Biomedical subjects

G L Asherson

Publications and source records attributed to G L Asherson.

At least 19 recordsLinked to original sources

PubMed2000

Whole body irradiation induces IFN-gamma production in BALB/c mice by preventing the appearance of a V alpha 14(+)NK T downregulatory population.

Lymph node cells from TNCB-immune BALB/c mice fail to produce IFN-gamma when exposed to antigen in vitro. Conversely, lymph node cells of irradiated (550 rads) BALB/c mice produce IFN-gamma. Transfer experiments show that normal BALB/c mice contain cells which suppress IFN-gamma production. These downregulatory cells are CD4(+)alpha beta(+)and rearrange the invariant V alpha 14-J alpha 281 T cell receptor alpha chain, thus belonging to the NK T cell subset. Downregulatory cells probably act by producing IL-4 as their effect is blocked by mAb to IL-4.

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PubMed1998

Cross-talk between V beta 8+ and gamma delta+ T lymphocytes in contact sensitivity.

We have previously reported that T lymphocytes proliferating in vitro to the hapten trinitrochlorobenzene (TNCB) exhibit a very restricted V beta gene usage and response to TNCB is limited to T-cell receptors (TCR) composed of V beta 8.2 in combination with V alpha 3.2, V alpha 8 and V alpha 10. This paper investigates the role played by T lymphocytes expressing the V beta 8.2 gene segment in the contact sensitivity (CS) reaction to TNCB in the intact mouse and in its passive transfer into naive recipient mice. Mice injected with monoclonal antibodies to V beta 8 are unable to develop CS upon immunization with TNCB and 4-day TNCB-immune lymph node cells from mice that had been depleted in vivo or in vitro of V beta 8+ T lymphocytes fail to transfer CS. However, when separated V beta 8+ and V beta 8- cells were used for passive transfer, it was found that V beta 8+ T lymphocytes failed to transfer CS when given alone to recipient mice and a V beta 8- population was absolutely required. Further analysis revealed that within the V beta 8- population, T lymphocytes expressing the gamma delta TCR were fundamental to allow transfer of the CS reaction. These gamma delta cells were found to be antigen non-specific, genetically unrestricted and to rearrange the V gamma 3 gene segment. This indicates that transfer of the CS reaction requires cross-talk between V beta 8+ and gamma delta+ T lymphocytes, thus confirming our previous results obtained using TNCB-specific T-cell lines. Time-course experiments showed that V beta 8+ lymphocytes taken 4-24 days after immunization with TNCB were able to proliferate and produce interleukin-2 (IL-2) in response to the specific antigen in vitro. Similar time-course experiments were then undertaken using the passive transfer of the CS reaction system. The results obtained confirm that TNCB-specific V beta 8+ T lymphocytes are present in the lymph nodes of immunized mice from day 4 to day 24, and reveal that gamma delta+ T lymphocytes are active for a very short period of time, i.e. days 4 and 5 after immunization. In fact, TNCB-specific V beta 8+ cells are able to transfer CS when taken 4-24 days after immunization, providing the accompanying V beta 8- or gamma delta+ T lymphocyte are obtained 4 days after immunization. In contrast, injection of V beta 8+ T lymphocytes together with V beta 8- or gamma delta+ T lymphocytes that had been taken 2 or 6 days after immunization, failed to transfer significant CS into recipient mice. Taken together, our results confirm that cross-talk between V beta 8+ and gamma delta+ T lymphocytes is necessary for full development of the CS reaction and may explain why the CS reaction in the intact mouse lasts up to 21 days after immunization while the ability of immune lymph node cells to transfer CS is limited to days 4 and 5 after immunization.

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PubMed1998

Development of hapten-induced IL-4-producing CD4+ T lymphocytes requires early IL-4 production by alphabeta T lymphocytes carrying invariant V(alpha)14 TCR alpha chains.

