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Biomedical subjects

T Hamaoka

Publications and source records attributed to T Hamaoka.

At least 199 records · Page 11Linked to original sources
PubMed1988

Immunologic abnormality in NZB/NZW F1 mice. Thymus-independent occurrence of B cell abnormality and requirement for T cells in the development of autoimmune disease, as evidenced by an analysis of the athymic nude individuals.

Both NZB nu/+ and NZW nu/+ mice were microbially clean by cesarean section. The (NZB x NZW)F1 hybrid (NZB/W) nu/nu mice and nu/+ littermates were then generated by mating of NZB nu/+ with NZW nu/+mice under specific pathogen-free conditions. The female NZB/W F1 nu/nu mice did not develop autoimmune kidney disease, whereas all of nu/+ female littermates mice exhibited proteinuria and died of renal failure with a 50% survival time of 35 wk. Namely, nude mice had no signs of proteinuria up to the time of their death caused by other diseases rather than glomerulonephritis, and their mean survival time was greater than 45 wk. Nude mice had also no anti-ssDNA antibody in their serum. However, splenic B cells of NZB/W nude mice exhibited hyper-responsiveness to both LPS and B151-TRF2, a T cell-derived polyclonal B cell-stimulation factor, and produced large numbers of Ig-secreting cells and anti-TNP plaque-forming cells as well as anti-ssDNA antibody comparable to the nu/+ littermate mice. Interestingly, thymus-engrafted NZB/W nude mice developed autoimmune disease exemplified by the induction of anti-ssDNA antibody and proteinuria at approximately the same time as their nu/+ littermates. These results indicate that the B cell hyper-responsiveness found in NZB/W mice is apparently determined by the T cell-independent process, and T cells are obligatorily required for the development of autoimmune disease in NZB/W mice.

Animals↗
PubMed1988

Type II collagen-induced murine arthritis. I. Induction and perpetuation of arthritis require synergy between humoral and cell-mediated immunity.

Immunization of DBA/1 mice with type II collagen resulted in typical and progressive arthritis, which is associated with the production of high titer of anti-collagen antibody and the induction of cell-mediated immunity as exemplified by delayed type hypersensitivity response as well as lymphokine production. In contrast, administration of heat-denatured collagen into DBA/1 mice failed to induce the arthritis. These mice produced only marginal antibody, whereas they developed comparable cell-mediated immunity to that induced by immunization with native collagen, and therefore the inoculation of heat-denatured collagen provided the regimen capable of inducing preferentially cell-mediated immunity without the generation of high level of antibody. Inasmuch as administration of antibody induced only marginal and transient joint swelling not associated with typical histologic lesion, the synergistic effect of humoral and cell-mediated immunities was investigated using antibody preparation and the regimen to induce selectively cell-mediated immunity. The results demonstrate that administration of antibody into DBA/1 mice pre-sensitized with heat-denatured collagen resulted in potent and progressive arthritis. Such synergy was further confirmed by the induction of arthritis in T cell-depleted DBA/1 mice that had been adoptively transferred with antibody and lymphoid cells from heat-denatured collagen-sensitized mice. Moreover, it was revealed that the nature of cells capable of transferring cell-mediated immunity was of Thy-1+ and L3T4+ Lyt-2-. These results indicate that anti-collagen antibody and L3T4+ T cell-mediated cellular immunity are crucially required for the perpetuated development of type II collagen-induced arthritis.

Animals↗
PubMed1988

Studies on the induction of tolerance to alloantigens. III. Induction of antibodies directed against alloantigen-specific delayed-type hypersensitivity T cells by a single injection of allogeneic lymphocytes via portal venous route.

