Adoptive immunotherapy against a local or widespread tumor of a highly malignant and poorly immunogenic mouse leukemia L1210.
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Animals↗
Biomedical subjects
F Nagase
Publications and source records attributed to F Nagase.
[Planning early social rehabilitation of an apoplexy patient using an ambulation table].
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Aged↗
Depression of afferent arc of the in vivo cytotoxic T-cell immunity by bacterial lipopolysaccharides.
The afferent arc of the in vivo cytotoxic T-cell immunity assessed by second set rejection of ascitic allogeneic tumors was shown to be depressed by bacterial lipopolysaccharide (LPS) that was administered simultaneously with or 1 day before injection of allogeneic spleen cells as stimulators. Two different LPSs from Escherichia coli O55 and Klebsiella O3 displayed similar activities whereas dextran sulfate, concanavalin A, or poly A:U was not effective. Stimulator activities of allogeneic cells was not directly modified by LPS. Any definite suppressor activity on afferent or efferent arc of the T-cell response was not demonstrable in mice receiving LPS and allogeneic cells. Further, the LPS effect for immune depression was not diminished by whole body X-ray irradiation to the recipient at 300 R, which ablated the B-cell reactivity to LPS for polyclonal activation, or by treatment of the recipient with carrageenan, a known toxic agent to macrophages. It was suggested from these results that LPS suppresses the cytotoxic T-cell immunity by modulating responder T cells to be temporarily refractory to the allogeneic stimulus rather than by activating suppressor cells such as radiation-sensitive lymphocytes and carrageenan-sensitive macrophages.
Animals↗
Genetic and stimulatory cell type requirements for inducing class I major histocompatibility complex alloantigen-specific in vivo cytotoxic T cell immunity.
Current interpretation based on analytical in vitro works that actions of Ia antigens and accessory cells such as macrophages and dendritic cells are crucial for inducing cytotoxic T cell responses to class I major histocompatibility complex (MHC) alloantigens has been challenged by experiments performed in a newly developed system handling in vivo cytotoxic T cell immunity. We first characterized the transplantation immunity for second-set rejection of ascitic tumor allografts as principally induced by allogeneic stimulator cells via direct pathway, and as exclusively mediated by class I MHC alloantigen-specific in vivo cytotoxic T cell activity. By comparison of activities of limiting effective doses (10(4)-10(5) cells per mouse) of various stimulator cells in this defined system, we could demonstrate that genetic disparity at the D region of H-2 to the recipient is just enough for inducing the immunity, and presence of allogeneic or syngeneic Ia antigens in addition to H-2D alloantigens on stimulator cells does not give any premium effect. Further study revealed that allogeneic peritoneal cells rich in macrophages or glass-adherent spleen cells enriched for dendritic cells are not stronger stimulators than allogeneic adherent cell-depleted spleen cells and semi-allogeneic thymocytes. These results fit with the alternative concept that the physiological pathway inducing in vivo cytotoxic T cell immunity for graft rejection entirely depends on class I MHC antigens on live lymphocytes as self-supported stimulators, and does not crucially involve additional stimulator activities of Ia antigens and special accessory cell types, which must be in vivo concerned with induction of other types of transplantation immunity.
Animals↗
Potent adjuvant action of lipopolysaccharides possessing the O-specific polysaccharide moieties consisting of mannans in antibody response against protein antigen.
It was previously reported that Klebsiella O3 lipopolysaccharide (LPS) exhibits extraordinarily strong adjuvant activity in augmenting antibody response against protein antigens in mice compared with other kinds of LPS, for example, LPS from Escherichia coli O55, O111, and O127 and Salmonella enteritidis. The present study was undertaken to clarify the relationship between the strong adjuvant activity in augmenting antibody response against deaggregated bovine gammaglobulin and the chemical structure of LPS. Among LPS from Klebsiella O1, O4, O5, and O7, only O5 LPS exhibited nearly the same degree of the strong adjuvant activity as did O3 LPS. The adjuvant activity of the other LPS was very weak in a degree similar to that of LPS from E. coli O55 and O127. Even when the natural forms of Klebsiella O3 LPS and O1 LPS were converted to various defined uniform salt forms, their adjuvant activity did not significantly differ from that of the respective natural forms. It is therefore unlikely that the difference in strength of the adjuvant activity between Klebsiella O3 LPS and O1 LPS is due to the difference in their salt forms. The common feature in the structures of Klebsiella O3 LPS and O5 LPS is their O-specific polysaccharide chains consisting of the mannose homopolysaccharides (mannans). LPS from E. coli O8 and O9, the O-specific polysaccharide chains of which consist of the mannans, also exhibited much stronger adjuvant activity than do LPS from E. coli O55 and O127, and the strength of the adjuvant activities of the former two was comparable to that of LPS from Klebsiella O3 and O5. On the other hand, LPS from Klebsiella O3 and O5 and E. coli O8 and O9 showed the ability to activate B lymphocytes polyclonally in vivo in a degree similar to that of the other kinds of LPS. From the present results it can be concluded that LPS possessing the O-specific polysaccharide moieties consisting of the mannans exhibit extraordinarily strong adjuvant activity in augmenting antibody response against protein antigen.