This paper investigates the mechanisms responsible for the generation of IL-4-producing CD4+ T cells during contact sensitization with the hapten trinitrochlorobenzene (TNCB). Lymph node cells taken 1 day after immunization spontaneously released IL-4 while lymph node cells taken 2 and 3 days after immunization did not produce IL-4. A second wave of IL-4 production that was both antigen-specific and MHC class II (I-A)-restricted was observed 4 days after immunization. The spontaneous release of IL-4 at day 1 was due to the alphabeta+ double-negative (CD4- CD8-) T lymphocytes that also expressed NK1.1 and showed V(alpha)14 rearrangement, while alphabeta+ CD4+ T lymphocytes were the source of the antigen-specific IL-4 production at day 4. Early IL-4 production was required for the development of IL-4-producing CD4+ T cells as mice injected with anti-V(alpha)14 or anti-IL-4 mAb produced little IL-4 and IL-10, while production of IFN-gamma was increased approximately 2-fold. These results indicate that the development of IL-4-producing CD4+ T lymphocytes in the TNCB system requires early production of IL-4 by alphabeta+ double-negative cells carrying invariant V(alpha)14 TCR alpha chain.

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PubMed1997

Development of IFN-gamma-producing CD8+ gamma delta+ T lymphocytes and IL-2-producing CD4+ alpha beta+ T lymphocytes during contact sensitivity.

This paper describes the development of Ag-specific proliferation and the production of IFN-gamma and IL-2 during contact sensitivity (CS) to the hapten picryl chloride (PCl). Lymph node cells from mice immunized with PCl proliferate and produce IFN-gamma and IL-2 when re-exposed to the specific Ag in vitro. Time course experiments showed that the peak IFN-gamma production occurred at days 3 and 4 after immunization, with a sharp decline by day 6. In contrast, proliferation and IL-2 production peaked at day 3 but persisted up to day 10. Proliferation and IFN-gamma and IL-2 production displayed by immune lymph node cells were Ag-specific but required different cell populations. In fact, the production of IFN-gamma was due to a CD8+, gamma delta+ T cell, while proliferation and IL-2 production required the presence of a CD4+, alpha beta+ T cell. Furthermore, IFN-gamma production showed genetic (MHC) restriction, and finer analysis using congenic strains of mice indicated that the K molecule was the restricting element. This was confirmed by blocking the K molecule of the APC used to trigger IFN-gamma production with a specific mAb. In contrast, proliferation and IL-2 production were I-A-restricted, as demonstrated using congenic strains of mice and blocking the I-A molecule of the APCs. Further analysis using purified gamma delta+ cells revealed that these cells produced IFN-gamma in an Ag-specific and MHC (K)-restricted fashion. Injection of mice with a mAb to IL-2 blocked subsequent in vitro proliferation, as well as IL-2 and IFN-gamma production, while all three in vitro responses were unaffected by injection of a mAb to IFN-gamma given at the time of immunization. Furthermore, injection of mice with a mAb to IL-2 blocked the CS reaction when given at the time of immunization, while it had no effect when given at the time of challenge. Injection of mice with mAb to IFN-gamma at the time of challenge reduced but did not abolished CS, suggesting that IFN-gamma is important but not exclusively responsible for the CS reaction.

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PubMed1997

Three cell subsets are required for the transfer of delayed-type hypersensitivity reaction by antigen-specific T cell lines.

Antigen (trinitrochlorobenzene)-specific T cell lines were obtained by repeated stimulation of lymph node cells from immune mice with antigen in vitro. These T cell lines, consisting of more than 90% CD4+ Vbeta8.2+ and 6 to 9% gammadelta+ T lymphocytes, transfer contact sensitivity (CS) locally when injected at the same site as the challenge antigen, but fail to mediate a systemic passive transfer when injected i.v. Injection of T cell lines together with spleen cells from mice immunized 1 day beforehand (1-day cells) allowed a successful, specific systemic transfer of CS. Phenotypic analysis showed that the 1-day immune cell was alphabeta+, gammadelta-, sIg-, CD3+, CD4-, CD8-, CD5+, B220 (CD45R)+, Thy 1.2+. The effect of 1-day immune cells occurred through a mechanism involving IL-4, as 1-day immune cells failed to allow systemic transfer of CS by T cell lines in recipient mice treated with mAb to IL-4. These observations strongly indicate that three cell subsets are required for the systemic passive transfer of CS by T cell lines: alphabeta+ CD4+, gammadelta+, and a third cell subset, which is CD45R+, alphabeta+, CD3+, but double (CD4, CD8) negative.

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PubMed1997

gamma delta cells involved in contact sensitivity preferentially rearrange the Vgamma3 region and require interleukin-7.