BALB/c mice were inoculated with normal C3H/He spleen cells via the portal venous (p.v.) route. Intravenous injection of serum from these BALB/c mice into naive syngeneic mice resulted in almost complete abrogation of their ability to generate anti-C3H/He delayed-type hypersensitivity (DTH) responses as induced by s.c. immunization with C3H/He cells. Since a portion of the same serum did not inhibit the development of anti-C57BL/6 DTH responses, the suppressive effect of the transferred serum was alloantigen-specific. Such serum factor(s) was produced in normal but not in nude mice and the suppressive activity was transferred in H-2- or immunoglobulin allotype-incompatible combinations. Immunochemical analyses of this serum suppressive factor have revealed that its m.w. was approximately 150,000, corresponding to the size of immunoglobulin (Ig)G, and that the activity was trapped by protein A or by an anti-immunoglobulin column. Although the absorption of the serum from anti-C3H/He-tolerant BALB/c mice with C3H/He target spleen cells did not abrogate the suppressive activity, the additional absorption with spleen cells from anti-C3H/He hyperimmune BALB/c mice almost completely eliminated the suppressive potential. Moreover, pretreatment of BALB/c anti-C3H/He DTH effector spleen cells with the above serum from tolerant mice induced the inhibition of anti-C3H/He DTH responses. Taken together, these results indicate that a single injection of allogeneic cells via the p.v. route results in the production of antibody capable of inhibiting the capacity of DTH effector cells specific for alloantigens used for the p.v. presensitization.

Animals↗
PubMed1988

Thymic stroma-derived T-cell growth factor (TSTGF): II. Biochemical and functional characterization.

The culture supernatant (SN) from a cloned line of thymic stroma-derived cells in fibroblastic form (TSCF) contained a factor capable of supporting the growth of the interleukin (IL) 2-dependent, antigen-specific helper T cell (Th) clone 9-16 without requiring IL2 and antigen. This active substance, designated as thymic stroma-derived T-cell growth factor (TSTGF), was partially purified through DEAE-Sephacel chromatography and PBE 94 chromatofocusing. The original SN did not contain IL1, IL2, IL3, IL4, or interferon activities; but an appreciable magnitude of colony-stimulating factor (CSF) activity in addition to TSTGF was present, whereas the partially purified preparation of TSTGF was depleted of any type of CSF activity. The elution profile of TSTGF activity on the chromatofocusing has revealed that TSTGF has an isoelectric point (pI) of about 6.0. When a purified TSTGF sample was applied to Sephacryl S-200 column chromatography and sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, TSTGF activity was eluted in a single peak around an apparent molecular weight of about 25,000. The activity of TSTGF also was shown to be relatively stable with heat treatment and in the wide range of pH, but it was abolished by treatment with either trypsin or dithiothreitol. These results indicate that TSTGF, a novel T-cell growth factor, is the protein that has an apparent molecular weight of about 25,000 and a pI of 6.0, and in the intact molecule, it contains the disulfide bond(s) required to maintain and/or express its biologic activity.

Biological Products↗
PubMed1988

Helper strategy in tumor immunology: expansion of helper lymphocytes and utilization of helper lymphokines for experimental and clinical immunotherapy.

Two main kinds of immune strategy are possible against neoplasia. The first potentiates a selected effector arm. In vitro culture with exogenous interleukin-2 (IL-2) increases the activity of natural killer cells and leads to the expansion of T cytotoxic lymphocytes. Systemic reinfusion of both of these cells with high doses of IL-2 mediates the regression of a variety of murine and human tumors. In an alternative strategy, a few regulatory lymphocytes turn on immune reactivity by triggering a cascade of interconnected effector functions. The efficacy of this strategy rests on the repertoire of effector mechanisms moved to action. An effective immunoregulatory maneuver is the addition of helper determinants on the surface of tumor cells. Its power can be further increased by the pre-induction of helper T lymphocytes specific to the helper determinants. This approach can be achieved in mice by coupling muramyl dipeptides to tumor cells, along with eliciting T lymphocytes specifically reactive to Bacillus Calmette-Guerin. Noncytotoxic T helper lymphocytes produce factors which recruit nonspecific (macrophages) as well as specific (cytolytic T lymphocytes) anti-tumor attacking cells. In this way protection can be afforded against primary tumors and metastases, as well as leukemia cells. As the activity of helper lymphocytes rests mostly on lymphokine release, the use of molecularly defined lymphokines mimicking T-helper functions has also been attempted. In a few experimental models, the association of low doses of IL-2 with non-reactive lymphocytes from tumor-bearing mice promotes an effective anti-tumor reaction in the host. Moreover, the combination of distinct lymphokines can also build a molecularly defined helper system able to activate in sequence non-specific and specific anti-tumor reactions in vivo. Trials intended to evaluate the clinical impact of these helper approaches in the management of human tumors are being started or are already under way.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

