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Biomedical subjects

D D Taub

Publications and source records attributed to D D Taub.

At least 91 records · Page 5Linked to original sources
PubMed1994

Human RANTES induces the migration of human T lymphocytes into the peripheral tissues of mice with severe combined immune deficiency.

The human cytokine, Recombinant Human Regulated on Activation, Normal T Expressed and Secreted (rhRANTES), is a small glycoprotein secreted by activated T cells and platelets and is structurally related to a family of chemotactic cytokines called chemokines. Evaluation of the effects of chemokines on human cells has largely been limited to in vitro binding assays. In an effort to study the in vivo effects of chemokines on human leukocyte migration, we examined the ability of rhRANTES to induce human T cell infiltration using a human/severe combined immune deficient (SCID) mouse model. SCID mice received human peripheral blood lymphocytes, followed by sequential subcutaneous injections of rhRANTES in the hind flank for 3 days. The skin and underlying tissue from the rhRANTES injection site were then biopsied and examined for the extent of human mononuclear cell infiltration. rhRANTES induced significant mononuclear cell accumulation 72 h after injection. Immunohistological evaluation determined that the majority of the cells recruited in response to rhRANTES injections were human CD3+ T cells with equal numbers of CD4+ and CD8+ cells. In contrast, subcutaneous injections of recombinant human macrophage colony-stimulating factors resulted in little human cellular infiltration. Murine mononuclear cell infiltration in response to rhRANTES was also present suggesting that the in vivo effects of rhRANTES may be both direct and indirect. These results demonstrate that rhRANTES induces significant human T cell migration in vivo and suggests that the human/SCID mouse model may provide an important tool in studying the in vivo effects of chemokines on human leukocytes and leukocyte subsets.

Animals↗
PubMed1994

Growth hormone promotes human T cell adhesion and migration to both human and murine matrix proteins in vitro and directly promotes xenogeneic engraftment.

Recombinant human growth hormone (rhGH) promotes human T cell engraftment in mice with severe combined immunodeficiency, suggesting that rhGH may have effects on T cell adhesion and migration in vivo. The ability of rhGH to directly affect the adhesion capacity of human T cells to a variety of human or murine adhesion molecules and extracellular matrix proteins was examined. rhGH induced significant human T cell adherence to both human and murine substrates via either beta 1 or beta 2 integrin molecules. rhGH was capable of inducing significant migration of resting and activated human T cells and their subsets. Most of the migratory response to rhGH was chemokinetic rather than chemotactic. In vivo engraftment studies in severe combined immunodeficiency mice receiving human T cells revealed that treatment with rhGH resulted in improved thymic engraftment, whereas treatment with non-human-reactive ovine GH demonstrated no significant effects. These data demonstrate that rhGH directly augments human T cell trafficking to peripheral murine lymphoid tissues. rhGH appears to be capable of directly altering the adhesive and migratory capacity of human T cells to molecules of either murine or human origin. Therefore, GH may, under either isogeneic or xenogeneic conditions, play a role in normal lymphocyte recirculation.

Animals↗
PubMed1994

Chemokines, inflammation and the immune system.

The chemokine superfamily comprise two families of small secreted proteins that, with the exception of RANTES, beta-TG, and PF-4, are not expressed in resting cells but are rapidly induced in response to various inflammatory and mitogenic stimuli. These proteins function as chemoattractants and activating agents for inflammatory cells. At present, it appears that each of the chemokines have some activities that are unique and many that are overlapping. Important areas that still need to be unravelled are the signal transduction pathways that lead to induction of these genes and the identification of the serpentine receptors and signal transduction pathways that are activated by these proteins. alpha and beta chemokines are implicated as major participants in acute as well as chronic inflammatory reactions, inhibition of haematopoeisis, modulation of angiogenesis, and fibroplasia. Chemokines that act on T lymphocytes presumably influence the recruitment of immunocompetent cells to inflammatory sites. Although there is no evidence that chemokines play a role in the induction of immune reactions, they undoubtedly promote the effector limb of immunity. The likely possibility that chemokines may also contribute to the normal homing and distribution of leukocytes also needs to be evaluated. Although chemokines obviously have major differentiative effects on the functions of target cells, the possibility that they act as costimulants of cell growth also needs more study. Finally, chemokines are attractive targets for the development of new therapeutic agents. Inhibition of their activities may be an effective anti-inflammatory strategy; promoting their activity might enhance wound healing and tissue repair.

