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Biomedical subjects

K Inaba

Publications and source records attributed to K Inaba.

At least 91 records · Page 5Linked to original sources
PubMed1988

Immunological abnormalities in human interleukin-2 or interleukin-2/interleukin-2 receptor L chain transgenic mice.

We constructed two strains of transgenic mice that carry the cDNA of either human interleukin-2 (IL-2) or the L chain of its receptor under the control of the H-2Kd promoter. The IL-2 transgenic mice expressed human IL-2 mRNA in the thymus, spleen, bone marrow, lung, muscle, and skin. Human IL-2 protein was also detected in their sera. The IL-2 transgenic mice suffered from dermatitis and pneumonia. Immune responses of their spleen cells against antigens were significantly impaired whereas their spleen cells responded well to polyclonal lymphocyte activators, suggesting that constitutive expression of IL-2 might have affected the repertoire formation of T cells in the mice. The IL-2 receptor (IL-2R) transgenic mice were healthy. We crossed the IL-2 and IL-2R transgenic mice to yield hybrid mice expressing both the ligand and the receptor constitutively. The life span of the hybrid mice was remarkably shortened. In addition to several abnormalities found in the IL-2 transgenic mice, spleen cells of the hybrid mice showed the strong natural killer activity which was ascribed to a large number (18%) of Thy-1+/CD3-cells unique to their spleen.

Animals↗
PubMed1987

Role of macrophages as modulators but not as autonomous accessory cells in the proliferative response of immune T cells to soluble antigen.

The role of murine macrophages (M phi) and that of splenic dendritic cells (DC) were investigated in the antigen-specific proliferative response of memory T cells of mice primed with key-hole limpet hemocyanin (KLH) 6 weeks or more before. Peritoneal M phi, whether expressing Ia antigens or not, did not function as autonomous accessory cells (A cells). A-cell activity of the spleen adherent cell population, which comprised M phi in the majority and DC in the minority, was abolished by eliminating DC with a DC-specific monoclonal antibody and complement, and regained by the addition of a small number of DC. Though M phi did not function as autonomous A cells, they augmented the proliferative response in the presence of a small number of DC. This occurred not only in the presence of free antigen, but also when DC and/or M phi were pulsed with antigen. A culture supernatant of M phi having interleukin-1 activity was effective in enhancing the proliferation of T cells which responded to antigen-pulsed DC. On the other hand, interleukin-2 did not replace DC even in the presence of antigen-pulsed Ia+ M phi. We also investigated recently primed T cells, but no evidence was obtained in favor of the competence of M phi as autonomous A cells.

Animals↗
PubMed1987

Direct activation of CD8+ cytotoxic T lymphocytes by dendritic cells.

Recent experiments (11-13) have shown that antigen-specific, CD8+, CD4- T lymphocytes can be induced to proliferate and become killer cells in the absence of a second population of "helper" CD8-, CD4+ cells. We have studied early events in the activation of CD4+ and CD8+ T cell subsets in the primary mixed leukocyte reaction. Dendritic cells are a major if not essential accessory cell for the activation of both subpopulations. Antigen-bearing macrophages fail to stimulate unprimed CD8+ cells, but act as targets for the sensitized cytolytic lymphocytes that are induced by dendritic cells. The initial proliferative response is comparable for CD4+ and CD8+ lymphocyte subsets. For both subpopulations, dendritic cells efficiently cluster the responding lymphocytes on the first day and induce the release of IL-2. The data indicate that CD4+ and CD8+ lymphocytes can be activated by a similar mechanism, and illustrate the special role of dendritic cells in the sensitization stage of cell-mediated immunity.

Animals↗
PubMed1987

Monoclonal antibodies to LFA-1 and to CD4 inhibit the mixed leukocyte reaction after the antigen-dependent clustering of dendritic cells and T lymphocytes.