The augmentation of tumor-specific immunity using haptenic muramyl dipeptide (MDP) derivatives. III. Eradication of disseminated murine chronic leukemia cells by utilizing MDP hapten-reactive helper T-cell activity.

A previous paper has demonstrated that enhanced tumor-specific immunity could be induced by priming mice with Bacillus Calmette Guerin (BCG) and subsequently immunizing them with syngeneic tumor cells modified with BCG-cross-reactive muramyl dipeptide (MDP) hapten. The present study establishes a tumor-specific immunotherapy protocol for a murine chronic leukemia based on the above T-T cell collaboration between antitumor effector T cells and anti-MDP hapten helper T cells induced by BCG priming. BALB/c mice which had been primed to BCG were injected intravenously (i.v.) with viable, syngeneic BCL1 leukemia cells. One week later, these mice were immunized intraperitoneally (i.p.) with unmodified or MDP hapten-modified, 10,000 R X-irradiated BCL1 cells, followed by 4 booster immunizations at 5-day intervals. The administration of unmodified BCL1 tumor cells into BCG-primed mice failed to prevent them from tumor death due to the persistent growth of preinjected BCL1 cells. In contrast, the immunization of BCG-primed, BCL1 leukemia-cell-bearing mice with MDP-modified BCL1 cells resulted in a high growth inhibition of leukemia cells and protection of these mice from death by leukemia. It was also revealed that potent tumor-specific, T-cell-mediated immunity was generated in mice which survived in this immunotherapy model. Thus, these results indicate that administration of MDP hapten-modified, syngeneic leukemia cells into leukemia-bearing mice which have been primed with BCG results in potent tumor-specific, T-cell-mediated immunity attributable to preventing the growth of disseminated leukemic cells.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

The mode of recognition of tumor antigens by noncytolytic-type antitumor T cells: role of antigen-presenting cells and their surface class I and class II H-2 molecules.

The present study investigated the role of antigen-presenting cells (APC) in the activation of noncytolytic T cells against tumor antigens. The noncytolytic-type T cells exerted their antitumor effect by producing gamma-interferon (IFN-gamma) and by activating macrophages as the ultimate effectors. The production of IFN-gamma by these noncytolytic T cells following the stimulation with tumor cells required the participation of Ia+ APC, since the depletion of APC from cultures of tumor-immunized spleen cells resulted in almost complete inhibition of the IFN-gamma production. Both L3T4+ and Lyt-2+ subsets of T cells were capable of producing IFN-gamma, and the requirement of APC for the production of IFN-gamma was the case irrespective of whether noncytolytic T cells were of L3T4+ or Lyt-2+ phenotype. More importantly, it was demonstrated that the production of IFN-gamma by L3T4+ and Lyt-2+ T cells was inhibited by addition of the respective anti-class II and anti-class I H-2 antibody to cultures. These results indicate that antitumor L3T4+ or Lyt-2+ noncytolytic T cells are activated for the IFN-gamma production by recognizing tumor antigens in the context of self-class II or -class I H-2 molecules on APC.

Animals↗
PubMed1988

Meal-stimulated cholecystokinin release and exocrine pancreatic secretion in dogs.