Adjuvants, Immunologic↗
Nonspecific immune modulating effects of ascites fluid and hyperimmune sera in vivo.
To determine whether the appearance of interferon (IFN) and the modulation of humoral responses observed following injection of irradiated tumor cells were mediated by suppressor cells, the effects of in vivo injection of I-Js specific antibodies were studied. We found that anti-I-J-containing, as well as normal ascites fluids, obtained after repeated ip injection of complete Freund's adjuvant, contain a factor which (a) induces the appearance of serum IFN, (b) enhances the response to SRBC, and (c) suppresses the response to TNP-Ficoll, when injected 1 day before antigen. This effect is not immunologically specific, is probably not caused by intact Ig, and does not appear to be mediated by T cells. Although the nature of the factor(s) responsible for the observed results has not been fully clarified, we report these findings now as a cautionary note for the interpretation of studies where in vivo injection of unfractionated ascites fluids containing monoclonal antibodies are used.
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Simultaneous development of humoral and cellular tumor-specific immunity against L1210 mouse leukemia.
We have recently described that a variant of L1210 leukemia cell (L1210/LN-1) originally fused with Lesch-Nyhan fibroblast is highly immunogenic for inducing tumor-specific transplantation immunity in (BALB/cxDBA/2)F1 mice. This finding has clearly been confirmed in the present study by in-vitro cell-mediated cytotoxicity assay. Direct cytotoxic tests and competitive inhibition tests using tumor cells such as P388, LS-1 and L5178Y as target or inhibitor cells showed that the cell-mediated immunity is specific to L1210 leukemia. In the process of this study, we found that the CD2F1 mice hyperimmune to L1210 leukemia cells developed co-existing humoral anti-L1210 leukemia immunity. In an in vitro complement-dependent cytotoxicity test and absorption test, antisera from hyperimmune mice reacted specifically to L1210 leukemia cells, but not other tumor cells such as P388, L5178Y, LS-1, DB27C and BW5147 or normal cells from various tissues of DBA/2, BALB/c and AKR mice. In an in vitro cytotoxicity blocking test, the cytotoxic antisera specifically reactive to L1210 cells totally failed to inhibit lysis of L1210 cells by cytotoxic cells, suggesting that antigens recognized by cell-mediated cytotoxicity assays are not identical to serologically defined tumor-cell surface antigens.
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Ontogeny of the transplantation immunity of mice for rejecting ascitic allogeneic tumors.
Ontogeny of the murine transplantation immunity for rejecting ascitic allogeneic tumors (chemically-induced RG lymphoma and L1210 leukemia) as a model of in vivo cytotoxic T cell immunity was studied. Challenge by 10(6) to 10(7) allogeneic tumor cells per 20 g body weight (b.w.) of the mouse was fatal to 1-3 day-old mice, whereas 7-30 day-old mice rejected the tumor. In newborn mice however some yet undetermined mechanism worked to temporally depress the initial tumor growth. Injection of low (10(6) cells per 20 g b.w.) to moderate (10(7)) doses of semiallogeneic spleen cells into newborn mice prepared for second set rejection of the tumor carrying the same alloantigens as the spleen cells, although injection of high dose (3 X 10(8)) cells reduced the tumor rejecting immunity. This second set rejection occurred even against the allogeneic tumor inoculated as early as 3 days old, if the mice had been primed with the alloantigens at birth. It appears therefore that newborn and early suckling mice are protected from tumor invasion by cytotoxic immunity more powerfully than expected from earlier in vitro works.
Age Factors↗
Immune reactivity of allogeneically pregnant mice to paternal MHC antigens on fetal and placental cells assessed by second set rejection of ascites tumor cells.
