Mechanism of action of cyclosporine A on the lymphocytic choriomeningitis virus infection of mice.
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Biomedical subjects
P Truffa-Bachi
Publications and source records attributed to P Truffa-Bachi.
Effect(s) of lipopolysaccharide on lectin-induced T-cell activation.
The present study focuses on the effect of lipopolysaccharide (LPS) on the cellular events leading to T-cell activation by concanavalin A (Con A). Interleukin 2 (Il-2) production is much reduced in Con A-stimulated cultures of spleen cells derived from LPS-treated mice. This depressed Il-2 synthesis is not related to the eventual activity of LPS-activated suppressive B cells. Rather, it reflects an ineffective collaboration between adherent cells and T lymphocytes. The low level of Il-2 produced by LPS-sensitized spleen cells is sufficient for lectin-induced T-cell proliferation. Moreover, acquisition of responsiveness to Il-2 is unaltered by LPS. No strict correlation was found between the deficiency in Il-2 production and the inability of LPS-sensitized spleen cells to generate a thymus-dependent response. Less time (5 hr) is needed for LPS to exert its inhibitory effect on an anti-sheep red blood cell response than on Il-2 synthesis (at least 24 hr). Results are discussed in terms of cellular interactions implicated in a polyclonal T-cell response and with regard to the contribution of Il-2 to the LPS-induced immune unresponsiveness.
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Immune memory expression to Tnp-Ficoll in CB.20 mice: evidence for a multigenic control.
Trinitrophenyl (Tnp)-Ficoll, a class 2 thymus-independent (TI) antigen, generates in most mouse strains Tnp-specific B-memory cells which can be detected in situ 1 week after priming by a heterologous stimulation with Tnp-lipopolysaccharide (LPS) but not by a homologous Tnp-Ficoll challenge. We have investigated the secondary responses raised in CB.20 congenic mice by a homologous challenge in situ occurring at various time intervals after priming. We report that a memory-type response is obtained, culminating when the challenge is performed at 4 weeks; this finding assesses definitely the ability of TI-2 antigens to produce immunological memory under standard conditions. However, the same immunization procedure elicits no memory-type response in the majority of other mouse strains, suggesting a possible genetic control of the expression of memory to class 2 TI antigens. The utilization of F1 hybrids between C57BL/6 and BALB/c and of appropriate congenic strains shows indeed that this memory expression is under multigenic control: Igh-V or closely linked genes are clearly involved but a complementation with other gene(s), located outside the H-2 complex, is required for a memory-type response to Tnp-Ficoll. We have also analyzed the secondary heterologous response to Tnp-LPS in CB.20 mice at different times after Tnp-Ficoll priming. The difference in the kinetic profile of the heterologous (TI-2----TI-1) versus homologous (TI-2----TI-2) secondary responses is discussed in terms of B-memory-cell ontogeny and humoral regulation.
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Effects of suramin on the immune responses to sheep red blood cells in mice. I. In vivo studies.
The effect of Suramin on the cell-mediated delayed-type hypersensitivity (DTH) and the humoral immune responses elicited in mice by sheep erythrocytes was studied. The results show that administration of Suramin, at various times before or after antigenic sensitization, results in a profound inhibition of cell-mediated responses but has no adverse effect on antibody production. Suramin was particularly effective when given during the effector phase of DTH: mice which were treated with this drug, 4 days after immunization, at the time of skin testing, exhibit negative or low DTH responses compared to control mice. Evidence is presented that this short-term Suramin-induced suppressive effect on the expression of DTH is related to a defective recruitment, by sensitized T lymphocytes, of phagocytic cells at the site of the inflammatory reaction. In addition, when treatment with Suramin precedes by 8 days (Day -8) or by 1 hr sensitization with sheep erythrocytes for DTH, decreased DTH reactions over controls were observed. The inhibitory effect exerted by Suramin administered on Day -8 can be reversed by increasing the dose, from 10(6) to 10(8) sheep erythrocytes, of the sensitizing antigen. The possibility is discussed that, in this case, Suramin may interfere with the generation of DTH-mediating cells through a rapid degradation of antigen related to the Suramin-induced hyperplasia of the mononuclear phagocyte system. In contrast, DTH anergy in mice treated with Suramin 1 hr before sensitization is maintained regardless of the sensitizing antigen dose. Analysis of the sensitized lymphocyte population in these mice indicates that Suramin does not prevent the induction of DTH-mediating cells and suggests that the expression of these latter is inhibited by suppressive cells which are generated as a result of drug treatment.
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Effects of suramin on the immune responses to sheep red blood cells in mice. II. In vitro studies.