To confirm the role of cholecystokinin (CCK) and secretin in digestion, exocrine pancreatic secretion, plasma CCK, and secretin were measured simultaneously in six dogs prepared with gastric and pancreatic fistulas after feeding a solid meal. Plasma CCK concentration determined by radioimmunoassay increased significantly from the basal level, reached a peak 35 min after meal ingestion, and after a dip it further increased toward the end of the 3-h observation. Pancreatic protein output increased significantly, peaked at the fifth 10-min period, and then declined progressively. Plasma CCK concentration and pancreatic protein output correlated significantly during the first postprandial hour. Plasma secretion demonstrated significant elevation at 15 min and a peak at 25 min after a meal. Plasma secretin correlated significantly with both bicarbonate output and flow rate during the 3 h. Simultaneous measurements of plasma CCK and secretin and of pancreatic secretion suggested that postprandial pancreatic secretion is primarily mediated by releases of CCK and secretin, but these hormones do not seem to be the only factors responsible for the secretion.

Animals↗
PubMed1988

Immunoblotting analysis of antibody response in swine experimentally inoculated with Mycoplasma hyopneumoniae.

Serological cross-reactivity among swine mycoplasmas, and porcine antibody response to Mycoplasma hyopneumoniae antigens during experimental infection were investigated by enzyme-linked immunosorbent assay (ELISA) and the immunoblotting technique. Mycoplasmas solubilized with Tween 20 were used as antigen. Cross-reactivity between M. hyopneumoniae and M. flocculare was indicated by ELISA and it was demonstrated by immunoblotting, which revealed that the predominant cross-reactive antigens were components of M. hyopneumoniae with molecular weights of 74,000 (74 K) and 53 K. Further, it was indicated that 96 K, 70 K, 46 K and 38 K antigenic components of M. hyopneumoniae and 67 K, 56 K and 23 K antigens of M. flocculare were specific for the respective species. Antibodies to 96 K, 76 K, 70 K, 53 K, 46 K and 38 K antigens were detected in serum from pigs experimentally infected with M. hyopneumoniae. Of these antibodies, those against the 46 K antigen reacted early and were most consistently detected during experimental infection. Therefore, the antibodies against the 46 K antigen of M. hyopneumoniae proved to be excellent markers of mycoplasmal pneumonia of swine.

Animals↗
PubMed1988

Gastrin-releasing peptide stimulates cholecystokinin secretion in perfused rat duodenum.

We examined the effect of porcine gastrin-releasing peptide (GRP-27) and other analogous neuropeptides on cholecystokinin (CCK) secretion from the isolated perfused rat duodenum. GRP-27 stimulated CCK secretion in a monophasic pattern and in a dose-dependent manner ranging from 10(-9) M to 10(-6) M, and 10(-7) M of GRP-27 led to an increment of 442 +/- 120.8 fmol/3 min. The stimulatory effect of GRP-27 on CCK was not inhibited by 10(-5) M of atropine. 10(-7) M of neuromedin C and B, analogs of GRP, stimulated CCK secretion to increments of 382 +/- 64.1 and 289 +/- 47.2 fmol/3 min, respectively. Carbachol (10(-9) to 10(-6) M), VIP (10(-9)M), secretin (10(-9)M) and glucose (11 mM) did not stimulate CCK secretion, and the addition of atropine (10(-5)M) to them led to no significant changes. These results suggest that GRP may directly stimulate CCK secretion from the duodenum and work as a non-cholinergic, peptidergic neurotransmitter.

Animals↗
PubMed1988

Plasmid-mediated serum resistance and alterations in the composition of lipopolysaccharides in Salmonella dublin.

Survival rates of Salmonella dublin in rabbit serum after culture for 1 h at 37 degrees C were compared between a wild-type strain (5240) carrying a 50 MDa plasmid, a plasmid-cured strain (C524), and a cured strain containing the 50 MDa plasmid tagged with Tn1 (5241). Strain C524 was more susceptible to the bactericidal activity of normal serum than its parent strain 5240 (percentage survival less than 1% and 52.5 +/- 9.2%, respectively). On the other hand, the percentage survival of strain 5241 was significantly increased (90.4 +/- 4.0%), indicating that the reintroduction of the plasmid into the cured strain restored the serum resistance. Moreover, this change in the serum resistance properties correlated with changes in the neutral sugar composition of the lipopolysaccharides (LPS) of these strains, suggesting that the 50 MDa plasmid is necessary for O-side chain expression in the LPS of S. dublin.