In vivo immunogenicity of fetus- and placenta-derived cells as well as the immune reactivity of pregnant mice to fetal cells were examined for graft rejecting response (GRR). Systemic administration of small numbers of fetal cells but not placental cells from allogeneically pregnant mice (10(6) cells per mouse) or adult allogeneic spleen cells (10(4) cells) sensitized mice for second-set rejection of an ascitic tumor bearing paternal major histocompatibility complex (MHC) antigens. Despite this fact and the known positive humoral response, pregnant and parous mice are not even minimally sensitized with fetal MHC antigens for GRR transplacentally. Nevertheless, any pregnancy-related systemically active control, which would selectively prevent the mother from being sensitized for GRR by limiting numbers of semi-allogeneic fetal cells, was not demonstrable in either allogeneically or syngeneically pregnant mice. Irrespective of pregnancy, mice did not, however, respond to repeated administration of very small numbers of allogeneic spleen cells (5 X 10(2) cells per mouse) for graft rejection. These findings support the notion that deviation of maternal immunity to fetal antigens away from harmful GRR is mediated principally by local mechanisms which inhibit fetal cells from gaining access to the mother for GRR, and additionally by the innate inability of mice to respond to very small numbers of allogeneic cells that might escape past the local maternal-fetal barrier.
Animals↗
Direct activation of Sendai virus (HVJ)-specific cell-mediated immunity of mice for second set rejection of the virus-infected syngeneic tumor by noninfectious virus-sensitized spleen cells.
Syngeneic spleen cells (SPC) sensitized in vitro with noninfectious NVJ were shown to effectively stimulate mice to generate the HVJ-specific cell-mediated immunity for second set rejection (SSR) of virus-infected syngeneic leukemia cells. As few as 10(4) live but not disrupted SPC either infected with a temperature-sensitive mutant of HVJ (HVJts) or sensitized passively with ultraviolet (UV)-inactivated HVJts were active as immunogen. Syngeneic SPC as the carrier of virus could be replaced by allogeneic SPC or L cells, a fibroblast cell line, without reduction of the immunogenicity. Further study demonstrated that a special density of antigen on the surface of HVJts-sensitized SPC is required for high immunogenicity. It was suggested that live cells appropriately sensitized with noninfectious virus would serve as an excellent vaccine for virus-specific cell-mediated immunity.
Animals↗
Strong adjuvanticity of bacterial lipopolysaccharides possessing the homopolysaccharides consisting of mannose as the O-specific polysaccharide chains.
The lipopolysaccharides (LPS) from Klebsiella 03 and 05 and Escherichia coli 08 and 09 are unique in having linear homopolysaccharides consisting of mannose as the O-specific polysaccharide chains. All four kinds of LPS were found to exhibit very strong adjuvanticity in induction of delayed-type hypersensitivity to ovalbumin in mice compared with other kinds of LPS from Klebsiella, E. coli and Salmonella. Even if the natural forms of Klebsiella 03 LPS and 01 LPS were converted to various defined uniform salt forms, their adjuvanticity did not differ significantly from that of the respective natural forms. It was concluded therefore that the difference in strength of the adjuvanticity between them is not due to the difference in their salt forms, solubility and physical state. Correspondingly, with strong adjuvanticity of Klebsiella 03 LPS and 05 LPS, their activity in enlarging the regional lymph node was also strong. Various uniform salt forms of Klebsiella 03 LPS caused stronger regional lymph node enlargement than those of Klebsiella 01 LPS. However, the activity of E. coli 08 LPS and 09 LPS in enlarging the regional lymph node was significantly weaker than that of Klebsiella 03 LPS and 05 LPS, and there were other kinds of LPS which showed a capacity to enlarge the regional lymph node similar to that of E. coli 08 LPS and 09 LPS, despite their weak adjuvanticity. Therefore, correlation did not necessarily exist between the degree of adjuvanticity of LPS and its activity in enlarging the regional lymph node.
Adjuvants, Immunologic↗
Characterization of a (BALB/c x C57BL/6)F1 T cell hybridoma with double specificity: recognition of antigen in context of I-Ad and autoreactivity to I-Ab.
An antigen-specific, IL-2-producing, Lyt-1+2-, T cell hybridoma has been derived by the fusion of keyhole limpet hemocyanin (KLH)-primed (BALB/c x C57BL/6)F1 lymph node with BW5147 thymoma cells. The hybridoma FN13-21 recognizes KLH in association with I-Ad of BALB/c parental antigen-presenting cells, and also responds to I-Ab of the other parent C57BL/6 spleen cells in the absence of antigen. The KLH-specific response of FN13-21 is blocked by monoclonal anti-I-Ad antibody, while the response to C57BL/6 spleen cells is blocked by anti-I-Ab antibody. The specificity of the autoreactivity is to an antigen encoded for in the I-Ab region, as shown by the pattern of stimulation obtained with spleen cells from H-2-recombinant mice.