The effect of Suramin on the secondary in vitro response to sheep erythrocytes (SRBC) was studied. Spleen cells from mice which were treated with Suramin immediately prior to sensitization with SRBC failed to respond to an in vitro SRBC challenge. This Suramin-induced immunosuppression is not related to a defect in macrophage or B-cell function(s). Suramin does not interfere with the induction by SRBC of radioresistant and radiosensitive helper-T-cell subpopulations. Cell separation studies, using wheat germ agglutinin, showed radiosensitive helper-T-cell function in the nonagglutinated fraction while the radioresistant helper activities are carried out by the agglutinated subpopulation. Evidence is presented that Suramin administration results in a suppressive T-cell activity which can be demonstrated in the subpopulation agglutinated by wheat germ agglutinin. The role of such suppressive T cells in the inhibitory effect exerted by Suramin on the cell-mediated delayed-type hypersensitivity response to SRBC is discussed.
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Cyclosporin A inhibits the delayed-type hypersensitivity reaction: impaired production of early pro-inflammatory mediator(s).
The effect of cyclosporin A (CsA) on the delayed-type hypersensitivity (DTH) elicited in mice by sheep red blood cells was investigated. Evidence is presented that a single injection of CsA adversely affects the inflammatory reaction. Sensitized T lymphocytes initiate the DTH reaction by their recruiting activity on phagocytic cells which infiltrate the cutaneous site of antigen deposition. CsA administration has no adverse effect on the recruitment of phagocytic cells at the site of the inflammatory reaction. The present studies show that CsA acts on specific T cells: (a) in adoptive transfer, T-DTH-mediating cells cannot elicit a response in mice treated with CsA 8 h before; (b) when collected 8 h after a single injection of CsA, T-DTH-mediating lymphocytes are no longer able to adoptively transfer the reaction. This conclusion is strengthened by in vitro studies: (a) the frequency of T-DTH-mediating lymphocytes is 50-fold decreased after a short in vitro incubation with CsA; (b) in vitro production by concanavalin A-activated lymphocytes of chemotactic pro-inflammatory mediator(s) is abolished in presence of CsA.
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Beneficial effect of cyclosporin A on the lymphocytic choriomeningitis virus infection in mice.
The effect of cyclosporin A on the course of lymphocytic choriomeningitis virus infection in mice was investigated. Evidence is presented that administration of this immunosuppressive drug spares a majority of lethally infected mice. This beneficial effect is different from the one obtained with other treatments leading to the abolition of T cell functions. Surviving animals rapidly eliminate the virus and produce high titers of neutralizing IgG antibodies.
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Study on B-memory generation by Tnp-Ficoll: induction but not expression is observed among various inbred mouse strains.
The primary and secondary responses to Tnp-Ficoll, a class 2 thymus-independent antigen, were assessed in various inbred strains of mice. The eventual implication of H-2 or IgH linked genes was searched for. Contrasting with our previous reports using Tnp-LPS, a class 1 thymus-independent antigen, no homologous memory-type response to Tnp-Ficoll and consequently no genetic control was observed. However Tnp-specific B-memory lymphocytes were induced in most strains since a heterologous challenge with Tnp-LPS evoked a typical memory type response characterized by an increased number of antibody-secreting cells and/or significant amount of anti-Tnp antibodies of the IgG isotype. The lack of memory revelation by Tnp-Ficoll is discussed in terms of a possible humoral or cellular regulation and of B-memory cell generation and maturation.
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Rapid enrichment of mouse natural killer cells by use of wheat germ agglutinin.
The separation of mouse T and B lymphocytes by differential agglutination with wheat germ agglutinin (WGA) also enriches natural killer (NK) activity 2-7-fold. NK cells are recovered within the agglutinated cell population indicating that NK cells bind WGA. This technique can be applied to endogenous or interferon-induced NK cells.
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Igh-V or closely linked gene(s) control immunological memory to a thymus-independent antigen.
Mice mount a normal primary antibody response on stimulation with the thymic-independent antigen trinitrophenylated lipopolysaccharide (TNP-LPS). Although we have previously reported the generation of functional B-memory lymphocytes to TNP-LPS, this memory response was only observed in few mouse strains. Here we have used congeneic mouse strains in an attempt to locate the genetic regions involved in the memory response. We show that genes of the major histocompatibility complex (MHC) do not have a critical role but that genes coding for the variable region of immunoglobulin heavy chains or gene(s) closely linked to them are required for memory cell induction by TNP-LPS.
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Effect of cyclosporin A on the induction and activation of B memory cells by thymus-independent antigens in mice.
The effect of cyclosporin A on the induction and activation of B memory cells by thymus-independent (TI) antigens was investigated. Studies were carried out in C57BL/6 mice, a strain in which TI.1 trinitrophenyl-lipopolysaccharide (TNP-LPS) and TI.2 dinitrophenyl-(DNP)-Ficoll antigens can elicit a secondary response. Evidence is presented that cyclosporin A does not adversely affect the primary or secondary response to TNP-LPS. In contrast, this fungal metabolite prevents the triggering of virgin B lymphocytes and TNP-LPS-induced memory cells by DNP-Ficoll. Cyclosporin A does not interfere with the generation of hapten-specific B memory cells by TNP-LPS or DNP-Ficoll. These findings are discussed in terms of B cell lineages leading to antibody-forming cell precursors and memory cells.