Animals↗
PubMed1988

Tolerance induction of alloreactivity by portal venous inoculation with allogeneic cells followed by the injection of cyclophosphamide. II. Cellular and molecular mechanisms underlying tolerance.

BALB/c mice receiving allogeneic C3H/He or C57BL/6 spleen cells via portal venous (p.v.) route or a single administration of cyclophosphamide (Cy) were capable of rejecting the respective allogeneic C3H/He- or C57BL/6-derived tumor cells. In contrast, the combined treatment of p.v. inoculation with allogeneic lymphocytes and Cy administration abrogated the capability of rejecting allogeneic tumor cells. Such abrogation of alloreactivity was alloantigen-specific and associated with the suppression of potentials to generate delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) responses to alloantigens. This was further substantiated by the inhibition of molecular mechanisms underlying anti-allo-DTH and -CTL responses. Thus, the above combined treatment led to the decreased production of lymphokines such as macrophage-activating factor (MAF) and interleukin 2 (IL2) following the stimulation with the relevant alloantigens. These results demonstrate that p.v. inoculation of allogeneic cells followed by a single administration of Cy results in the effective elimination of alloreactivity as verified by the suppression of cellular and molecular mechanisms of alloreactive responses.

Animals↗
PubMed1988

Mediation of in vivo tumor-neutralizing activity by Lyt-2+ as well as L3T4+ T cell subsets.

The present study reexamines the cell surface nature of T cells mediating in vivo protective tumor immunity with the use of anti-L3T4 and -Lyt-2 antibodies. C3H/HeN mice hyperimmune against syngeneic MH134 hepatoma or MCH-l-Al fibrosarcoma were prepared by intradermal (id) inoculation of viable tumor cells followed by surgical resection of the tumor and by repeated challenges with viable tumor cells. Spleen cells from these mice were fractionated into L3T4+ or Lyt-2+ T cell subset by treatment with anti-Lyt-2 or -L3T4 antibody plus complement (C). Winn assays performed by utilizing such fractionated T cells have revealed that both L3T4+ and Lyt-2+ T cell subsets from hyperimmune mice produced complete tumor protection. Flow microfluorometry study illustrated that the treatment with anti-L3T4 or -Lyt-2 antibody plus C resulted in the complete isolation of L3T4- Lyt-2+ (Lyt-2+) or L3T4+ Lyt-2- (L3T4+) T cell subset, respectively. This contrasted with the failure of treatment with anti-Lyt-1 antibody plus C to isolate all T cells expressing Lyt-2 marker. It was further demonstrated that each subset of T cells exerted its anti-tumor effect in a tumor-specific way and without a requirement for the other alternative subpopulation of unprimed T cells. These results indicate that Lyt-2+ T cell subset can be successfully isolated by treatment with anti-L3T4 but not with anti-Lyt-1 antibody plus C, and that each single subset of Lyt-2+ and L3T4+ T cells can function as in vivo effector T cells.

Animals↗
PubMed1988

Mechanisms for recognition of tumor antigens and mediation of anti-tumor effect by noncytolytic Lyt-2+ T cell subset.

The mode of anti-tumor function in vivo of noncytolytic Lyt-2+ T cells from C3H/He mice hyperimmune to syngeneic MH134 hepatoma was investigated in a double diffusion chamber system which was recently established in our laboratory. C3H/He mice were implanted intraperitoneally with the double diffusion chamber unit in which each chamber contained either L3T4+ T cell-depleted MH134-hyperimmune spleen cells plus mitomycin C-treated MH134 tumor cells or other syngeneic X5563 viable tumor cells plus normal spleen cells as a source of macrophages. Inclusion of anti-MH134 Lyt-2+ T cells together with MH134 tumor cells in one chamber resulted in comparable growth inhibition of viable X5563 tumor cells in the other chamber to that obtained by unfractionated MH134-hyperimmune spleen cells. The induction in the Lyt-2+ T cell-containing chamber of anti-tumor effect to be delivered into the other chamber was dependent on the co-existence of Ia-positive adherent cells along with Lyt-2+ T cells. Although adherent cell-depleted Lyt-2+ T cells regained the inducibility of anti-tumor immunity when supplemented with splenic adherent cells, the addition of adherent cells pretreated with chloroquine failed to restore the ability of Lyt-2+ T cells to induce their anti-tumor effect. In addition, paraformaldehyde-treated MH134 tumor cells instead of untreated tumor cells were not capable of activating Lyt-2+ T cells. These results indicate that a portion of Lyt-2+ T cells exerts their anti-tumor effect by a mechanism distinct from direct tumor cell lysis and that their activation for mediation of this type of tumor immunity requires the recognition of tumor antigens processed and presented by Ia-positive adherent cells.