Animals↗
Genetic controls of T cell-independent Thy-1 alloantibody responses.
Early and late primary IgM antibody responses of mice to Thy-1.1 antigens showed different antigenic and cellular requirements. We studied genetic controls of the early primary responses, which could be induced by subcellular thymocyte antigens independently of host T-cell activity. All Thy-1.2 mouse strains of Igha (BALB/c and BC8), Igh-VaCb (BAB14), Ighd (AKR/Cum), Ighj (CBA/J, C3H/HeN, C3H.SW, and C3H.JK), and Ighn (NZB) definitely responded early to Thy-1.1 antigens from AKR/J (Ighd), A.Thy-1.1 (Ighe), or B10.Thy-1.1 (Ighb) mice or SD rats, whereas all strains of Ighb (C57BL/6, C57BL/10, B10.D2, B10.BR, B10.A, CB20 and CWB), Ighc (DBA/2), Ighe (A/J), and Igho (C.AL20) responded poorly to the same antigens. This contrasts with the observation that both strains of Ighj (C3H/HeN) and Ighb (B10.BR) responded well at later times. As was the case for late responses, the matching of H-2 between donor and recipient resulted in early responses of exceptional quality in high-responder strains. It was concluded that under the influence of H-2, whose incompatibility between donor and recipient partially interferes with responses, early but not late primary Thy-1.1-specific antibody responses are selectively controlled by Igh-V or closely linked Ir gene(s) as a new VH marker.
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Ontogeny of the erythrocyte-dependent IgM antibody responses to cell membrane antigens.
Our previous experiments characterized the T-cell independent type 2 B-cell responses to cell membrane antigens that are controlled by two donor cell types with different antigen-presenting (AP) activities. We here report about the ontogeny of this novel type of responses with special reference to the mutual relation of the development among two AP activities and their acceptor functions. The responses of mice to H-2d antigens on allogeneic cells and hapten (fluorescein isothiocyanate) antigens on syngeneic cells were examined in parallel. The positive AP activity displayed by red blood cells (RBC) for induction of anti-hapten responses was fully developed in the fetus, although H-2d antigens on the RBC for induction of anti-H-2d responses was immature in mice under 7 days old. In contrast, the negative AP activity displayed by spleen cells (B cells) for inhibition of the RBC-dependent anti-hapten and anti-H-2d responses was first developed in mice about 3 weeks old. The B cell functions accepting the positive and negative AP activities were also matured by that time. The possible significance of these findings in the physiology and pathology of the unique responses was discussed.
Age Factors↗
Antigen presentation by murine and human cells to a murine T-cell hybridoma: demonstration of a restriction element associated with a major histocompatibility complex class II determinant(s) shared by both species.
A CB6F1 murine T-cell hybridoma, FN1-18, secreting interleukin 2 in response to presentation of keyhole limpet hemocyanin (KLH) by syngeneic cells in the context of an I-E gene complementation product, also exhibited a major histocompatibility complex-restricted response to KLH presented by human leukocytes. The murine restriction element was I-E beta b or k E alpha d or k. The KLH-induced interleukin 2 production was inhibited by the monoclonal antibody 17-3-3s with similar but not identical anti-I-E specificity. This antibody reacted with human Ia-like antigens on T-depleted mononuclear cells in 10 of 30 humans, as assessed by immunofluorescence. The presence of the epitope recognized by antibody 17-3-3s was closely correlated with MT3 allospecificity. The ability of human cells to present KLH to the murine hybridoma strongly correlated (r = 0.768) with the expression of this epitope and was also inhibited by 17-3-3s. Another monoclonal antibody, 109d6, of the same isotype and with related but not identical MT3 specificity, caused only limited inhibition. The ability of human cells to present KLH segregated as a dominant trait linked to the major histocompatibility complex. The results indicate that the restriction element recognized by FN1-18 on both human and mouse cells is a determinant closely related to but not identical with the antigenic determinant to which 17-3-3s binds. This determinant is not influenced by the considerable species differences in the remainder of the Ia molecules.
Animals↗
Regulation of immune responses in SJL and F1 hybrid mice by gamma-irradiated syngeneic lymphoma cells.