Ptak and Askenase showed that both alphabeta and gammadelta cells are required for transfer of contact sensitivity (CS). This study confirms that day 4 immune cells depleted of gammadelta cells fail to transfer CS to trinitrochlorobenzene (TNP-Cl) systemically and demonstrates that administration of anti-gammadelta monoclonal antibodies (mAb) in vivo abolishes the CS reaction. Moreover, gammadelta cells accumulate at the antigen challenge site: these cells have the unusual phenotype CD8alpha+, CD8beta-, IL-4 R+ which we suggest is due to their state of activation. Following immunization with contact sensitizer on the skin, the absolute number of gammadelta cells increases in the regional lymph nodes with a peak at 4 days. Of the gammadelta cells, 80 %, both in the lymph nodes of TNP-Cl-immune mice and accumulating at the antigen challenge site are Vgamma3+. The gammadelta cells expressing Vgamma3, which is characteristic of dendritic epithelial T cells (DETC), obtained 4 days after sensitization, proliferate in response to interleukin (IL)-7, but only poorly to IL-2 and IL-4. They also respond to concanavalin A and immobilized anti-gammadelta mAb, but not to haptens or heat-shocked syngeneic spleen cells. Furthermore, injection of mice with mAb to IL-7 inhibits accumulation of Vgamma3+ cells both in the lymph nodes after skin sensitization and at the antigen-challenge site. Altogether, these results strongly support the view that DETC are related to, or the original source of, the gammadelta cells found in the lymph node after skin sensitization and at the site of challenge, and that IL-7 is implicated in these phenomena.

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PubMed1997

TCR V alpha chain expression influences reactivity to the hapten TNP.

We have recently demonstrated a remarkable selection of in vitro cultivated, TNP-specific polyclonal T cell lines for the expression of a TCR beta chain encoded by the V beta 8.2 gene. The goal of the present study was to analyse V alpha usage in V beta 8.2 T cells responsive to TNP, using TNP-specific T cell lines derived from three common strains of mice, as well as from V beta 8.2 transgenic mice. Results indicate that in vitro TNP stimulation of T cells from TNP-immune mice results in significant skewing of V alpha usage among responding V beta 8.2+ T cells, with overexpression observed for V alpha 3.2 and V alpha 8. These results indicate that V alpha expression influences recognition of TNP by T cells, and suggest that the hapten TNP might be recognized like typical peptide antigens by combinatorial TCR alpha and beta contact sites.

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PubMed1996

Treatment of Candida albicans mannan-specific downregulatory cell populations with divergent concentrations of monophosphoryl lipid A and intact lipopolysaccharide in vitro abrogates their effect on delayed hypersensitivity.

We have shown previously that splenocytes from mice injected with Candida albicans mannan (MAN) suppress MAN-specific delayed hypersensitivity (DH) when transferred to immunized recipients and that treatment of donor mice with monophosphoryl lipid A (MLA) derived from Salmonella typhimurium or Salmonella minnesota shortly before transfer abrogated the downregulatory activity. We now show that treatment of splenocytes in vitro at 4 degrees C with 5 ng/ml MLA or 0.05 ng/ml S. typhimurium lipopolysaccharide (LPS) for 30 min before transfer also abrogated downregulatory activity. Higher or lower doses of MLA, 5 micrograms or 5 pg, appeared to increase the suppressor activity slightly (5 micrograms) or had no effect (5 pg). LPS induced similar effects but the concentrations of LPS required to show the effects were 100-fold less than those of MLA. The effect of MLA appeared to be on cell(s) in the transfer population involved in MAN-specific DH, in that spleen cells from normal mice treated with MLA prior to transfer had no effect on DH. Finally, the population of MLA-responsive cells mediating downregulation could not be concentrated on MLA-coated plates, suggesting that the MAN-specific downregulatory cell(s) either did not bind to MLA or did not bind to MLA with sufficient avidity to remain attached during the washing procedures. The feasibility of abrogating suppression by treatment of lymphoid cells in vitro will allow a more detailed analysis of the mechanism of abrogation.

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PubMed1996

Interleukin 4 suppresses primary interferon gamma response by T cells immunized in vivo and cultured in vitro with interleukin 2.

