bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant effects of nonionic block polymer surfactants on liposome-induced humoral immune response.
Authors: Zigterman G J , Snippe H , Jansze M , Willers J M
Published: December 2022

The ability of several surface-active agents to stimulate the humoral immune response in mice against haptenated liposomes was tested. The surfactants were block copolymers of hydrophilic polyoxyethylene (POE) and hydrophobic polyoxypropylene (POP) that differed in m.w., percentage of POE, and mode of linkage of POP to POE. The liposomes were haptenated with tripeptide-enlarged dinitrophenyl coupled to phosphatidylethanolamine, which was incorporated into the liposomal membrane. Additional injection of mice with surfactant stimulated serum hemagglutination titers and splenic plaque-forming cell (PFC) numbers to varying extents. Block polymers with POP chains flanking a POE center, as well as polymers with POE chains flanking a POP center, displayed high adjuvant activity. These block polymers stimulated the antibody response in a dose-dependent manner. They stimulated the antibody response with both high and low antigen doses. Furthermore, the addition of one of these adjuvants (25R1) reduced the amount of carrier lipid required in the liposome in order to obtain an optimal antibody response. The surfactants, which displayed high adjuvant activity, did not interfere with liposome stability as measured with a liposome lysis assay. Moreover, in vitro preincubation of liposomes with a block polymer did not affect their immunogenicity. Optimal adjuvant activity was observed when both adjuvant and liposomes were administered by the same route. Simultaneous injection of both components, however, is not a prerequisite. Conclusively, it can be stated that nonionic block polymer surfactants are potent adjuvants for stimulation of the antibody response against haptenated liposomes.
Retention of T cell reactivity to mitogens and alloantigens by Peyer's patch cells of aged mice.
Authors: Ernst D N , Weigle W O , Thoman M L
Published: December 2022

Immune function generally declines with advancing age. However, recent evidence suggests that this decline may differentially affect the lymphoid compartments comprising the immune system. The effect of age on the T cell-mediated competency of cells from two different lymphoid compartments, Peyer's patch (PP) and spleen, was studied. PP cells of aged C57BL/6 mice retained a greater capacity to proliferate in response to concanavalin A, phytohemagglutinin, and alloantigen and to generate alloimmune cytotoxic cells than did splenocytes of aged mice when compared with their young counterparts. These results could not be explained by significant shifts in the response kinetics or in the proportions of T cells in individual tissues. These results support the concept that lymphoid compartments are not equally sensitive to the deleterious effects of the aging process.
The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis.
Authors: Orme I M
Published: December 2022

Mice infected i.v. with the virulent Erdman strain of Mycobacterium tuberculosis exhibited three distinct phases of infection within the spleen. These consisted of a primary phase, characterized by the progressive growth of the organism; a secondary phase, in which the viable organism was progressively eliminated; and a tertiary phase, characterized by a chronic or slowly recrudescing disease state. Passive transfer experiments, in which T cell-enriched spleen cells from immune donors were infused into T cell-deficient recipients and were measured for their capacity to adoptively protect these mice from challenge with M. tuberculosis, provided evidence that at least three separate populations of protective T cells were acquired in response to the infection within the time frame of the experiments. These populations of T cells could be distinguished in that they differed in their expression of the L3T4 and Lyt-2 cell surface molecules, in terms of their kinetic profiles of emergence and loss, and (c) in terms of their susceptibility to cyclophosphamide. The results may suggest that different populations of protective T cells can be generated at different times during the infection as various classes of antigens (for example, metabolic or structural antigens) become available for presentation by host macrophages. It is hypothesized, furthermore, that the kinetics of emergence and loss of these various populations may reflect switching in the mode of immunity being expressed, particularly during the chronic phase of the infection, from that of a state of active immunity to one of immunologic memory.
Human T clones reactive to the sexual stages of Plasmodium falciparum malaria. High frequency of gamete-reactive T cells in peripheral blood from nonexposed donors.
Authors: Good M F , Quakyi I A , Saul A , Berzofsky J A , Carter R , Miller L H
Published: December 2022

Malarial gametocytes, which are taken up by mosquitoes during a blood meal, develop in the gut of the mosquito into gametes. Gametes and gametocytes contain the target antigens of transmission-blocking immunity. Here, we show that the peripheral blood of nonexposed donors contains Plasmodium falciparum gamete-reactive T cells at frequencies ranging from 1/300 to 1/4000. Studies on long-term clones demonstrated that these cells often recognized antigens shared between gametes and asexual stage parasites or even between heterologous gametes, although it has been possible to derive a P. falciparum gamete-specific T clone. The T clones examined were T3+, T4+, T8-, and either HLA-DR- or HLA-DQ-restricted. They responded to gametes by both proliferation and the secretion of gamma-interferon. The gamete-specific clone and other asexual cross-reactive clones examined could be stimulated in vitro by a preparation of mature gametocytes within RBC, but not by RBC alone, suggesting that gametocytes are immunogenic or can become immunogenic for T cells in vivo. The significance of these observations to mosquito transmission of malaria and development and application of a gamete vaccine are discussed.
Protective immunity to progressive tumors can be induced by antigen presented on regressor tumors.
Authors: Flood P M , Schreiber H , Ron Y
Published: December 2022

