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Biomedical subjects

S Izui

Publications and source records attributed to S Izui.

At least 19 recordsLinked to original sources
PubMed1992

Murine autoimmune hemolytic anemia resulting from Fc gamma receptor-mediated erythrophagocytosis: protection by erythropoietin but not by interleukin-3, and aggravation by granulocyte-macrophage colony-stimulating factor.

We have evaluated the therapeutic activity of recombinant erythropoietin (rEpo), in comparison with recombinant interleukin-3 (rIL-3) and granulocyte-macrophage colony-stimulating factor (rGM-CSF), on a lethal form of acute anemia resulting from Fc gamma receptor-mediated erythrophagocytosis after a single injection (500 micrograms) of a monoclonal anti-mouse red blood cell (MRBC) autoantibody. Continuous perfusion of rEpo before the administration of anti-MRBC monoclonal antibody completely protected animals from death due to anemia with a rapid recovery, while no protection was obtained by rIL-3 perfusion. In contrast, rGM-CSF perfusion markedly accelerated the progression of anemia and the mortality rate. This was found to result from an enhancement of erythrophagocytosis by Kupffer cells and by polymorphonuclear leukocytes that massively infiltrated the livers. Even after the injection of a sublethal dose (100 micrograms) of anti-MRBC monoclonal antibody, rGM-CSF-perfused mice died of a severe form of acute anemia. Furthermore, we have shown that rEpo was able to treat efficiently a spontaneous form of autoimmune hemolytic anemia in a majority of anemic NZB mice, whereas rGM-CSF markedly aggravated anemia. This may be of clinical importance, because GM-CSF administration could exhibit an adverse effect in some autoimmune diseases that involve autoimmune anemia.

Anemia, Hemolytic, Autoimmune↗
PubMed1992

H-2-linked control of the Yaa gene-induced acceleration of lupus-like autoimmune disease in BXSB mice.

The accelerated development of lupus-like autoimmune disease in male BXSB mice (H-2b, I-E-) is associated to the presence of a mutant gene, designated Yaa, located on their Y chromosome. To investigate whether the H-2b haplotype and/or the lack of expression of I-E molecules play any role in the Yaa-linked acceleration of autoimmune disease, an I-E+ BXSB.H-2d congenic strain was created by backcross procedures. We compared the development of autoimmune disease in the novel BXSB.H-2d (I-E+) strain to that of BXSB.H-2b (I-E-) and BXSB.H-2b/d (I-E+) heterozygous mice. Male BXSB.H-2d (I-E+) mice exhibited only a limited production of autoantibodies and a lower incidence of glomerulonephritis with a markedly prolonged survival rate, which were essentially identical to those of female BXSB mice of both-H-2b and H-2d haplotypes. However, BXSB.H-2b/d (I-E+) heterozygous males developed an accelerated disease comparable to that of conventional BXSB.H-2b (I-E-) male mice. These results indicate that the expression of I-E molecules and consequent clonal deletion or anergy of I-E reactive T cells does not appear to be responsible for the prevention of accelerated autoimmune disease in BXSB.H-2d (I-E+) male mice. The finding that the Yaa gene-induced acceleration of lupus-like autoimmune disease is modulated by gene(s) within or closely linked to the H-2 complex underlines the crucial role of the major histocompatibility complex and the polygenetic nature of autoimmune disease in BXSB mice.

Animals↗
PubMed1992

Epidermal and splenic antigen-presenting cell function in a retrovirally induced murine immunodeficiency syndrome (MAIDS).

Since alterations of epidermal Langerhans cells (LC) have been observed in humans infected with HIV, we investigated the morphology and function of these cells in murine acquired immunodeficiency syndrome (MAIDS), a murine model closely resembling human AIDS. The number as well as the shape of dendritic MHC class II+ cells from ear skin of C57BL/6 mice were similar in normal and infected animals. In mixed epidermal cell (EC) lymphocyte cultures, EC from infected mice and from normal mice stimulated allogeneic T cell proliferation to the same extent. In contrast to T cells from normal mice, however, T cells from infected mice did not respond to allogeneic spleen cells, confirming the presence of a T-cell defect in MAIDS. Subcutaneous injection of syngeneic mice with trinitrophenyl-modified MAIDS EC resulted in delayed ear swelling responses after challenge that were equivalent to those induced by hapten-modified EC from normal mice, suggesting that the contact sensitivity inducing potential of MAIDS LC was preserved. To investigate antigen presenting and processing function, EC and spleen cells were tested with the ovalbumin-specific IAb-restricted T cell hybridoma BO.17.10 and either ovalbumin 323-339 peptide or intact ovalbumin protein. MAIDS spleen cells had a reduced antigen presenting capacity compared with normal spleen cells, whereas EC from these mice showed the same processing and presenting capacity as normal controls. In summary, our results demonstrate that the frequency, morphology, level of MHC class II antigen expression and ability to process and present antigen is normal for LC from mice with MAIDS whereas the function of splenic T cells and APC from infected mice is significantly impaired.