This paper describes a novel primary in vivo/in vitro culture system which allows analysis of the effect of IL-4 added to culture 1 day after immunization on the production of IFN-gamma. Mice are immunized epicutaneously with picryl chloride (TNP) and draining lymph node cells were harvested 1 day later. These cells (1 day lymph node cells), when cultured in vitro for 3 days in the presence of IL-2, either continuously or as a pulse, give an IFN-gamma response on reexposure to antigen 3 days later. This production of IFN-gamma is both antigen-specific and genetically (MHC)-restricted and is due to both CD8+ and CD4+ T cells. However, if 1 day lymph node cells are cultured with both IL-2 and IL-4, no IFN-gamma is produced on subsequent reexposure to antigen, but the cells acquire the ability to produce IL-4 and IL-10. Moreover, cells pulsed with IL-4 blocked IFN-gamma production when cocultured with cells pulsed with IL-2. IL-4 only exerted its inhibitory activity on IFN-gamma production when added on the first or second day of culture and had no effect at later times. Finally, the inhibitory activity of IL-4 on IFN-gamma production may depend on the production of IL-10, induced by the IL-4, as the inhibitory effect of IL-4 is reversed by mAb against IL-10.

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PubMed1996

Role of IL-4 in delayed type hypersensitivity.

IL-4 plays a key role in the contact sensitivity skin reaction. This has several implications. First, the view that contact sensitivity (CS) is only mediated by cells with a Th1 profile of cytokine secretion needs modification, in the light of the essential role of IL-4 at the effector stage. Second, the concept of a single cell involved in the systemic transfer of CS is no longer tenable, as it is known that both alpha beta and gamma delta cells are required. Studies with the cell lines (which contain both alpha beta and a few gamma delta cells) suggest that this double requirement may involve the action of IL-4 on gamma delta cells, which bear receptors for IL-4. Finally, the view that T cell lines only transfer CS when injected locally, but not when injected intravenously (systemic transfer), is correct but incomplete, as T cell lines actually give systemic transfer of CS, providing the cell line or the recipient is treated with IL-4.

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PubMed1995

IL-5 enhances in vitro and in vivo antigen-specific IgA production in MHC genetically determined low IL-5 responder mice.

Lymphonode cells from BALB/k mice, but not from BALB/c mice, immunized with picryl chloride (PCl) produce IL-5 when stimulated with the specific antigen in vitro and this correlates with picryl-specific IgA levels in vivo, which are 6 to 10 times higher in BALB/k mice. B lymphocytes from BALB/k mice cultured with PCl-immune T cells from BALB/k produce in vivo anti-PCl-IgA, while B lymphocytes from BALB/c mice, cultured with T cells from BALB/c mice, fail to produce appreciable amounts of anti-PCl IgA, unless IL-5 is added to cultures. B lymphocytes from both strains of mice produce similar amounts of total IgA antibodies when stimulated in vitro with lipopolysaccharide. In vivo administration of IL-5 to BALB/c mice increases significantly PCl-specific IgA levels to those observed in BALB/k mice and a dose-response analysis reveals that 500 units of IL-5 was the minimal effective dose, although a small increase in PCl-specific IgA levels was observed with 100 units of IL-5. Total IgA levels were increased in both strains of mice following in vivo injection of IL-5, but no significant difference in the values was observed. Our results therefore indicate that IL-5 in vivo enhances antigen-specific IgA production in MHC-determined low IL-5 responder mice and suggest an explanation for IgA deficiency in humans.

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PubMed1995

Major histocompatibility complex control of the class of the immune response to the hapten trinitrophenyl.

This paper investigates major histocompatibility complex (MHC) regulation of the class of the immune response given in vitro and in vivo following immunization of the congenic BALB/k (H-2k) and BALB/c (H-2d) mice with the hapten trinitrophenyl (TNP). TNP-immune lymph node cells from BALB/k mice produced high levels of interferon-gamma (IFN-gamma), interleukin-5 (IL-5) and IL-2 when stimulated with TNP-antigen-presenting cells (APC) in vitro, while TNP-immune lymph node cells from BALB/c mice produced very low levels of these cytokines. No significant difference was found in antigen-specific production of IL-3, IL-4 and tumour necrosis factor-alpha (TNF-alpha). There was a strong correlation between the pattern of cytokine production in vitro and the secondary antibody production in vivo. Sera from BALB/k mice had anti-TNP IgG2a, IgG2b and IgG3 levels threefold greater, and anti-TNP IgA levels eightfold greater, than BALB/c mice. The level of specific IgG1 and IgE was only marginally raised in BALB/k mice. In contrast to these strain differences in cytokine and antibody production, there was no difference in two measures of cellular immunity: contact sensitivity in vivo and antigen-specific lymphocyte response in vitro. Our results suggest that there is a good correlation between the production of cytokines in vitro and antibody response in vivo, but not with measures of cellular immunity. Moreover, this MHC control of the class of the immune response to TNP does not fit into the T-helper type-1 (Th1)-Th2 paradigm.