Immunization of animals with 1591-RE tumor cells, a highly immunogenic UV-induced epithelia cell tumor from C3H/HeN mice, that were haptenated with trinitrophenol (TNP) leads to protective immunity against a challenge of TNP-haptenated 3152-PRO tumor cells, a progressive highly malignant. MCA-induced fibrosarcoma from syngeneic mice. Animals that rejected TNP-1591-RE and subsequently TNP-3152-PRO tumor cells showed increased tumor-specific resistance to another challenge of 3152-PRO tumor cells, even when these fibrosarcoma cells had not been haptenated with TNP. Induction of protection required the presence of TNP-hapten groups on both 1591-RE and 3152-PRO during the initial immunization, and could be induced by immunization with other haptenated syngeneic highly immunogenic regressor tumor lines. In addition, TNP-haptenated progressor variants of the 1591-RE were ineffective in generating protection, suggesting that the immunogenicity of the haptenated tumor used for the initial immunization was a determining factor in whether or not protective immunity against the highly malignant tumor was later generated. Protection required at least two T cell types: a Lyt-1-2+ T cells, and a Lyt-1+2- T cell that also expressed I-J determinants and was Vicia villosa lectin adherent, suggesting it was not a classical helper T cell. These results suggest that presentation of a hapten by highly immunogenic tumor cells can lead to enhanced protective immunity to poorly immunogenic noncross-reactive tumors that co-express the same hapten, and rejection of these haptenated poorly immunogenic tumors leads to enhanced protection against a subsequent challenge of the same, but not noncross-reactive progressor tumors.
Defective lymphopoiesis in the bone marrow of motheaten (me/me) and viable motheaten (mev/mev) mutant mice. II. Description of a microenvironmental defect for the generation of terminal deoxynucleotidyltransferase-positive bone marrow cells in vitro.
Authors: Medlock E S , Goldschneider I , Greiner D L , Shultz L
Published: December 2022

We have presented evidence in a previous paper that the development of prothymocytes, pre-B cells, and TdT+ lymphoid precursor cells in the bone marrow of motheaten (me/me) and viable motheaten (mev/mev) mice is defective. In the present study, we have used a selective culture system that supports the generation of rat- and mouse-origin TdT+ bone marrow lymphoid cells in vitro to further investigate the early stages of lymphopoiesis in me/me and mev/mev mice. The results demonstrate that bone marrow stromal cell feeder layers derived from me/me and mev/mev mice do not support the growth of rat TdT+ cells in vitro, whereas stromal cell feeder layers from heterozygous (+/-) littermates and wild type (+/+) control mice do. Moreover, composite feeder layers formed by mixing as few as one part me/me and mev/mev bone marrow cells with 7 to 9 parts +/- littermate bone marrow cells also fail to effectively support the generation of TdT+ cells in vitro. In contrast to me/me and mev/mev mice, other mutant mouse models of autoimmune (NZB, NZB/W), immunodeficient (nu/nu), and hemopoietic (W/Wv, Sl/Sld) disorders form feeder layers that support normal to elevated levels of TdT+ cell growth in vitro. Thus, to date, only the me/me and mev/mev mutant mice have been found to lack the appropriate microenvironment for the generation of TdT+ bone marrow cells. Histologic analysis of the stromal cell feeder layers that are formed in our culture system shows that multilayered cellular patches, which normally are the most active sites of TdT+ cell development in vitro, are absent in feeder layers of me/me and mev/mev cells. Moreover, feeder layers from mev/mev mice contain a population of MAC 1+, basophilic, nonvacuolated, macrophage-like cells; whereas feeder layers from control mice contain MAC 1+, eosinophilic, vacuolated macrophage-like cells. Stromal cell feeder layers formed by mixtures of me/me or mev/mev and control mouse bone marrow cells contain numerous multilayered cellular patches and vacuolated mononuclear cells, but also contain large numbers of basophilic mononuclear cells. These composite feeder layers have a disproportionately reduced capacity to support the generation of TdT+ cells in vitro. Although the stromal microenvironment of me/me and mev/mev bone marrow does not support the growth of TdT+ cells in vivo or in vitro, the bone marrow from these mutant mice contains detectable numbers of pre-TdT+ cells. Thus, when cultured on normal mouse feeder layers, mutant mouse bone marrow rapidly generates TdT+ cells in vitro, albeit at significantly reduced levels as compared to +/- littermate controls.(ABSTRACT TRUNCATED AT 400 WORDS)
Precursor phenotype of lymphokine-activated killer cells in the mouse.
Authors: Salup R R , Mathieson B J , Wiltrout R H
Published: December 2022

Lymphokine-activated killer (LAK) activity has been proposed to functionally differ from natural killer (NK) activity largely on the basis of a broader target cell spectrum and different kinetics of response to interleukin 2 (IL 2). Similarly, it has been proposed that the precursor cells for LAK activity are phenotypically distinct from NK cells. In most precursor studies, phenotype comparisons have been made between fresh NK cells and LAK cells which have been generated by 3 to 5 days of culture in IL 2. In the present study, we utilized positive selection with monoclonal antibodies to characterize the surface phenotype of precursor cells which give rise to rIL 2-augmented NK activity within 24 hr and to classically generated LAK activity which appears after 3 to 5 days of culture in rIL 2. The results demonstrated that highly purified (93 to 95%) Lyt-2+ or L3T4+ T lymphocytes were unable to generate appreciable amounts of either augmented NK activity or LAK activity when cultured with rIL 2, whereas the highly purified (98%) Lyt-2-, L3T4-, asialo GM1+ lymphocyte subset gave rise to both augmented NK and LAK activities. These findings demonstrate that both augmented NK and LAK activities can arise from precursors expressing the same phenotype. Overall, the results suggest that NK cells in mouse spleen constitute a major precursor component for the generation of LAK activity from that organ.
Requirements for triggering of lysis by cytolytic T lymphocyte clones.
Authors: Lancki D W , Weiss A , Fitch F W
Published: December 2022

