG, 100 u of IL-2 was better than 1000 u (P less than 0.05-0.01). These results indicate that IL-2 limits mycobacterial infections in mice, and raise the question of its possible use in humans.

Animals↗

PubMed1987

F1 mice make two species of antigen-specific, parental haplotype-restricted, T-helper factor whose restrictions correspond to the phenotype of the I-A determinants that they bear.

Antigen-specific T-helper factor (ThF) bears I-A determinants and is I-A restricted in its action. This I-A restriction may be explained by ThF binding, and hence approximating antigen to its own I-A determinants, thereby facilitating recognition by the T cell (I-A presentation theory), or by a recognition site for I-A on the ThF which approximates the antigen to I-A+ antigen-presenting cells (I-A recognition theory). When ThF is produced in F1 mice there may be a dissociation between the I-A phenotype of the ThF and the I-A restriction of any recognition site for I-A. In practice, ThF is made by spleen cells from (CBA x B10)F1 [(H-2k x H-2d)F1] mice pretreated with cyclophosphamide (100 mg/kg) and immunized with picrylated parental spleen cells intravenously (3 x 10(7)). This procedure produces haplotype-restricted contact sensitivity (corresponding to the parental cells) but the unfractionated F1 ThF does not show haplotype-specific restriction in its action. In fact, the F1 mice produces two species of ThF, each bearing determinants of the I-A molecule of one parental haplotype (k or d). When the two species were separated with monoclonal anti-I-Ak and anti-I-Ad antibodies, the genetic restriction in their action corresponded to the phenotype of the I-A determinants that they carried. In a further experiment, F1 ThF was split into its constituent antigen-binding (Ag+) and antigen non-binding (Ag-) chains by reduction, and the two species of Ag- chains separated with monoclonal anti-I-A antibodies. After complementation with the Ag+ chain, the two species of Ag- chains showed genetic restriction in their action that corresponded to the phenotype of the I-A determinants that they carried. These findings support the I-A presentation hypothesis that antigen-specific ThF acts by approximating antigen to its own I-A determinants, and hence facilitates recognition by I-A-restricted T cells.

Animals↗

PubMed1987

Generation of lymphokine-activated killer cells does not require DNA synthesis.

We studied the role of DNA synthesis in the induction of lymphokine-activated killer (LAK) cells by recombinant interleukin-2 (IL-2) and the dependence of this phenomenon on DNA synthesis. Doses of gamma-irradiation (1000-5000 rads) that profoundly reduced DNA synthesis in human peripheral blood mononuclear leucocytes (PBL) also effectively suppressed the development of cytotoxic activity in the absence of IL-2. However, the same doses of irradiation affected the induction of LAK activity by IL-2 to a much lesser extent. Blocking the formation of deoxyribonucleotides by hydroxyurea, which resulted in a complete inhibition of DNA synthesis in PBL or purified T lymphocytes, had virtually no effect on the generation of LAK cells. These results indicate that the expression of LAK activity is not dependent on DNA synthesis.

Cytotoxicity, Immunologic↗

PubMed1987

Increased lymphokine activated killer (LAK) activity in the regional lymph nodes of mice following immunization with contact sensitizing agents.

The regional lymph nodes of mice show increased IL-2 activated killer (LAK) activity following immunization with the contact sensitizing agents, 'oxazolone' and picryl chloride. This is best elicited with 500 mu/ml human recombinant IL-2 and can be demonstrated with both YAC-1 and K562 targets. There is also a lesser increase in NK activity.

Animals↗

PubMed1986

Nonspecific T suppressor factor (nsTsF) cascade in contact sensitivity: nsTsF-1 causes an Ly-1+2- I-A+ immune T cell to produce a second, genetically restricted, nsTsF-2.

We studied the mode of action of the nonspecific T suppressor factor (nsTsF-1) made in the picryl (TNP) system when T acceptor cells armed with antigen-specific TsF are triggered by antigen in the context of I-J. This suppressor factor does not inhibit the passive transfer of contact sensitivity directly, as shown by its failure to inhibit passive transfer by immune cells deprived of I-A+ cells. Its immediate target is an immune, antigen-specific, Ly-1+2-, I-A+ T cell. This cell, which may be regarded as a T suppressor effector cell (Ts-eff-2), produces nsTsF-2 when exposed sequentially to nsTsF-1 and antigen. This nsTsF subsequently inhibits the passive transfer of contact sensitivity. The action of nsTsF-2 is MHC genetically restricted. As the nsTsF-2 bears I-A determinant(s), this raises the possibility that it may act by combining with the recognition site for I-A on the T cell that mediates contact sensitivity.

Animals↗

PubMed1986

Isolation of retroviruses from two patients with "common variable" hypogammaglobulinaemia.

Retroviruses related to human T-lymphotropic virus III/lymphadenopathy-associated virus (HTLV-III/LAV) have been isolated from peripheral-blood mononuclear cells of two patients with "common variable" hypogammaglobulinaemia who were being treated with intravenous gammaglobulin. One has had three different opportunistic infections. In both patients hypogammaglobulinaemia developed within 6 years of a longlasting undiagnosed viral-like illness in adolescence, and it is suggested that the virus causing that illness also gave rise to the hypogammaglobulinaemia. However, iatrogenic infection from intravenous gammaglobulin cannot be ruled out.

Adolescent↗

PubMed1986

T-cell depletion of allogeneic bone marrow prevents acceleration of graft-versus-host disease induced by exogenous interleukin 2.

Highly purified human recombinant interleukin 2 (IL-2) markedly accelerated lethal GVHD in the H-2-identical B10.BR----CBA combination, but had no effect when the donor cells were depleted of mature (Thy-1.2-positive) T lymphocytes, indicating a strong immunopotentiating effect of IL-2 on mature T cells causing GVHD. In the same donor-host combination, IL-2 did not influence the recovery from the post-transplantation bone marrow aplasia. The results suggest that IL-2 could be considered for adjuvant hormonal therapy to enhance immune recovery in recipients of T-cell-depleted allogeneic marrow.

Animals↗