Amino Acid Sequence↗
PubMed1993

Cytotoxic T-cell response and in vivo protection against tumor cells harboring activated ras proto-oncogenes.

BACKGROUND: Activated forms of the ras proto-oncogene have been found in approximately 30% of human malignancies, including pancreatic, colon, and lung adenocarcinomas. Ras oncoproteins arise by somatic mutation and contain amino acid changes at residues 12, 13, or 61, thus generating unique tumor-specific proteins that are attractive targets for cancer therapy. PURPOSE: The goal of this study was to determine whether vaccination with mutant Ras protein could lead to the generation of cytotoxic T lymphocytes (CTLs) specific for the mutant epitope and to protection against challenge with tumor cells expressing the mutant oncoprotein. METHODS: To determine a methodology for generating CTL responses following immunization with soluble protein, ovalbumin was used as a model tumor antigen. C57BL/6 mice were immunized with soluble ovalbumin administered intraperitoneally at 2-week intervals or with intravenous injection of ovalbumin or osmotically loaded splenocytes. Immunized mice were challenged with E.G7 cells (which express a transfected ovalbumin gene), and tumor growth was monitored. Generation of ovalbumin-specific CTLs was determined by 51Cr release assays. Purified wild-type or mutant H-Ras proteins (containing single amino acid substitutions at position 12 converting Gly to Arg or Val) were used to immunize BALB/c mice intraperitoneally. Ras-immunized mice were challenged with tumor cells containing Arg 12 or Val 12 mutations or not harboring mutant forms of Ras. Cytolytic and proliferative responses to mutant forms of Ras were studied, and the effects of in vivo depletion of CD4+ or CD8+ T lymphocytes were determined. RESULTS: In vivo challenge with E.G7 showed that intraperitoneal immunization with soluble ovalbumin was as effective as osmotic loading, resulting in long-term disease-free survival of some mice and the development of ovalbumin-specific CTLs. Immunization with Arg 12 Ras led to disease-free survival in nine of 10 animals challenged with tumor cells containing an Arg 12 mutation, while no protection was afforded against tumors expressing other forms of Ras or other oncogenes. Splenocytes from BALB/c mice immunized with Arg 12 Ras demonstrated cytolytic activity specific against tumor cells expressing Arg 12 Ras, with most of this activity residing in the CD8+ subset. Mutation-specific proliferation to Arg 12 Ras peptides was also observed. Immunization with Val 12 Ras did not elicit detectable Val 12-specific immunity. CONCLUSIONS: Antigen-specific CTLs can be induced following intraperitoneal immunization of mice with purified, soluble proteins. For both ovalbumin and Arg 12 Ras, specific in vivo protection against tumor cell challenge was observed.

Amino Acid Sequence↗
PubMed1993

Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells.

The human cytokine interferon-inducible protein 10 (IP-10) is a small glycoprotein secreted by activated T cells, monocytes, endothelial cells, and keratinocytes, and is structurally related to a family of chemotactic cytokines called chemokines. Although this protein is present in sites of delayed-type hypersensitivity reactions and lepromatous leprosy lesions, the biological activity of IP-10 remains unknown. We report here that recombinant human IP-10 stimulated significant in vitro chemotaxis of human peripheral blood monocytes but not neutrophils. Recombinant human IP-10 also stimulated chemotaxis of stimulated, but not unstimulated, human peripheral blood T lymphocytes. Phenotypic analysis of the stimulated T cell population responsive to IP-10 demonstrated that stimulated CD4+ and CD29+ T cells migrated in response to IP-10. This resembles the biological activity of the previously described T cell chemoattractant RANTES. Using an endothelial cell adhesion assay, we demonstrated that stimulated T cells pretreated with optimal doses of IP-10 exhibited a greatly enhanced ability to bind to an interleukin 1-treated endothelial cell monolayer. These results demonstrate that the IP-10 gene encodes for an inflammatory mediator that specifically stimulates the directional migration of T cells and monocytes as well as potentiates T cell adhesion to endothelium.