Syngeneic mixed lymphocyte-stimulating la+ lymphomas of SJL mice [reticulum cell sarcoma(s) (RCS)] were found to modulate immune responses in vivo. Simultaneous injection of 2 X 10(7) gamma-irradiated or glutaraldehyde-fixed RCS cells with the antigen sheep red blood cells (SRBC) or 2,4,6-trinitrophenol (TNP)-Ficoll markedly suppressed the subsequent plaque-forming cell response in the spleen. The suppression of the anti-SRBC response was prevented by pretreatment of the mice with cyclophosphamide, whereas the suppression of the anti-TNP-Ficoll response was not affected. RCS injection induced high interferon serum titers within 24 hours after injection, which were not prevented by pretreatment with cyclophosphamide. Injection of gamma-irradiated RCS cells (gamma-RCS) or RCS cell extract 2 days prior to antigen enhanced the anti-SRBC but markedly suppressed the anti- TNP-Ficoll response. Injection of RCS both on day -2 and day 0 enhanced the anti-SRBC response. SJL mice 8-9 months of age showed much less or no suppression when gamma-RCS cells were injected on day 0. Certain F1 hybrids of SJL also showed the gamma-RCS-induced suppression of the anti-SRBC response. Suppression was seen in SJL X BALB.B but not in SJL X BALB/c mice and in SJL X A.TH but not in SJL X A.TL mice, suggesting an I-region effect. F1 hybrids of SJL by B10 background mice showed no significant suppression. Enhancement of the anti-SRBC response by prior injection of gamma-RCS was seen in all F1 hybrid mice examined.
Aging↗
Paradoxical effects of LPS on the T-cell-independent type 2 anti-H-2 alloantigen antibody responses to allogeneic erythrocytes.
Murine allogeneic red blood cells (RBC) induce primary IgM antibody responses to H-2 alloantigens T-cell-independently (TI). In this study we showed that bacterial lipopolysaccharide (LPS), which should activate B lymphocytes polyclonally, could not trigger an anti-H-2d plaque-forming cell response. We then demonstrated that administration of LPS (on days 0-1) with allogeneic RBC suppressed the response of mice to H-2d, while giving LPS 4-6 days after RBC augmented the response. In contrast, LPS did not enable allogeneic spleen cells to induce an anti-H-2d response. Additional experiments showed that the allogeneic RBC behave as a TI class 2 antigen. It was concluded from these results that allogeneic RBC display a peculiar activity that exclusively triggers a TI type-2 B cell response that cannot be initiated by LPS and is modulated by LPS in an abnormal fashion. The possible significance of this finding in the mechanism of occurrence of natural H-2-specific IgM alloantibodies in aged mice is discussed.
Animals↗
Cellular mechanism of primary anti-Thy-1 antibody responses in vitro induced by uniquely immunogenic thymocyte antigens.
Thy-1 antigens are the only cell membrane antigens known to be able to induce primary antibody responses in vitro. We have shown that antigens from the thymocytes of mice and rats were highly immunogenic in cultures of murine spleen cells for the induction of Thy-1.1-specific plaque-forming cell responses, whereas antigens from other tissues, including brains and bone marrow, were poorly immunogenic, if at all. The thymocyte-specific Thy-1 immunogenicity was carried by disrupted cell membranes, and the specific activity for inducing responses was closely linked to Thy-1. We then tried to determine the mechanism of anti-Thy-1 antibody responses in vitro that were induced by the uniquely immunogenic thymocyte antigens. The thymocyte Thy-1 antigens behaved as T cell-independent class 2 (TI-2) antigens: they induced responses in athymic nude mice but not in CBA/N mice with a B cell defect. The apparent TI-2 responses to thymocyte Thy-1 did, however, require Thy-1+ cells in the responder, similar to anti-DNP-Ficoll responses. The full development of the anti-Thy-1 responses required the participation of splenic adherent cells (SAC). Nevertheless, the mechanism of the SAC dependency of anti-Thy-1 responses did not involve antigen presentation to lymphocytes by antigen-pulsed SAC, which contrasted with the finding that the presentation of antigen by live SAC to lymphocytes was indispensable for responses to DNP-Ficoll. The poor Thy-1 responsiveness of SAC-depleted spleen cells was fully restored by the addition of soluble factors (IL 1-like molecules) released from SAC into the culture, which did not replace the SAC-requirement of responses to DNP-Ficoll. It was concluded from these results that Thy-1 or Thy-1-linked structures on thymocyte membranes have an intrinsic activity to directly signal either TI-2 B cells or immature T cells, or both, for activation in the presence of soluble factors released from adherent accessory cells. This conclusion is discussed in relation to a hypothetical view that the thymocyte Thy-1 would physiologically mediate cell-to-cell interactions among special subsets of lymphocytes under thymic influence.
Animals↗