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PubMed1995

Interleukin-4 is a critical cytokine in contact sensitivity.

This study demonstrates an essential role for interleukin-4 (IL-4) in the delayed hypersensitivity reaction, as illustrated by contact sensitivity (CS) to trinitrochlorobenzene (TNCB). Injection of mice with monoclonal antibody to IL-4, but not with control antibody, reduced CS after active immunization by 75%, as judged by ear swelling. The histological alterations of CS were also reduced. IL-4 was essential to the effector stage, as inhibition of its production or action blocked the passive transfer of CS. In particular, treatment of immune lymph node cells with antisense oligonucleotide to IL-4 inhibited the systemic transfer of CS. Transfer was also inhibited by monoclonal antibody to IL-4 given to the recipient. The present results indicate that IL-4 is an essential cytokine at the effector stage of the CS reaction.

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PubMed1994

IL-4 is essential for the systemic transfer of delayed hypersensitivity by T cell lines. Role of gamma/delta cells.

Hapten (trinitrophenyl)-specific T cell lines were obtained by repeated stimulation of lymph node cells from immune mice with Ag in vitro. These T cell lines show phenotypic properties and a pattern of cytokine production typical of Th1 cells and consisted of more than 90% V beta 8.2+ T lymphocytes and 6 to 9% gamma/delta + T lymphocytes. The lines mediate a local passive transfer of DTH when injected at the site of Ag challenge but fail to mediate a systemic passive transfer of DTH when injected i.v. However, a successful systemic passive transfer of DTH was observed when IL-4 was given to recipient mice together with the T cell lines or when the T cell lines were incubated in vitro with IL-4. IL-4 enables systemic, specific passive transfer of DTH at a dose of 10 pg/ml in vitro and at a dose of 10 pg/mouse in vivo; it is effective when injected 4 h before cell transfer but not when given 1 to 5 days earlier. Cytofluorimetric analysis shows that the gamma/delta + cells and not the V beta 8.2+ cells of the line express IL-4R and a good systemic transfer of DTH is observed when gamma/delta + cells are incubated in vitro with IL-4 and then injected together with V beta 8.2+ cells into recipient mice. In contrast, injection of V beta 8.2+ cells treated with IL-4 together with gamma/delta + cells fails to transfer DTH. Overall, the present results show that IL-4 is an important mediator in the DTH reaction and that gamma/delta + cells are one of the targets of its action.

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PubMed1994

I-J revisited: is the I-J genetic restriction in downregulation due to an endogenous superantigen analogous to mammary tumour virus (Mtv)-encoded endogenous superantigen?

This article puts forward the hypothesis that the I-J genetic restriction observed between certain downregulatory (suppressor) T cells and antigen presenting cells is due to an endogenous superantigen analogous to the mouse mammary tumour virus (Mtv) products encoded by the open reading frames in the 3' long terminal repeat (LTR) of mtv's. In its weak form this hypothesis asserts that the I-J genetic restriction is due to an endogenous superantigen ligand on antigen presenting cells, which crosslinks the V beta and/or V alpha chains of certain T cell receptors (TCR) with major histocompatibility complex (MHC) class II, and that MHC together with this superantigen ligand causes positive selection of T cells bearing the appropriate I-J+ TCR in the thymus. In the periphery these T cells recognize peptide/MHC complex in the presence of the superantigen. In its strong form the hypothesis states that this superantigen ligand for TCR and MHC is encoded by integrated virus genome, e.g. Mtv. These possibilities can now be approached experimentally and their exploration may uncover one of the ways in which T cells are assigned to different functions, including downregulation.

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PubMed1994

Dominant V beta 8 gene usage in response to TNP: failure to use other V beta chains following removal of V beta 8+ T cells by monoclonal antibody in vivo.