Cloned murine cytolytic T lymphocytes (CTL) having defined specificity were triggered by the phorbol ester together with a calcium ionophore (either A23187 or Ionomycin) to lyse syngeneic or third party target cells efficiently. Neither phorbol 12-myristate 13-acetate (PMA) nor calcium ionophore alone induced efficient lysis. The characteristics of the lytic process induced by these signals are similar to those of antigen-specific or lectin-facilitated lysis by CTL. Lysis is calcium and temperature dependent and shows kinetics which are not grossly different from lysis mediated via the antigen receptor. Two helper T lymphocyte clones were not induced to lyse efficiently EL-4 target cells by concanavalin A or PMA + ionophore. Triggering of lysis induced with PMA plus ionophore by the CTL clone L3 differed from antigen-mediated lysis in specificity and in the susceptibility to inhibition by cytochalasin B. Properties of the target cell determine which cell surface associative recognition structures are important in the efficient lysis of these cells. Anti-LFA-1 monoclonal antibodies inhibited efficiently both antigen-mediated and PMA + ionophore-induced lysis of P-815 or EL-4 target cells which are of hematopoietic origin. However, anti-LFA-1 antibodies do not inhibit antigen-mediated, lectin-facilitated, or PMA + Ionomycin-induced CTL cytolysis of target cells derived from the L cell fibroblast line. We conclude that two intracellular signals, which can be provided by the combination of PMA + ionophore, are required for efficient lysis by antigen-specific murine CTL clones. When the T cell receptor for antigen is bypassed using PMA + ionophore to trigger lysis, we show that Lyt-2 and LFA-1 molecules may be required for efficient lysis. These associative recognition structures appear to play an important role in postactivation steps leading to efficient delivery of the lethal hit to the target cell.
Immunoregulation by antigen/antibody complexes. I. Specific immunosuppression induced in vivo with immune complexes formed in antibody excess.
Authors: Caulfield M J , Shaffer D
Published: December 2022

Specific immune complexes, prepared at different ratios of antibody to antigen, were examined for their effects on the antibody response of BALB/c mice to the cell wall polysaccharide antigen (PnC) extracted from Streptococcus pneumonia R36a. Mice immunized with complexes formed in antigen excess developed a PnC-specific antibody response that was equivalent to that in mice injected with free antigen. On the other hand, mice injected with complexes formed in antibody excess developed very little PnC-specific antibody. Furthermore, administration of immune complexes (formed in antibody excess) resulted in suppression of the response to an immunogenic dose of PnC given concurrently or 1 day after injection of immune complexes but not when the antigen was given 1 day before injection of the immune complexes. Injections of free antibody (TEPC-15) also resulted in suppression of the response to antigenic challenge; however, suppression was greatest when the antibody was injected concurrently with the antigen, suggesting that the suppression was mediated through the formation of immune complexes in vivo. The suppression appears to be specific for the antigen (PnC), since in mice injected with TEPC-15/PnC complexes (formed in antibody excess) and challenged with PnC coupled to sheep RBC, only the response to PnC was suppressed.
Immune complexes bind to cultured rat glomerular mesangial cells to stimulate superoxide release. Evidence for an Fc receptor.
Authors: Sedor J R , Carey S W , Emancipator S N
Published: December 2022

Contractile mesangial cells (MC) possess a number of macrophage-like characteristics, including oxygen radical generation. We suggest that under certain conditions MC may serve as immune effector cells in glomerulonephritis. Immune complex (IC) deposits are a hallmark of glomerulonephritis. Because IC elicit oxygen radicals from other cell types and because oxygen radicals can induce glomerular injury, we measured release of O2- by cultured rat MC in response to IC and, in separate experiments, the binding of IC to MC. Soluble and insoluble IC markedly stimulated dose- and time-dependent, saturable O2- release. Specific antibody (Ab) alone or mixtures of nonimmune Ab and antigen had no significant effect. IC-induced O2- release was not affected by cytochalasin B, an inhibitor of phagocytosis. Binding studies with radioiodinated IC demonstrated specific binding with an affinity of 1.56 X 10(6) M-1 and 1.02 X 10(5) receptors per cell. Both binding and O2- release required the Fc region of Ab. IC formed with F(ab')2 fragments did not bind specifically to or stimulate O2- release by MC. Cultured cells from rats depleted of bone marrow-derived phagocytes by irradiation produced amounts of O2- similar to cells from normal rats. These results provide evidence that IC affect the biology of the contractile glomerular MC in a manner that is dependent on the Fc region of Ab and suggest that MC structure and function may be altered at sites of injury.
Lymphokine activation of T4+ T lymphocytes and monocytes.
Authors: Cruikshank W W , Berman J S , Theodore A C , Bernardo J , Center D M
Published: December 2022