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Generation of immune memory by haptenated derivatives of thymus-independent antigens in C57BL/6 mice. I. The differentiation of memory B lymphocytes into antibody-secreting cells depends on the nature of the thymus-independent carrier used for memory induction and/or revelation.
It has been previously reported that trinitrophenylated lipopolysaccharide (TNP-LPS), a thymus-independent (TI)-1 antigen, elicits an anamnestic response to TNP in C57BL/6 mice. The ability of these mice to mount a secondary response to TI-2 antigens was analyzed. Priming with DNP-Ficoll or DNP-Dextran, both TI-2 antigens, resulted in an increased frequency of TNP-binding B lymphocytes. Evidence is presented that memory cell-induction by DNP-Ficoll does not require functional T cells. The differentiation into antibody-forming cells (AFC) of memory cells generated by DNP-Dextran or DNP-Ficoll cannot be obtained by a challenge with either antigen. There was no indication that the lack of a secondary response to TI-2 antigens was related to suppressive T cells interfering with memory expression. Memory cells induced by DNP-Dextran or DNP-Ficoll can nevertheless be activated by TNP-LPS. In contrast to the restricted sensitivity of TNP-memory cells generated by TI-2 antigens, TNP-LPS-induced memory cells are indifferently susceptible to TI-1 or TI-2 antigenic stimulation. These results are discussed in terms of memory B-cell subpopulations.
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Is the delayed-type hypersensitivity observed after a low dose of antigen mediated by helper T cells?
In mice receiving, i.v., a dose of antigen optimal for antibody response, no delayed-type hypersensitivity (DTH) reaction is detectable. In contrast, in mice receiving a dose of antigen too small to induce B cell activation, a DTH reaction is elicitable shortly and transiently after immunization. Using a sensitive titration assay of DTH-mediating T lymphocytes, this reciprocal relationship between antibody production and DTH responses was reinvestigated. The absence of peripheral DTH reactivity in mice primed i.v. with a high dose of antigen (10(9) heterologous red blood cells) does not result either from the absence of activation and clonal expansion of DTH-mediating cells or from induction of suppressive mechanisms but results from a decreased circulation of DTH-mediating cells. The present studies show that DTH-mediating cells disappear from blood to enter the spleen only when specific B lymphocytes are present and activated by a high dose of antigen. These results are compatible with the hypothesis that T cells activated by antigen can function either as helper cells for B lymphocytes or as DTH-mediating cells, depending on the environment they reach during their migration. In order to demonstrate that the same cell may support the two functions, monoclonal T lymphocytes were assayed for their helper function and for their ability to transfer a DTH reaction.
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Lack of general immunosuppression during visceral Leishmania tropica infection in BALB/c mice: augmented antibody response to thymus-independent antigens and polyclonal activation.
Leishmania tropica causes a lethal visceral disease in highly susceptible BALB/c mice, with many immunopathologic features resembling those in human kala-azar. The responses to thymus-independent antigens of Type 1 and 2 (TI-1, TI-2) were compared in infected mice of susceptible BALB/c and resistant C57BL/6 strains at various times after infection. The infected BALB/c mice had an augmented response to both types of antigens at 45 days after infection. Later (day 76), the response to trinitrophenylated lipopolysaccharide (TNP-LPS, a TI-1 antigen) was diminished but that to dinitrophenylated Ficoll (DNP-Ficoll, a TI-2 antigen) remained statistically above the response of uninfected mice. The response of the resistant strain to either antigen was not modified as a result of the infection. Both strains showed significant polyclonal activation, which was considerably greater in the BALB/c than in the C57BL/6 mice. The observations presented here are in contrast to the widely held belief that a generalized nonspecific immunosuppression occurs in L. tropica infected BALB/c mice.
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Immune unresponsiveness of spleen cells from lipopolysaccharide-sensitized mice to particulate thymus-dependent antigens. II. Evidence for an abortive cooperation between T lymphocytes and antigen-presenting cells.
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Heterogeneity of mouse Thy 1.2 antigen expression revealed by monoclonal antibodies.
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Local adoptive transfer of skin delayed-type hypersensitivity initiated by a single T lymphocyte.
In vivo primed T cells injected in the footpad of naive recipients elicit a typical delayed-type hypersensitivity (DTH) reaction in the presence of their specific antigen. The values of the footpad swelling obtained after these transfers show a clear distinction between negative and positive responses. Serial dilutions of primed T cell populations allow the establishment of titration curves by limiting dilution analysis according to Poisson distribution. The single hit titration curve indicates that a unique cell type underlies the DTH reaction. Furthermore, by using cloned T cells it can be demonstrated that the transfer of a single cell is able to initiate a DTH reaction. The revelation of T cell activity at unit level needs an optimal dose of antigen mixed with the sampled cells.
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Induction and differentiation of B memory cells by a thymus-independent antigen, trinitrophenylated lipopolysaccharide.
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