Animals↗
PubMed1992

Induction of "wire-loop" lesions by murine monoclonal IgG3 cryoglobulins.

We have recently demonstrated that an IgG3 rheumatoid factor (RF) monoclonal antibody (mAb), clone 6-19, derived from unmanipulated autoimmune MRL/MpJ-lpr/lpr mice, is able to generate cryoglobulins via a non-immunological IgG3 Fc interaction, and to induce an acute glomerulonephritis associated with cryoglobulinemia. Using this experimental model, we have characterized the glomerular lesions induced by the 6-19 RF monoclonal cryoglobulin, in particular the ultrastructural localization of the cryoglobulin deposits. Although their initial localization was confined to the mesangium, the 6-19 cryoglobulins were progressively accumulated in the subendothelial spaces of glomerular capillary walls, leading to the formation of glomerular lesions resembling the "wire-loop" lesion characteristically described for lupus nephritis. In addition, we have found that identical glomerular "wire-loop" lesions were induced by the 6-19-J558 hybrid antibody, composed of the 6-19 gamma 3 heavy chain and J558 lambda 1 light chain, which loses the RF activity, but retains the cryoglobulin activity. These results strongly suggest that the direct deposition of IgG3 cryoglobulins by itself, without involvement of immune complex formation, results in the generation of the classical "wire-loop" lesion characteristic of lupus nephritis. In addition, we have found that similar "wire-loop" lesions were generated by one anti-DNA mAb derived from (NZB x NZW)F1 hybrid mice, and two of four IgG3 mAb of unknown specificities, derived from MRL/MpJ-lpr/lpr mice. The absence of significant glomerular lesions, in spite of large amounts of cryoglobulins, in mice receiving two IgG3 mAb suggests the importance of physicochemical property of cryoglobulins to provoke glomerular lesions.

Animals↗
PubMed1992

Effect of cyclosporin A and zidovudine on immune abnormalities observed in the murine acquired immunodeficiency syndrome.

Two therapeutic modalities, zidovudine (targeting retroviral replication) and cyclosporin A (targeting immunopathologic consequences of retroviral expression) were evaluated in a murine model of AIDS. In previous studies, cyclosporin A treatment (40 or 60 mg/kg/day) before and after infection with LP-BM5 murine leukemia viruses protected against the development of immunodeficiency disease. The present study extends these findings. First, a low dose of cyclosporin A (20 mg/kg/day) was ineffective, and treatment initiated 5 days after infection did not protect against virus-induced lymphoproliferation and hypergammaglobulinemia. Second, zidovudine added to drinking water (0.1 mg initiated 5 days after infection and continued for 8 weeks) was more effective than 0.2 mg/mL given day 5-12 after infection. This treatment reduced lymph node size, disease severity as determined histologically, retrovirus-induced gp70 expression, and IgE (but not IgM and IgG) levels. Third, combined treatment had an additive, protective effect on lymphocyte proliferative capacity. This successful dual therapeutic strategy in a mouse model has potential applicability for similar approaches in treating human immunodeficiency virus infection.

Animals↗
PubMed1992

Selective pathogenicity of murine rheumatoid factors of the cryoprecipitable IgG3 subclass.

To analyze the involvement of rheumatoid factors (RF) in the generation of cryoglobulins and the development of related tissue injuries, we have established a panel of anti-IgG2a RF mAbs derived from MRL/MpJ-lpr/lpr (MRL-lpr), C3H/HeJ-lpr/lpr, and 129/Sv mice. After injection of hybridoma cells to normal mice, all four IgG3 RF mAbs induced cryoglobulinemia, and various degrees of glomerulonephritis and skin leukocytoclastic vasculitis. In contrast, none of the RF mAbs of the other isotypes generated cryoglobulins or tissue lesions. Since the same observation was obtained with another panel of five clonally related anti-IgG2a RF mAbs of MRL-lpr origin with almost identical heavy and light chain variable (V) regions but five different isotypes, it seems unlikely that the absence of pathogenicity of non-IgG3 RF mAbs was due to differences in fine specificity or V framework regions. In addition, the analysis of serum RF in MRL-lpr mice has demonstrated that a majority of 4 month old MRL-lpr mice produced substantial amounts of IgG3 RF with cryoglobulin activity. Because the cryoglobulin activity is associated with the murine IgG3 heavy chain constant region, RF of this subclass may play a significant role in the development of autoimmune-related tissue injuries, especially in MRL-lpr mice.

Animals↗
PubMed1991

Prolactin influences autoimmune disease activity in the female B/W mouse.