Antigens, CD↗
PubMed1993

Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta.

Recombinant human macrophage inflammatory protein-1 alpha (rhMIP-1 alpha) and rhMIP-1 beta were potent chemoattractants of human T lymphocytes. These rhMIP-1 cytokines attracted only T cells activated by monoclonal antibody to CD3 and did not attract unstimulated lymphocytes. Phenotypic analysis revealed that CD4+ T cells were capable of migrating in response to rhMIP-1 beta, whereas rhMIP-1 alpha induced chemotaxis of predominantly CD8+ T lymphocytes. Activated naïve and memory T cells also migrated in response to rhMIP-1 cytokines. Furthermore, these cytokines enhanced the ability of T cells to bind to an endothelial cell monolayer. These results suggest that rhMIP-1 cytokines preferentially recruit specific T cell subsets during the evolution of the immune response.

Adult↗
PubMed1992

Effect of isotypic and allotypic variations of MHC class II molecules on staphylococcal enterotoxin presentation to murine T cells.

Staphylococcal enterotoxins (SE) are known to be potent T cell activators, stimulating +/- proliferation and lymphokine production. These toxins have recently have been termed "superantigens" because of their ability to bind directly to class II molecules forming a ligand that interacts with particular V beta gene elements within the TCR complex. This interaction between SE and MHC class II molecules plays a central role in toxin-induced mitogenesis. In the present study we have examined the effect of polymorphism on the ability of MHC class II molecules to bind and present SE. Through the use of H-2 congenic mouse strains, it was possible to look directly at haplotype differences within the MHC and their effect on SE presentation to a panel of responsive V beta-bearing T cells. The results demonstrate that toxin presentation by class II-bearing accessory cells to murine T cells is greatly affected by polymorphisms within the H-2 complex. Toxin-pulsed accessory cells obtained from mice of an H-2k and H-2u haplotype were found to be less efficient in activating a variety of T cell clones and hybridomas. However, one T cell clone responded similarly to the enterotoxins presented on all H-2 haplotypes, suggesting that differences in responses of T cells are not simply a function of the degree of binding of these toxins to various class II molecules. Neutralization analysis with monoclonal anti-class II antibodies demonstrates that both I-A and I-E molecules play a significant role in SEA and SEB presentation to murine T cells. These results suggest that the differential activation of T cells by a particular enterotoxin may reflect a difference in recognition of an SE:class II ligand by a surface T cell receptor complex.

Alleles↗
PubMed1992

Direct activation of murine T cells by staphylococcal enterotoxins.

The capacity of staphylococcal enterotoxins to stimulate all T cells bearing certain TCR variable region alleles has generated a great deal of interest. This stimulation appears to involve specific binding of the toxin to class II molecules and subsequent stimulation of the T cell via the TCR V beta elements. Recent studies from our laboratory have focused on the ability of staphylococcal enterotoxins to directly activate purified lymph node T cells and a panel of T cell clones and hybridomas. A T cell costimulation assay was performed to assess cellular activation requirements and cytokine receptor expression. Activation of highly purified lymph node T cells by staphylococcal enterotoxin B (SEB) required costimulatory signals which could be provided by IL-1, IL-2, IL-4, or IL-6, whereas SEB alone demonstrated no significant proliferative response. Using a panel of TH1 and TH2 cell clones and T cell hybridomas possessing various responsive and nonresponsive V beta alleles, it was possible to demonstrate that SEA and SEB costimulate T cells via the TCR complex. Additionally, enterotoxin-pretreated T cells demonstrated a significant proliferative response upon exposure to class II-bearing accessory cells, suggesting that these toxins bind directly to T cells. Highly purified T cells cultured with both SEB and IL-1 exhibit significantly increased levels of IL-2 receptor, whereas cells cultured with SEB or IL-1 alone demonstrated low levels of this receptor. These results do not exclude an association of the staphylococcal enterotoxins with class II molecules in a manner which results in a high avidity binding to the TCR required for transduction of the appropriate activation signals. In the absence of class II molecules, however, these superantigens can still bind to T cells, and the activation signal is delivered in the presence of cytokines that trigger T cell growth and lymphokine production.