Animals↗
PubMed1988

Selective suppression of the generation of anti-tumor L3T4+ but not of Lyt-2+ T cell-mediated immunity in the tumor-bearing state.

C3H/He mice hyperimmune against syngeneic MH134 hepatoma were prepared by intradermal (id) inoculation of viable tumor cells followed by surgical resection of the tumor and by repeated id challenges with viable tumor cells. Winn assays performed utilizing spleen cells from these mice have revealed that both Lyt-2+ and L3T4+ T cell subsets from MH134-hyperimmune mice produced complete tumor protection. The in vivo tumor-neutralizing activity was also found in spleen cells from tumor-bearing mice at various times after id implantation of MH134 tumor cells. However, in contrast to comparable tumor-neutralization by Lyt-2+ and L3T4+ T subsets from hyperimmune mice, only the Lyt-2+ T cell subset from tumor-bearing mice was capable of mediating the in vivo protective immunity. L3T4+ T cell-mediated immunity was not detectable in the tumor-bearing state irrespective of the length of the sensitization period with a primary growing tumor, but emerged in the mice which resisted the first tumor challenge after the resection of the primary tumor. These results indicate that the emergence of L3T4+ T cell-mediated anti-tumor immunity is stage-dependent and the Lyt-2+ T cells represent the main functional subset in the tumor-bearing state, although both subsets of T cells are potentially capable of effecting anti-tumor in vivo immunity. The results are discussed in relation to the selective suppression of the L3T4+ but not of Lyt-2+ T cell function in the tumor-bearing state.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Separation of the tumor rejection antigen of Rous sarcoma virus-induced murine fibrosarcoma.

The tumor antigen capable of inducing tumor resistance (tumor rejection antigen; TRA) was separated and some of its physicochemical properties were characterized. Cytosol and plasma membrane fractions were separated from Rous sarcoma virus (RSV)-induced CSA1M tumor cells. Immunization with membrane but not cytosol fraction of these tumor cells together with complete Freund's adjuvant resulted in complete protection against subsequent challenge with viable CSA1M cells. The TRA activity contained in the membrane fraction was recovered in the sodium dodecyl sulfate (SDS)-solubilized fraction after the SDS-extraction of CSA1M membranes. This CSA1M SDS-solubilized preparation gave protection against syngeneic RSV-induced CSA9F tumor cells as well as the homologous tumor cell type, but failed to induce resistance to RSV-unrelated tumor cells. The membrane or SDS-solubilized fraction from RSV-unrelated tumor cells was unable to generate anti-CSA1M protective immunity. Physicochemical analyses have demonstrated that TRA activity in the SDS-solubilized fraction was completely abolished by treatment with proteinase K but was only marginally affected after treatment with glycosidase mixture. When the SDS-solubilized preparation was applied to a Sephacryl S-300 superfine column, TRA activity was recovered in the range of molecular weight of 50-90 kD. Further fractionation of this TRA-positive fraction by SDS-polyacrylamide gel electrophoresis revealed that the molecular size of TRA is 56-68 kD. These results indicate that membrane proteins which were isolated from CSA1M tumor cells and have a molecular size of about 60 kD are capable of inducing RSV-induced tumor-specific in vivo protective immunity.

Animals↗