This paper investigates the V beta usage of lymph node cells from mice immunized with TNP and of cell lines made from them. In cell lines stimulated weekly with TNP in vitro for 1 month, about 87% of the cells were V beta 8+ and further analysis showed that these cells were actually V beta 8.2+. This was also true for the cells that proliferated in lymph nodes in response to TNP 4 days after primary immunization, i.e. proliferation occurred mainly in the V beta 8+, and in particular in the V beta 8.2+, population while much less proliferation occurred when the V beta 8- or V beta 8.2- T-cell populations are used. This was not due to non-specific damage during separation, as the response to concanavalin A and alloantigen was intact. In a separate series of experiments, mice were acutely depleted of V beta 8+ T cells by treatment with F23.1 or a control monoclonal antibody (mAb) in vivo given before immunization. Treatment with the relevant mAb virtually abolished the response to TNP. In contrast, SJL mice, which lack the gene segment coding for the V beta 8 family and several other V beta chains, made a normal proliferative and delayed-type hypersensitivity (DTH) response to TNP. This poses the problem, which may be important in the study of the T-cell repertoire, of why acute removal of V beta 8+ T cells, which are dominantly used in the response to TNP, does not allow T cells using other chains to substitute in the response, while the absence of this population over a long period of time, because of a deletion in the genome, allows the use of T cells bearing other V beta chains.

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PubMed1993

Abrogation of suppression of delayed hypersensitivity induced by Candida albicans-derived mannan by treatment with monophosphoryl lipid A.

Monophosphoryl lipid A (MLA), derived either from Salmonella minnesota or Salmonella typhimurium, was tested for its ability to alter Candida albicans mannan (MAN)-specific suppression. Since we showed previously that naive mice injected intravenously (i.v.) with MAN developed suppressor T cells capable of down-regulating delayed-type hypersensitivity when transferred to immunized recipients, MLA was tested for its ability to influence suppressor activity in the donors of suppressor cells. T-lymphocyte-enriched suspensions from donor mice treated with MLA, especially that derived from S. typhimurium, 2 or 3 days after the injection of MAN lost the ability to suppress delayed-type hypersensitivity when transferred to immunized mice. Transferable suppressor activity was reduced but not always completely abrogated when donor animals were treated with MLA 1 day following the administration of MAN. In several experiments, S. minnesota MLA also abrogated activity, but it was not effective in other transfer experiments. In a different type of experiment, MLA was given to immunized mice which had been suppressed directly with MAN. Mice were immunized, either by the introduction of C. albicans intragastrically followed by inoculation intradermally (i.d.) or by two i.d. inoculations, and MAN-specific suppressor cells were induced in such animals by the i.v. injection of MAN 1 day before the first or second i.d. inoculation in animals given intragastric plus i.d. inoculations and those given two i.d. inoculations, respectively. MLA was administered to such mice prior to the i.v. injection of MAN, on the same day, or 1 to 4 days thereafter. S. typhimurium MLA, especially when given to mice 2 days following the administration of MAN, caused a partial abrogation of suppressor activity. Overall, however, MLA, at 5 to 100 micrograms, had variable and minimal effects on suppressor activity in immunized mice suppressed by the i.v. administration of MAN. In summary, MLA is clearly capable of abrogating MAN-induced suppression when given to nonimmunized animals in which MAN-specific suppressor cells had been induced, but its efficacy in immunized animals suppressed by the i.v. administration of MAN was marginal.

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PubMed1993

Augmented passive transfer of contact sensitivity in severe combined immunodeficiency mice and its dependence of V beta 8+ cells in the picryl system.

The passive transfer of contact sensitivity using picryl chloride immune cells from H-2 syngenic BALB/c donors was analyzed in severe combined immunodeficiency (SCID) mice which lack functional T and B lymphocytes. H-2-restricted and antigen-specific contact sensitivity was transferred to SCID mice, and comparison between the level of contact sensitivity and the number of transferred cells showed a significantly more efficient transfer to SCID than to BALB/c mice. The cells passively transferring contact sensitivity were shown to carry the V beta 8 phenotype. Moreover, chromium-labeled cells from BALB/c PC1-primed donors localize normally in peripheral lymphoid organs and an increased percentage of cell arrival in the ears is clearly observed in SCID after challenge with picryl chloride.

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