The function of the T4 antigen, a marker for a differentiated T cell subset, is not well understood. Our previous observation that a chemoattractant human lymphokine, lymphocyte chemoattractant factor (LCF), which selectively induces motile responses in unactivated T4+ lymphocytes, led us to investigate whether LCF could also induce T4+ cell activation. Because LCF acts selectively on T4+ cells, we next determined whether the T4 antigen has a function in this LCF-induced cellular activation. A T4+ lymphocyte migratory response is induced by divalent anti-T4 antibody, but not by corresponding Fab fragments of the same antibody. Fab fragments of anti-T4 antibody, but not Fab fragments of anti-T3 antibody, block the migratory effect of both LCF and divalent anti-T4. Furthermore, LCF but not divalent anti-T4, evokes the expression of interleukin 2 (IL 2) receptors and HLA-DR antigen on T4+ lymphocytes in 24 hr. These effects are quantitatively similar to those observed by anti-T3 antibody activation. LCF-induced IL 2 receptor expression is blocked by co-incubation with anti-T4 antibody and anti-T4 Fab fragments, whereas anti-T3 activation is not inhibitable by anti-T4 Fab fragments. Because cultured monocytes express the T4 antigen, we investigated the action of LCF on cultured monocyte migration and HLA-DR expression. Induction of monocyte migration by LCF and anti-T4 antibody increases proportionally as T4 antigen expression increases in vitro. This enhanced migration is inhibitable by anti-T4 Fab fragments. Monocyte activation, as measured by augmented HLA-DR expression 24 hr after incubation with LCF, but not anti-T4 antibody, is quantitatively similar to the effects of interferon-gamma. Augmented HLA-DR expression is blocked by anti-T4 Fab fragments but not by antibody to interferon-gamma. These studies indicate that LCF interacts with T4+ lymphocytes and monocytes to induce migration and cellular activation.
Cytokine-dependent granulocytic differentiation. Regulation of proliferative and differentiative responses in a murine progenitor cell line.
Authors: Valtieri M , Tweardy D J , Caracciolo D , Johnson K , Mavilio F , Altmann S , Santoli D , Rovera G
Published: December 2022

Human granulocyte colony stimulating factor (G-CSF) can support the survival and short term proliferation of the interleukin 3 (IL 3)-dependent diploid murine hemopoietic progenitor cell line 32D C13. After 8 days in the presence of 30 U/ml of G-CSF and in the absence of IL 3, the great majority of 32D C13 cells becomes positive for myeloperoxidase (a marker that appears at the promyelocytic stage of the granulocytic lineage) and progressively differentiates into lactoferrin-containing neutrophilic granulocytes. Myeloperoxidase mRNA rapidly increases after 24 to 48 hr of treatment with G-CSF, peaks at day 6 and is no longer detectable at day 9 and 12, paralleling the appearance of myeloperoxidase-positive promyelocytes and myelocytes in the culture. After 12 days, 100% of the cells terminally differentiate, and clonogenic assays in IL 3-containing semisolid media indicate that the whole population has irreversibly lost proliferative capability. By using varying concentrations of both murine IL 3 and recombinant human G-CSF, the cultures develop an heterogeneous population of cells representing all the differentiation stages of the myeloid lineage, and the relative ratios of immature proliferating precursors and terminally differentiated cells present in the cultures can be modulated by modifying the concentrations of IL 3 or recombinant human G-CSF. Isobolic curves indicate that IL 3 and G-CSF have an antagonistic effect on the proliferation of 32D C13 cells. Thus, these cells represent a simplified in vitro model of normal granulocytic differentiation whose extent may be modulated completely in the presence of serum by two well-defined growth and differentiation factors: IL 3 and G-CSF.
A polymorphism of the complement regulatory protein MCP (membrane cofactor protein or gp45-70).
Authors: Ballard L , Seya T , Teckman J , Lublin D M , Atkinson J P
Published: December 2022

Membrane cofactor protein (MCP or gp45-70) is a recently described regulatory glycoprotein of the complement system which binds iC3 or C3b and is present on human platelets, T cells, B cells, monocytes, and mononuclear-derived cell lines. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, MCP migrates as a doublet with an Mr of the upper band of 63,000 and the lower band of 58,000. The same pattern was found on all cell populations in a given individual and was stable over time. In order to further characterize the two band pattern on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, MCP was isolated by affinity chromatography or immunoprecipitation from 72 healthy unrelated donors. All individuals expressed both bands and, based on the densitometric scanning of gels, three patterns were noted: upper band predominant in 65%, approximately equal distribution of upper and lower bands in 29%, and lower band predominant in 6%. These observed phenotypic frequencies fit with expectations based on Hardy-Weinberg equilibrium for a two-allele system. Family studies also support this model as none of the 26 offspring had a phenotype that deviated from the expected, assuming an autosomal codominant model of inheritance. These results are consistent with a simple two-allele system that controls the expression of the two bands of MCP.
Production of platelet-activating factor by stimulated human polymorphonuclear leukocytes. Correlation of synthesis with release, functional events, and leukotriene B4 metabolism.
Authors: Sisson J H , Prescott S M , McIntyre T M , Zimmerman G A
Published: December 2022