T cell proliferation in response to many stimuli is known to occur in discrete clusters of dendritic cells (DC) and CD4+ helper lymphocytes. The role of lymphocyte function-associated antigen (LFA-1) and CD4 in the formation and function of these clusters has been evaluated in the mixed leukocyte reaction (MLR). By day 1 of the control MLR, most of the DC and responsive T cells are associated in discrete aggregates. Addition of anti-LFA-1 and CD4 reagents does not block DC-T aggregation but reduces the subsequent proliferative response by 80-90%. Anti-LFA-1 disassembles newly formed DC-T cell aggregates, whereas anti-CD4 inhibits blastogenesis without disrupting the cluster. Binding of DC to sensitized, antigen-specific CD4+ cells has been studied using lymphoblasts isolated at day 4 of the MLR. It has been shown previously that greater than 80% blasts rebind to DC in an antigen-specific fashion in rapid (10 min) binding assays. Antigen-dependent DC-T binding is blocked by anti-Ia but not by mAb to LFA-1 or CD4. However, the bound anti-CD4-coated lymphocytes are unable to release IL-2. Anti-LFA-1-coated T cells release IL-2 but are easily disaggregated after binding to DC. These findings lead to two conclusions. LFA-1 and CD4 are not involved in the initial steps whereby DC bind to T cells but exert an independent and subsequent role. LFA-1 acts to stabilize the DC-T cluster, while CD4 contributes to lymphocyte blastogenesis and IL-2 release. Because DC but not other presenting cells cluster unprimed lymphocytes, it seems likely that an antigen-independent mechanism distinct from LFA-1 and CD4 mediates aggregate formation at the onset of cell-mediated immunity.

Animals↗
PubMed1987

Dendritic and B-cell function during antibody responses in normal and immunodeficient (xid) mouse spleen cultures.

Dendritic cells (DC) act as accessory cells for T-dependent antibody responses in two ways. One is to induce a class of stimulating factors (BSF) which allow B lymphocytes to respond to heterologous red cells as antigen. xid DC induce the production of these BSF, but xid B cells totally lack responsiveness. A second mechanism of DC function applies to red cell and haptenated-protein antigens. Here DC, helper T lymphocytes, and antigen-specific B cells interact in discrete clusters. Then the B cells become responsive to BSF. xid DC are fully active in this pathway, and xid B cells develop significant (10-20% of control) responses. This partial reduction in xid B-cell function could be due to the poor viability of xid lymphocytes in vitro. There is a comparable reduction in xid polyclonal responses to alloreactive helper T blasts. The other severe deficit in xid involves antibody formation to haptens on polysaccharide carriers. This response in normal mice is not influenced by DC or by BSF. The only similarity between DNP-Ficoll and RBC plus BSF responses is that both utilize B lymphocytes that do not associate with DC-T clusters, even though helper cells for DNP-Ficoll and for RBC are present in the culture. We conclude that DC function is not altered in xid. The main deficit seems to be in a B-cell activation pathway that is shared by polysaccharide carriers and some but not all BSF, and/or in a B-cell subpopulation that does not interact with carrier-specific helper cells. We speculate that this B-cell alteration primarily involves the Ig delta-poor marginal zone subpopulation of splenic B lymphocytes.

Animals↗
PubMed1987

Interleukin 1 enhances T-dependent immune responses by amplifying the function of dendritic cells.

The function of exogenous murine recombinant IL-1 alpha as a T lymphocyte-activating molecule was examined. IL-1 did not induce IL-2 release or responsiveness in purified T cells regardless of their state of activation: unprimed lymphocytes, freshly sensitized lymphocytes, or memory cells derived from the blasts. Nor did IL-1 synergize with mitogens, or with antigens, to stimulate proliferation. For example the combinations of IL-1 plus Ia+ peritoneal macrophages, or IL-1 plus Con A, were less than 5% as effective in triggering T cell growth as a low dose (1%) of dendritic cells. However, when IL-1 was added at the onset of culture, the response to limiting doses of dendritic cells was increased 3- to 10-fold in several systems: the syngeneic and allogeneic MLR, Con A- and periodate-induced polyclonal mitogenesis, and T-dependent antibody formation against foreign red cells. The amplifying effect of IL-1 could be obtained if the dendritic cells but not the responding lymphocytes were exposed to IL-1 before use as accessory cells. Optimal activation of dendritic cells required a dose of 5 U/ml (50 pM) and 18 h of exposure, and was not due to carryover of IL-1 into the lymphocyte culture. IL-2, IL-3, and cachectin/TNF did not amplify dendritic cell function, while IFN-gamma diminished it. The enhanced function of IL-1-treated dendritic cells was due to an enhanced clustering with helper T lymphocytes in the first day of the MLR response. Therefore IL-1 does not seem to act as an activating factor for most peripheral T lymphocytes. Instead, IL-1 enhances the function of accessory dendritic cells and represents the first molecule that has been shown to enhance the immune response at this critical level.