Animals↗
PubMed1991

Characterization of antigen-specific suppressor factors induced by staphylococcal enterotoxin B.

Previous studies from this laboratory have shown that staphylococcal enterotoxin B (SEB) has the capacity to nonspecifically induce multiple T suppressor cell populations which are capable of regulating both primary and secondary in vitro antibody responses. Additional studies have revealed that the suppressive activity of these cells is mediated, at least in part, by an I-J-restricted suppressor-inducer factor. Efforts to characterize the specificity of this inducer molecule have demonstrated the presence of multiple antigen-specific suppressor factors within SEB-stimulated supernatants. Antigen-binding molecules present within these SEB-induced factor preparations were isolated and concentrated over antigen-coupled columns. The results have demonstrated that eluates from trinitrophenyl-ovalbumin and trinitrophenyl-keyhole limpet hemocyanin-coupled columns significantly suppress both primary and secondary anti-TNP plaque-forming colony responses, whereas the filtrates from these columns demonstrated little to no inhibitory activity. The filtrates, but not eluates, from these columns exhibited significant suppressive activity for anti-poly(L-Phe,L-Glu)-poly-DL-Ala-poly-L-Lys, anti-azobenzenearsonate, and anti-sheep red blood cell antibody responses. Additional studies using eluates and filtrates from a variety of antigen-coated columns have demonstrated that suppressor factors of multiple antigenic specificities are present within SEB-induced supernatants. These studies suggest that SEB polyclonally activates antigen-specific suppressor cells which produce suppressor factors which specifically regulate the antibody response.

Animals↗
PubMed1991

Immunomodulatory activity of mu- and kappa-selective opioid agonists.

Opioids and opioid peptides have been shown by numerous laboratories to modulate various parameters of the immune response, but little attention has been given to the type of opioid receptor that might be involved. This study focuses on the in vitro influences of morphine and DAMGE (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol), mu-selective agonists, and U50,488H and U69,593, kappa-selective agonists, on the generation of antibody to sheep erythrocytes in vitro. It was found that the mu and kappa opioid agonists were able to inhibit the capacity of murine lymphoid cells to generate antibody at concentrations as low as 10(-10) M. The effects were almost completely blocked by pretreatment with naloxone or naltrexone, opioid-specific antagonists. Only the kappa-agonist activity was abrogated by pretreatment with norbinaltorphimine, a kappa-specific antagonist. The stereospecificity of the kappa effect was demonstrated using isomers of U50,488H, with the (-) form possessing significantly greater immunomodulatory activity. Additional studies, using a mu receptor-deficient mouse strain, demonstrated that only the kappa agonists were capable of suppressing antibody responses, whereas mu- and kappa-selective agonists suppressed the parent mu-responsive strain. Our results clearly indicate that mu and kappa opioid receptors are involved in regulation of lymphoid cell production of antibodies.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Characterization and genetic restriction of suppressor-effector cells induced by staphylococcal enterotoxin B.

The capacity of the staphylococcal enterotoxins to stimulate all T cells bearing certain (but not all) TCR has generated a great deal of interest. This stimulation appears to involve specific binding of the toxin to class II Ags and subsequent stimulation via the TCR. Previous studies from this laboratory have demonstrated that staphylococcal enterotoxin B (SEB) induces multiple T suppressor cell populations that inhibit both primary and secondary plaque-forming cell responses. Efforts to characterize these suppressor cell populations have demonstrated that the suppressor population active early in the antibody response expresses the Lyt-1-2+ cell surface phenotype, whereas depletion analysis suggests that the population active late in an ongoing response bears the Lyt-1+2+ cell-surface markers. In the present study, enrichment for this late acting effector population with the use of sequential panning with anti-Lyt mAb reveals significant suppressive activity at both the initiation and effector phases of a 5-day Mishell-Dutton coculture. Additional experiments using I-J disparate strains of mice have demonstrated a genetic restriction at the "I-J" gene locus between the cells mediating SEB-induced suppression and their target. Depletion of SEB-primed splenocytes with anti-I-J mAb suggests that both the early and late effector cells bear I-J molecules on their surface. Taken together, these results show that SEB induces suppressor cell populations with properties similar to those exhibited by Ag-specific cell circuits.