Platelet-activating factor (PAF) is a phospholipid mediator of inflammation that is synthesized by several human cell types including polymorphonuclear leukocytes (PMN). We examined the synthesis and release of PAF by stimulated human PMN under several conditions, assayed by the incorporation of [3H]acetate into PAF and by bioassay. PAF synthesis was induced by calcium ionophore A23187 (IoA), opsonized zymosan (OpsZ), and N-formyl-methionyl-leucyl-phenylalanine (FMLP) with the relative order of potency IoA much greater than OpsZ greater than FMLP. A variety of other agonists, including phorbol myristate acetate, an activator of protein kinase C and of PMN functional responses, did not stimulate PAF synthesis. PAF synthesis by PMN in response to IoA, OpsZ, and FMLP was concentration- and time-dependent but release of the phospholipid was not: little PAF (1 to 10%) was released from PMN in suspension regardless of the total amount produced, the agonist, its concentration, the time of incubation, or the concentration of extracellular albumin. This was also the case with functionally altered neutrophils that had been "primed" with cytochalasin B or lipopolysaccharide or that had adhered to surfaces. PAF synthesis was tightly coupled with leukotriene B4 production by adherent PMN as well as by neutrophils in suspension, supporting the hypothesis that the two lipid autacoids may be derived from a common precursor. However, PAF synthesis could be dissociated from aggregation and surface adhesion, indicating that it is not absolutely required for these responses of activated PMN. The total amount of PAF that accumulated, but not the percentage that was released, was altered in adherent PMN compared to cells in suspension. These experiments demonstrate that PAF production and its subsequent processing by human neutrophils are highly regulated events. PAF synthesis is associated with PMN activation, but it is not a requisite for early adhesive responses of neutrophils. Because little of the PAF produced by stimulated PMN is released from the cells, it appears that PAF has an intracellular role in PMN function and/or that it may have novel intercellular effects that do not require release into the fluid phase.
Reduced allorecognition of adenovirus-2 infected cells.
Authors: Andersson M , McMichael A , Peterson P A
Published: December 2022

The early region 3 of adenovirus 2 encodes the membrane glycoprotein E19. This protein specifically binds class I transplantation antigens of a variety of species. Concomitant with this interaction the intracellular transport of newly synthesized class I heavy chains is abrogated. At late stages of the virus infection this leads to a notable decrease in the cell surface expression of class I antigens. We have studied how infection with adenovirus 2 influences target cell recognition by alloreactive cytolytic T lymphocytes. We found that the E19 protein-induced reduction of the HLA-B7 cell surface expression led to a greatly reduced lysis of the infected cells. These findings support our hypothesis that the E19 protein has evolved to facilitate the in vivo replication of the virus by reducing the expression of HLA class I antigens.
Maleylated-BSA suppresses IFN-gamma-mediated Ia expression in murine peritoneal macrophages.
Authors: Hamilton T A , Gainey P V , Adams D O
Published: December 2022

Maleylated bovine serum albumin (maleyl-BSA) and other polyanionic polymers that are recognized by cell surface receptors on macrophages have been shown to induce chemotaxis, protease secretion, and tumoricidal function in this cell type. In this paper the effect of maleyl-BSA on Ia antigen expression has been evaluated. In a fashion similar to LPS, maleyl-BSA suppressed IFN-gamma-induced expression of Ia in a time- and dose-dependent manner. Also like LPS, maleyl-BSA stimulated the production and secretion of substantial amounts of PGE2 over a 24-hr period. This did not, however, appear to be the primary mechanism by which expression of Ia was suppressed, because co-treatment of the cells with indomethacin, which totally inhibited the production of PGE2, only minimally affected the suppressive activity. Surprisingly, the suppressive activity of both maleyl-BSA and LPS could be largely abrogated by co-treatment of the cells with cyclohexamide during the time period when Ia expression was sensitive to suppression. This effect was selective in that PGE2- or dibutyryl cyclic AMP-induced suppression of Ia expression was not affected by cyclohexamide treatment. The data support the concept that there are multiple molecular mechanisms involved in the negative regulation of IFN-gamma-induced Ia expression in macrophages. Such mechanisms may include, in addition to the synthesis of PGE2 and consequent elevation in intracellular levels of cyclic AMP, one or more proteins made early after treatment with either maleyl-BSA or LPS. Thus the function of some of these early gene products may be to regulate expression of functional genes such as that encoding Ia antigen.
Natural suppressor (NS) activity from murine neonatal spleen is responsive to IFN-gamma.
Authors: Maier T , Holda J H
Published: December 2022

Natural suppressor (NS) cell activity is the ability of apparently unprimed "null" cells to nonspecifically suppress immune responses. Previously we have shown that NS cell activity from the spleens of mice undergoing chronic graft-vs-host disease (GVHD) is enhanced in vitro by activated T cell signals (e.g., Con A supernatant [CAS]). Here we asked if the naturally occurring suppressor activity found in the neonatal mouse spleen is caused by NS cells, and if so whether this NS activity is also responsive to T cell signals. Finally, we wanted to identify the material in the CAS to which the NS cells respond. Spleen cells from (BALB/c X B10.D2)F1 neonates contain potent, genetically unrestricted suppressor activity toward normal mitogen responses. The cells responsible for this suppression are nonadherent, Thy-, Ig- and are thus by definition NS cells. Neonatal spleen NS cells suppress the indicator Con A response of all mouse strains tested, but their behavior with regard to LPS responses is different. They significantly inhibit the indicator LPS response of allogeneic strains, but are less inhibitory of LPS-stimulated syngeneic (BALB/c X B10.D2)F1 and parental strains. However, the addition of CAS to these latter cultures enhances the NS inhibition of the LPS response to the level of suppression seen with a Con A response. Two lymphokines were able to replace the CAS. Recombinant interferon-gamma (rIFN-gamma) closely mimics the activity found with whole CAS, with low concentrations (1 U/well) being capable of enhancing the neonatal NS activity to near-maximal levels. Recombinant interleukin 2 (rIL 2) is also capable of stimulating the neonatal NS activity to near maximum. However, the rIL 2 must be added at much higher concentrations, taking greater than 50 U/well to get maximum activation of NS suppression. The addition of anti-IFN-gamma antiserum to these LPS suppression assays removes the ability of CAS to activate the neonatal NS cells. Anti-IFN-gamma antiserum also removes the ability of rIL 2 as well as rIFN-gamma to activate the NS cells. It thus appears that the rIL 2 is working by its ability to stimulate IFN-gamma production. Anti-IFN-gamma also removes the ability of the neonatal NS cells to suppress a Con A response. Therefore, it appears that neonatal splenic NS cells respond to, and are activated by, IFN-gamma to carry out their suppressive activity.(ABSTRACT TRUNCATED AT 400 WORDS)
CTLA-1 and CTLA-3 serine esterase transcripts are detected mostly in cytotoxic T cells, but not only and not always.
Authors: Brunet J F , Denizot F , Suzan M , Haas W , Mencia-Huerta J M , Berke G , Luciani M F , Golstein P
Published: December 2022