Animals↗
PubMed1987

Inhibitory mechanism of the proliferative response of B lymphocytes: suppression of the proliferation induced by anti-mu antibody and BSF1 by immune complexes.

We studied the effect of immune complexes (IC) on the responses of polyclonally activated murine B cells. For this, normal resting B cells were stimulated with the F(ab')2 fraction of goat anti-mouse mu-chain antibody and B-cell stimulating factor 1 (BSF1) after preculturing them with IC. Next, the relative membrane potential changes and the subsequent proliferative response were analysed. IC, particularly in antibody excess, inhibited both membrane depolarization and while those in antigen excess did poorly. Neither antigen nor antibody alone was effective. Inhibition was mediated via binding of IC to FcR gamma on B cells in a dose-dependent manner. Kinetic experiments showed that at least 6 hr was necessary for inducing the suppression of B-cell responses after binding of IC. We conclude that IC bound to FcR gamma on B cells regulates B-cell responses by acting on the initial step of activation.

Animals↗
PubMed1987

Accessory cell functions of dendritic cells and macrophages in the thymic T-cell response to Con A.

Accessory cell (A cell) functions of splenic dendritic cells (DC) and peritoneal macrophages (M phi) were investigated in the Con A-stimulated proliferative response of thymic T cells. DC were more efficient as A cells than M phi in respect of their necessary cell numbers, Con A dose and culture period required for optimal response. Con A-pulsed T cells proliferated with the aid of lymphocyte activating factor(s) (LAF) derived from M phi, even in the apparent absence of A cells. Con A-pulsed M phi were superior to unpulsed M phi in the secretion of LAF to induce a high response of Con A-pulsed T cells. A cell activity of M phi in different preparations appeared to parallel the ability to secrete LAF, and was totally abolished by fixation of M phi with paraformaldehyde. The fixation of DC, however, resulted in only a partial reduction of the A cell activity. These results argue that both DC and M phi can serve as A cells in the T-cell response to Con A, but that the mechanism to manifest A cell activity is somewhat different between DC and M phi.

Animals↗
PubMed1986

Immunologic properties of purified epidermal Langerhans cells. Distinct requirements for stimulation of unprimed and sensitized T lymphocytes.

Langerhans cells (LC) are Ia+ leukocytes that account for less than 2% of the cells in murine epidermal isolates. We purified LC by cell sorting to study their capacity to stimulate antigen-specific responses from unprimed and sensitized T cells. Sorting was performed after 12 or 72 h of epidermal culture, since our earlier work had indicated that LC became immunologically active during that time interval. At 12 and 72 h, the LC were uniformly and equally rich in the Ia glycoproteins that are recognized by helper T cells. At both time points, LC were comparable in their capacity to stimulate sensitized helper T lymphocytes, and would cluster the T cells in an antigen-dependent fashion at 4 degrees C. However, 12-h LC did not sensitize T cells, as indicated by their inactivity in stimulating the primary MLR or antibody response, and they were unable to cluster T cells in an antigen-independent fashion at 37 degrees C. The latter properties were acquired during 72 h of culture. As a result, the function of 72-h LC fully resembled that of lymphoid dendritic cells. We propose that the maturation of stimulatory function within the dendritic cell lineage represents an important control point in the induction phase of cell-mediated immunity.

Animals↗
PubMed1986

Contrasting effect of alpha/beta- and gamma-interferons on expression of macrophage Ia antigens.