Animals↗
PubMed1990

Immunosuppressive activity of staphylococcal enterotoxin B. I. Characterization of staphylococcal enterotoxin-B-induced suppressor cells.

Staphylococcal enterotoxin B (SEB) binds specifically to major histocompatibility complex class II molecules on the surface of accessory cells and stimulates virtually all T cells bearing certain, but not all, T cell-receptor V beta alleles. We have previously shown that this superantigen is a potent inducer of multiple regulatory T cell populations. In the present report we show that SEB induces a population of suppressor T cells which inhibits the generation of alloantigen-induced cytotoxic T cell activity. Using both negative- and positive-selection analysis, we found that this suppressor population is a CD4- CD8- CD5+ IL-2R+ T cell. This cell population inhibited both syngeneic and allogeneic cytotoxic T lymphocyte activity, but the cell population which inhibited allogeneic CTL activity was radiation sensitive. In addition, allogeneic SEB-primed cells appeared to develop cytolytic activity as a result of the additional stimulation in the mixed-lymphocyte reaction culture. The relationship of the SEB-primed CD4- CD8- CD5+ T cells to related regulatory T cell populations is discussed.

Animals↗
PubMed1990

Immunosuppressive activity of staphylococcal enterotoxin B. II. Activation of suppressor-effector cells by a staphylococcal enterotoxin B-induced suppressor factor.

The capacity of staphylococcal enterotoxins to stimulate all T cells bearing certain T cell receptors has recently generated a great deal of interest. These toxins are believed to bind directly both to the TCR:CD4 complex via its V beta domains and to class II MHC molecules on accessory cells prior to T cell activation. Previous studies from this laboratory have demonstrated that staphylococcal enterotoxin B (SEB) is capable of inducing multiple T suppressor cell populations which can inhibit in vitro antibody responses. Additional studies have demonstrated that the suppressive activity of these cells is mediated, at least in part, by an I-J-restricted suppressor factor. Efforts to characterize the inhibitory activity of this factor have demonstrated that the suppressive element is capable of activating both early and late acting suppressor cell populations in vitro. Analysis by both positive and negative selection shows that cells bearing the Lyt1-2+ surface marker phenotype are active early, whereas Lyt1+2+ cells are active both early and late in the antibody response. Additional experiments using various strains of mice as sources of suppressor factor and of naive splenocyte populations have demonstrated that activation of suppressor-effector cells by this suppressor factor is restricted at the I-J, but not Igh, gene locus. These studies suggest that this SEB-induced suppressor factor alone provides the signals necessary for the induction and activation of suppressor-effector cell activity.

Animals↗
PubMed1990

Immunomodulatory activity of kappa-, mu-, and delta-selective opioid compounds.

1. Morphine, DAMGE and U50,488H each inhibit the in vitro proliferative response of murine splenocytes to the mitogenic agents PMA or SEB. The kappa agonist U50,488H is much more potent than either of the mu-receptor agonists. The immunosuppressive activity of U50,488H is reversed by the opioid antagonists naloxone or norBNI. On the other hand, the immunomodulatory activity of morphine is reversed only by naloxone. 2. The mu-receptor agonists morphine and DAMGE also inhibit the development of an antibody response in vitro. Much more potent inhibitory activity was also observed for the kappa agonists U50,488H and U69,593. The delta agonist DPDPE failed to exert measurable immunomodulatory activity under these experimental conditions. 3. The immunosuppressive activity of the kappa agonists was reversed by both naloxone and norBNI. In addition, the activity of these opioid compounds exhibited stereospecificity. 4. Strain analysis has revealed the existence of two groups of mouse strains. The relatively sensitive mouse strains appear to include the BALB/c, C57BL/6 and B10.A(5R) strains. Four relatively less sensitive strains have also been identified. 5. Immunomodulatory activity has been detected for the kappa-selective agonists in the mu receptor-deficient strain CxBK/ByJ. Both mu and delta agonists fail to exert immunosuppressive activity in this mouse strain.

Adjuvants, Immunologic↗