We and other investigators previously reported the cloning of CTLA-1 (or CCP-1) and CTLA-3 (or H Factor) serine esterase-related transcripts preferentially expressed in cytolytic T lymphocytes. We extended the survey of the tissue specificity of these molecules. Two main sets of results were obtained. First, both CTLA-1 and CTLA-3 transcripts could be found in the various cytolytic T cells tested, although in widely different amounts, and in some cases just at the threshold of detection. Secondly, these transcripts were not found in most of the other cells tested, including in some natural cytotoxic cells and in activated cytotoxic macrophages; however, they could be detected in mast cells for CTLA-1 and in some noncytotoxic lymphocytes for CTLA-3. Thus, the CTLA-1 and CTLA-3 serine esterase products are most probably not required for macrophage or natural cytotoxicity; their presence cannot be taken as characteristic of cytotoxic T cells; and a discussion about their relevance to T cell-mediated cytotoxicity should take into account their widely different amounts from one cytotoxic T cell to another.
Humans express natural cytotoxic (NC) cell activity that is similar to murine NC cell activity.
Authors: Collins J L , Kao M S , Patek P Q
Published: December 2022

The expression of natural cytotoxic (NC) activity is well defined in mice, but poorly defined in humans. In this paper we report that humans express naturally occurring cytotoxic cell activity that recognizes and lyses murine targets that are sensitive to lysis mediated by murine NC cells, but not murine targets that are resistant to lysis by murine NC cells. We present data showing that these naturally occurring human cytotoxic cells and murine NC cells have similar lytic mechanisms. Both the human cytotoxic cells described here, and murine NC cells, use tumor necrosis factor (TNF) to mediate the lysis of sensitive targets. Moreover, targets that resist murine NC-mediated lysis by a protein synthesis-dependent post-recognitive mechanism use a similar mechanism to prevent lysis mediated by naturally occurring human cytotoxic cells. In addition to the similarity of naturally occurring human cytotoxic cells and murine NC cells in their specificity and lytic mechanism, naturally occurring human cytotoxic cells and murine NC cells are also similar in that their activity is both associated with a monocyte lineage and age independent. Taken together, these data indicate that humans express NC activity.
Interleukin 1 and myelin basic protein synergistically augment adoptive transfer activity of lymphocytes mediating experimental autoimmune encephalomyelitis in Lewis rats.
Authors: Mannie M D , Dinarello C A , Paterson P Y
Published: December 2022

This investigation focused on the role of adherent accessory cells and their cellular product, interleukin 1 (IL 1), in cellular immune responses associated with experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Guinea pig myelin basic protein (GPMBP)-sensitized lymph node cells (LNC) responded in culture with GPMBP by undergoing activation as measured by augmented transfer of EAE to syngeneic recipients, and proliferation as measured by [3H]thymidine incorporation. GPMBP-sensitized LNC, after depletion of adherent accessory cells, no longer responded to GPMBP in the EAE transfer activation assay. In contrast, aliquots of the same LNC preparation exhibited proliferative responses to GPMBP that were only partially reduced. Addition of irradiated thymocytes to adherent cell-depleted cultures fully reconstituted responsiveness to GPMBP in the activation assay and restored full reactivity to GPMBP in the proliferation assay. Furthermore, addition of either purified human IL 1 or recombinant human IL 1 to adherent cell-depleted cultures reconstituted reactivity to GPMBP in the EAE transfer activation assay and augmented GPMBP-specific proliferative responses. Anti-Ia monoclonal antibodies blocked GPMBP + IL 1-induced cellular activation of nonadherent LNC. These results demonstrate that both IL 1 and Ia molecules are important in the pathway leading to GPMBP-induced activation of EAE-inducing T lymphocytes. Furthermore, these results suggest that different accessory signals may be required for optimal induction of GPMBP-induced lymphocyte activation vs GPMBP-specific proliferative responses.
Genetic regulation of lipopolysaccharide-induced interleukin 1 production by murine peritoneal macrophages.
Authors: Brandwein S R , Skamene E , Aubut J A , Gervais F , Nesbitt M N
Published: December 2022