IFN-gamma is known to induce the expression of Ia antigens on macrophages. We found that murine IFN-alpha and -beta blocked the effects of IFN-gamma in a dose-dependent manner. The antagonistic effect of IFN-alpha and -beta was observed even when macrophages were prestimulated with IFN-gamma. These inhibitory effects of IFN-alpha or -beta were blocked by their respective antibodies. The block exerted by IFN-alpha/beta was similar whether Ia levels were monitored by immunofluorescence with anti-Ia mAb, or by stimulation of freshly sensitized, alloreactive T lymphoblasts. Adherent macrophage-rich populations from newborn mice were incapable of expressing Ia antigens following stimulation with IFN-gamma, and would inhibit the response of adult macrophages to this lymphokine. Addition of anti-IFN-beta mAb, but not anti-IFN-alpha allowed newborns' macrophages to express Ia in response to IFN-gamma, and ablated the suppressive activity toward adult cells. These results indicate that IFN-alpha and -beta, which can be produced in the course of self-defense responses and during ontogeny, may contribute to the down-regulation of macrophage Ia expression.

Animals↗
PubMed1986

Accessory cell-T lymphocyte interactions. Antigen-dependent and -independent clustering.

Previous work documented the capacity of dendritic cells (DC) to stimulate primary immune responses and to physically cluster with the responding lymphocytes. Rapid cell-cell aggregation assays were used here to study the interaction of DC and other types of APC with T lymphocytes. Graded doses of APC were sedimented with T cells that had been primed to alloantigens, soluble proteins, or lectin, and then labeled with carboxyfluorescein diacetate. The number of clustered T cells was measured after 10 min at 4 or 37 degrees C. At 4 degrees, binding was antigen-dependent and included greater than 50% of the added T cells. Clustering was mediated by all types of APC tested, including DC, macrophages, B lymphocytes, and fresh Langerhans cells, although DC were the most effective. Specificity was evident in the findings that alloreactive T lymphoblasts bound to allogeneic but not syngeneic APC; KLH- and OVA-reactive T cells bound to syngeneic APC in the presence of specific protein: and Con A blasts needed lectin to cluster. A 30 min pretreatment with chloroquine, a drug known to inhibit APC activity, markedly blocked the specific binding of alloreactive and protein-specific T blasts at 4 degrees C. Since Lyt-2- alloreactive blasts should specifically recognize Ia, presentation of Ia seems to be altered by chloroquine. Binding assays at 37 degrees C gave similar results to those performed at 4 degrees C, with one exception. When DC were used as APC, striking antigen-independent clustering occurred. DC could efficiently cluster primed T cells in the absence of alloantigen, soluble protein, or lectin. We suggest that antigen-independent binding contributes to the distinctive capacity of DC to prime T cells in the afferent limb of the immune response, whereas antigen-dependent binding between other APC and sensitized lymphocytes is critical in the efferent limb.

Animals↗
PubMed1986

Electron microscopic observations of Descemet's membrane of peripheral cornea.

The posterior portion of the Descemet's membrane was studied by scanning and transmission electron microscopy; the materials comprised 87 human peripheral corneas with ages from 2 to 98 years, 5 monkey corneas and 4 rabbit corneas. In some specimens, the endothelium was removed by ultrasonication. After removal of the endothelium, "curly structures" were recognized on the surface of the Descemet's membrane, where the membrane showed a gradual thinning. These structures appeared along the whole circumference of the cornea with variable width in the human specimens, but in monkey and rabbit corneas, the extent of these structures was less than in the human cornea. The "curly structures" were not encountered in young subjects, and they increased with age. There was a positive correlation (r = 0.60, P less than 0.001) between the age and the extent of these structures. Other aging products of the Descemet's membrane, ie, Hassall-Henle bodies, were partly surrounded by the "curly structures". The human "curly structures" consisted of collagen fibrils, halo structures in the collagen bundles, wide-spacing fibers, microfibrils, ground substances containing minute filaments and a structure resembling the Descemet's membrane. Components of "curly structures" of the monkey and rabbit were almost the same as those of the human except for the Descemet's membrane-like structure.

Aging↗
PubMed1985

Role of macrophages as modulators but not as autonomous accessory cells in primary antibody response.

The role of macrophages (M phi) in the in vitro primary antibody response of murine lymphocytes to sheep erythrocytes was investigated. Peritoneal M phi were activated to express Ia antigens either in vitro or in vivo. Nonactivated Ia- M phi were also examined. We observed that only Ia- M phi but also Ia+ M phi failed to trigger the antibody response, in contrast with splenic dendritic cells (DC) which served as potent and autonomous accessory cells, but that M phi modulated the level of response which was dependent primarily on the DC content of culture. The modulation appeared to incline to suppression rather than enhancement, when M phi were allowed to remain throughout the culture period for 4 days. A highly enhancing capacity of M phi, however, could be revealed by removing M phi 2 days after the initiation of culture, indicating that M phi exerted their suppressive effect more strongly in the late phase than in the early phase of in vitro antibody response. The modulatory activity seemed higher in Ia+ M phi than in Ia- M phi.

Animals↗
PubMed1985

Protein-specific helper T-lymphocyte formation initiated by dendritic cells.

Antibody responses to hapten-polypeptide conjugates require peptide-specific helper T cells. The latter can be primed in tissue culture by providing small numbers of dendritic cells. Primed, irradiated helper T cells then induce B-cell growth and differentiation in the apparent absence of dendritic cells. Both stages of the antibody response--the induction of helper T lymphoblasts by dendritic cells and the delivery of help from T to B cell--occur in discrete cell aggregates that can be isolated by velocity sedimentation. If helper T blasts revert to smaller "memory" lymphocytes, dendritic cells again are needed to initiate the antibody response.

Animals↗
PubMed1985

Antibody responses to T-dependent antigens: contributions of dendritic cells and helper T lymphocytes.

Dendritic cells (DC) are important accessory cells for T-dependent antibody formation. Other leukocytes -- such as macrophages and B cells -- do not independently initiate antibody responses. DC induce the two principal functions of helper T cells, i.e., direct activation of small, antigen-specific B cells, and release of B cell stimulating factors. These two helper functions can operate in tandem during the 1 degree response to hapten-carrier conjugates. Once the helper cell is sensitized in concert with DC, it interacts directly with B cells apparently in the absence of DC. These functions of helper cells all occur in discrete aggregates which contain DC and the appropriate responding lymphocytes. The DC/lymphocyte aggregates likely represent the appropriate structural unit for the study of cell-cell interactions during antibody responses.

Animals↗
PubMed1985

Ontogeny of 'macrophage' function. V. Differential effect of prostaglandin E2 on the activation of newborn and adult mouse macrophages.

Our previous papers indicate that peritoneal exudate macrophages (PM) of newborn mice are strongly suppressive for the tumor cell growth in comparison with those of adult mice. Neither newborn PM nor adult PM are cytolytic, but they both can be activated to be cytolytic by being cultured overnight either with a high concentration of bacterial lipopolysaccharide (LPS) or with a low concentration of LPS plus lymphokine. This paper shows that the activation of adult PM was inhibited by prostaglandin E2 (PGE2) added simultaneously with LPS, though that of newborn PM was not affected by PGE2. Adult PM, however, acquired the resistance to PGE2 by the preculture with LPS and/or lymphokine for 4 hr so as to be activated by LPS in the presence of PGE2. These results indicate that newborn PM are more activated than adult PM to a state which adult PM attain after moderate activation with LPS or lymphokine.

Age Factors↗
PubMed1985

Properties of memory T lymphocytes isolated from the mixed leukocyte reaction.

During the primary mixed leukocyte reaction, T lymphocytes of the lyt-2- helper subclass proliferate in response to transplantation antigens on allogeneic dendritic cells. We have isolated populations of antigen-specific proliferating lymphoblasts and recultured them in fresh medium. Within 2 days, the blasts become smaller in size, lose responsiveness to T-cell growth factor or interleukin 2, but retain vigorous reactivity to the original alloantigen. Two new biologic properties of these "memory" lymphocytes have been noted. First, they primarily respond to alloantigen on dendritic cells, whereas freshly sensitized lymphoblasts react to allogeneic dendritic cells, macrophages, and B lymphocytes. Second, the memory lymphocytes quickly aggregate with dendritic cells that are either syngeneic or allogeneic, but not with B cells. The aggregates that form with syngeneic dendritic cells disassemble within hours and do not release interleukin 2 or proliferate. The aggregates that form with allogeneic dendritic cells remain intact, release large amounts of interleukin 2 on the first day of culture, and synthesize DNA on the second day. Therefore, dendritic cells actively cluster memory lymphocytes by an antigen-independent mechanism, and this may underlie the heightened functional activity of each cell type.

Antigen-Presenting Cells↗