The production of IL 1 by LPS-stimulated peritoneal macrophages from inbred mouse strains was studied. Macrophages from A/J (A) mice were deficient in IL 1 production, when compared with high IL 1-producing strains, including C57BL/6J (B). The difference between A and B macrophages was maintained over a wide LPS concentration range and throughout a 72-hr incubation period. Because of these differences, it was possible to investigate the mechanisms regulating IL 1 production by applying techniques of genetic analysis by using recombinant inbred (RI) strains derived from the A and B progenitors. A strain distribution pattern (SDP) of IL 1 production (low/high response) was obtained with the use of 15 AXB/BXA RI strains. This suggested the presence of a major gene locus controlling the production of IL 1 in response to LPS stimulation, with allelic differences presumably resulting in deficient or efficient IL 1 production. In addition, there appeared to be one or more other loci involved in determining the magnitude of the IL 1 response to LPS in the responder mice. The IL 1 response did not appear to be linked to the major histocompatibility complex, since B10.A mice (which share the same H-2a haplotype as A/J) were efficient IL 1 producers. There did not appear to be any correlation between the degree of IL 1 production and the magnitude of the peritoneal macrophage inflammatory response, or between IL 1 production and LPS responsiveness (as determined by splenocyte proliferation). SDP analysis also indicated that the IL 1 response was not linked to macrophage tumoricidal activity. A comparison of the SDP for IL 1 production with a library of SDP for other known genetic waits suggested linkage with at least four loci on chromosome 1.
Interferon-gamma enhances expression of secretory component, the epithelial receptor for polymeric immunoglobulins.
Authors: Sollid L M , Kvale D , Brandtzaeg P , Markussen G , Thorsby E
Published: December 2022

Recombinant interferon-gamma (IFN-gamma) increased in a dose-dependent manner the intracellular pool, the membrane expression, and the shedding of secretory component (SC) in human colonic adenocarcinoma cell line (HT-29). A similar dose-response relationship was observed when we examined the binding of polymeric IgA to HT-29 cells treated with IFN-gamma, thus reflecting expression of functional SC. Because IFN-gamma is produced by T cells during immune responses, activated T cells may be able to promote the external transport of dimeric IgA and pentameric IgM and thereby enhance the efferent limb of the secretory immune system. This is, therefore, the first observation indicating how the secretory transport capacity may be adjusted to increased local immunoglobulin production.
The molecular basis of the hyaluronic acid-mediated stimulation of granulocyte function.
Authors: Håkansson L , Venge P
Published: December 2022

Previous investigations have demonstrated that the function of polymorphonuclear leukocytes (PMN) is stimulated by hyaluronic acid (HA). The aim of the present investigation was to study the molecular basis for the effect of HA. HA fragments of m.w. in the range from 792 (tetrasaccharide) to 3,000,000 all stimulated the chemotactic and phagocytic function of PMN. The active concentration ranged from 4 to 64 pmol/liter, irrespective of the molecular size. Further investigations demonstrated that N-acetyl-D-glucosamine (NAGA) was the smallest active fragment of HA. NAGA is one of the components from which HA is built up; the other component glucuronic acid was without effect, and so were the other glycosaminoglycans, N-acetyl-D-mannosamine, N-acetyl-D-galactosamine, and D-glucosamine. Finally, Con A, the glucopyranosyl and glucomannosyl binding lectin, inhibited the stimulatory effect of NAGA. As is the case with HA, fibronectin also acts as a necessary cofactor to NAGA when incubations are made in the absence of whole blood or serum. The present results strongly indicated that the combined action of NAGA and fibronectin worked directly on the PMN by an interaction at the cellular membrane level. We conclude that the stimulatory action of HA on granulocyte functions is mediated through one of its two structural components, i.e., NAGA.
Streptococcal serotype carbohydrate represents a novel class of type 2 antigen which is T-independent.
Authors: Kimura S , Kiyono H , Beagley K W , Torii M , Eldridge J H , Hamada S , Michalek S M , Koopman W J , McGhee J R
Published: December 2022

Our studies reported here, fully characterize two unique type 2 antigens trinitrophenol (TNP)-M1 serotype carbohydrates (TNP-M1 g and TNP-M1 c) derived from streptococci, which fail to induce antibody responses in xid or neonatal mouse splenic cultures. These antigens generate brisk responses in normal spleen and Peyer's patch cell cultures of xid mice, all of which suggest that responses are elicited in the Lyb-3+, 5+ B subpopulation. The antibody responses to TNP-M1 g (and TNP-M1 c) are not dependent upon T cells. Furthermore, TNP-M1 carbohydrates induce anti-TNP plaque-forming (PFC) responses in cultures of small, resting splenic B cell populations without an added T cell requirement. Thus two categories of type 2 antigens are distinguished, one which requires T cells or derived factors, e.g., TNP-Ficoll, and a second TNP-carbohydrate antigen TNP-M1 that does not. Studies of the mitogenic and polyclonal B cell activation properties of M1 carbohydrates indicated that B cell proliferation is induced in both xid (Lyb-3-, 5-) and normal (Lyb-3-, 5- and Lyb-3+, 5+) splenic B cell subpopulations, but that differentiation to IgM synthesis fails to occur in the Lyb-3-, 5- B cell subpopulation. Thus M1 carbohydrates are unique probes that allow the selective induction of proliferation and differentiation of mature B cells that are presumably Lyb-3+, 5+. Because the M1 serotype carbohydrates induce polyclonal IgM synthesis and antigen-specific responses in only the mature B cell population in the absence of T cells, whereas TNP-Ficoll and other type 2 antigens require T cells or their derived factors, the Lyb-3+, 5+ B cell subpopulation may consist of a T cell-dependent and a T cell-independent compartment for responses to different carbohydrate type 2 antigens.
The immune response to bacterial dextrans. V. A "dominant" idiotype in IgCHb mice.
Authors: Lundkvist I , Ivars F , Holmberg D , Coutinho A
Published: December 2022

A battery of syngeneic monoclonal anti-idiotypic antibodies was prepared against a monoclonal C57BL/6 anti-Dextran B512 antibody (17-9). Two such anti-idiotypes were shown to bind to sites on the 17-9 molecule which are related to the Dex-binding site and were used to characterize the anti-Dex antibody response in a number of inbred mouse strains. The results show that the 17-9 idiotype is recurrently expressed by all mice carrying the IgCHb haplotype, regardless of H-2 or background genes, and that this idiotype accounts for roughly one-half of the primary, specific response to Dex B512 in C57BL/6 mice. Backcross analysis confirmed the allotype-linkage of idiotype expression in the antibody response. Mice carrying other allotypes, however, had detectable levels of the 17-9 idiotype in normal sera, which was not associated with anti-Dex antibody activity and was not raised by specific immunization. Together with previous observations, these results characterize a second "recurrent" idiotype in the anti-alpha,1-6 response of IgCHb mice, both of which are expressed in the normal serum of all mouse strains tested.
Humoral response in Treponema pallidum-infected guinea pigs. II. Circulating immune complexes and autoimmune responses.
Authors: Baughn R E , Wicher V , Jakubowski A , Wicher K
Published: December 2022

Guinea pigs of inbred strain 2 and of a strain deficient in complement component 4 (C4D) responded to intradermal infection with Treponema pallidum by production of antibodies to treponemal antigens, normal rabbit serum proteins, fibronectin, and creatine kinase and with formation of circulating immune complexes (IC). IC started to appear at low concentrations 1 mo after infection and increased between 3 and 5 mo post-infection. Antibodies to fibronectin appeared after the second month but were not detectable 30 days later. Antibody activity to creatine kinase was detectable at the fourth month and became significantly higher at 5 mo post-infection. Reinoculation with a dose similar to that used for primary infection caused a significant increase in all antibodies and IC. Dissociation products of IC formed after primary infection consisted predominantly of treponemal antibodies and antigens, whereas IC detected after reinfection consisted predominantly of antibodies and normal rabbit serum proteins. Antibodies to fibronectin and creatine kinase are considered autoantibodies, and the underlying mechanism responsible for their production in syphilis is discussed.
Functional properties of a rat monoclonal IgE antibody specific for Schistosoma mansoni.
Authors: Verwaerde C , Joseph M , Capron M , Pierce R J , Damonneville M , Velge F , Auriault C , Capron A
Published: December 2022

A rat monoclonal antibody of IgE isotype (B48-14) raised against Schistosoma mansoni has been generated by the fusion of mesenteric lymph node cells from LOU/M rats immunized with a preparation of adult schistosome worms and IR973F nonsecreting rat myeloma cells. Investigation of the in vitro effector functions of this IgE antibody showed a high level of cytotoxicity against S. mansoni schistosomula in the presence of eosinophils, macrophages, and platelets. A significant level of protection (40 to 60%) against a challenge infection with S. mansoni cercariae was achieved by passive transfer experiment of B48-14 IgE to naive recipient rats. By immunoprecipitation, B48-14 IgE antibodies were shown to react with an antigen of 26 kDa present in excretion-secretion products of schistosomula, previously described as a potential immunogen eliciting a protective IgE response against schistosomiasis.
Mechanism of escape of exoerythrocytic forms (EEF) of malaria parasites from the inhibitory effects of interferon-gamma.
Authors: Vergara U , Ferreira A , Schellekens H , Nussenzweig V
Published: December 2022

We have studied the mechanism of inhibition by interferon-gamma (IFN-gamma) of the development of exoerythrocytic forms (EEF) of Plasmodium berghei in the livers of rats. At the time corresponding to the maximum development of EEF (44 hr after injection of sporozoites), the livers of the IFN-gamma-treated rats contained less parasite DNA as compared with controls. Twenty-four to 72 hr later, the livers of both groups of animals were free of parasites; that is, IFN-gamma treatment does not delay the development of the EEF. The decrease in parasite DNA observed in the IFN-gamma-treated rats was due to a diminution in the number, but not the size, of EEF. It appears, therefore, that treatment with the lymphokine either destroys the parasites or does not affect their replication. To study the mechanism of resistance to IFN-gamma of a small population of EEF, we subjected the parasites to four cycles of selection by IFN-gamma. The parasites from the "selected" and "nonselected" populations were equally susceptible to inhibition by IFN-gamma, indicating that the escape from IFN-gamma activity is not inherited.
Cloning and expression of murine lymphotoxin cDNA.
Authors: Li C B , Gray P W , Lin P F , McGrath K M , Ruddle F H , Ruddle N H
Published: December 2022

The murine lymphotoxin (LT) gene has been cloned and used to identify cDNA clones in a library prepared from activated murine T cell mRNA. A recombinant murine genomic library was screened with a human lymphotoxin cDNA probe, resulting in the isolation of the entire LT gene. The murine LT gene structure is similar to the human gene, containing three intervening sequences. An activated murine T cell cDNA library was prepared with poly(A)+ RNA isolated 7 hr after concanavalin A stimulation of an L3T4+ interleukin 2-dependent murine T cell clone. Two colonies of the cDNA library that contained inserts that hybridized with the murine LT gene probe were sequenced and were used to construct expression plasmids. The amino acid sequence deduced from the cDNA indicates that murine LT is highly homologous to human LT (74%) and is related to murine tumor necrosis factor (35% homology). The cDNA was transcribed and was translated in vitro, and was expressed in COS-1 cells. This has resulted in the production of LT biological activity.