Prolactin, an anterior pituitary hormone, stimulates humoral and cell-mediated immunity. This study investigated effects of manipulating prolactin levels in the autoimmune B/W mouse model of SLE. A group of B/W females was treated with daily injections of the prolactin-suppressing drug, bromocriptine. These mice had delayed elevation of anti-DNA antibodies and serum IgG; longevity was increased compared to control mice. Functioning syngeneic pituitary glands, implanted under the renal capsule, produced prolonged hyperprolactinemia in a separate group of female B/W mice. Hyperprolactinemic animals were characterized by premature albuminuria, elevated circulating gp70IC and IgG, and accelerated mortality. Analyses of thymic and splenic lymphocytes revealed no differences in lymphocyte subpopulations in mice with altered prolactin levels. This is the first report to substantiate an immunomodulatory role for prolactin in B/W mice. Further evaluation of this model may identify specific means of intervening clinically with immunosuppressive hormone-modulating therapy in SLE.

Albuminuria↗
PubMed1991

Murine cryoglobulinemia: pathogenic and protective IgG3 self-associating antibodies.

A murine IgG3 mAb, 6-19, derived from autoimmune MRL-lpr/lpr mice, is a rheumatoid factor (RF) specific for IgG2a and is able to generate cryoglobulins via nonspecific IgG3 Fc-Fc interaction. Intra-peritoneal passive transfer of ascites containing the 6-19 mAb into BALB/c mice induces skin leukocytoclastic vasculitis and acute glomerulonephritis associated with cryoglobulinemia. Because IgG3 interact with each other, we have determined whether noncryoprecipitating IgG3 mAb were able to inhibit the cryoprecipitation of 6-19 mAb and the development of related tissue lesions. In vitro, the cryoprecipitation of 6-19 mAb was almost completely inhibited by a fourfold excess of a noncryoprecipitating non-RF IgG3 (9-106) mAb derived from MRL-lpr/lpr mice. Cryoprecipitation of five other IgG3 mAb was similarly inhibited by the 9-106 mAb, and two other noncryoprecipitating IgG3 mAb, including the 2-6D antinuclear autoantibody, inhibited the cryoprecipitation of 6-19 mAb. In vivo, pretreatment of BALB/c mice with 9-106 or 2-6D mAb prevented the development of skin vasculitis and glomerulonephritis induced by the 6-19 mAb. The cryoglobulin formation was greatly diminished in 9-106 or 2-6D mAb-treated mice, although their serum levels of 6-19 mAb and RF activity were comparable to those of control mice. This indicated that pretreatment with non-cryoglobulin IgG3 inhibited the cryoglobulin generation and cryoglobulin-associated tissue lesions induced by an IgG3 RF cryoglobulin-generating mAb. These results suggest that the balance of formation of IgG3 autoantibodies with or without the cryoglobulin activity may be critical for the development of IgG3 cryoglobulin-mediated tissue lesions in murine lupus, particularly in MRL-lpr/lpr mice.

Animals↗
PubMed1991

Selective autoantibody production by Yaa+ B cells in autoimmune Yaa(+)-Yaa- bone marrow chimeric mice.

The accelerated autoimmune syndrome observed in BXSB/MpJ male mice is associated with the presence on the Y chromosome of an as yet unidentified mutant gene, designated Y chromosome-linked autoimmune acceleration (Yaa). To study the mechanisms by which the Yaa gene accelerates and/or induces the production of autoantibodies, we have developed double-congenic bone marrow chimeras containing B cells from autoimmune males carrying the Yaa gene, and from nonautoimmune male or female mice lacking it and differing by the Igh allotype. The analysis of the allotype of total immunoglobulins and anti-DNA antibodies in Yaa+ male-normal female (Yaa-) chimeric mice revealed that the selective activation of B cells from autoimmune Yaa+ male mice was responsible for the hypergammaglobulinemia and autoantibody production. This phenomenon was not due to an anti-HY interaction between female T helper cells and male B cells, because first, Yaa+ B cells were selectively stimulated to produce autoantibodies in Yaa+ male-Yaa- male chimeric mice; and second, normal male and female chimeras failed to develop an autoimmune syndrome. In addition, the fact that both B cell populations in Yaa(+)-Yaa- chimeras similarly responded to a foreign antigen, human IgG, argues against the possibility that the selective activation of Yaa+ B cells may be due to their hyper-responsiveness to T helper signals. We propose that a cognate interaction of T helper cells with Yaa+ B cells, because of possible T cell recognition of a Yaa-related molecule expressed on Yaa+ B cells, may be responsible for the acceleration and/or induction of autoantibodies in BXSB/MpJ mice.

Animals↗
PubMed1991

Transient T and B cell activation after neonatal induction of tolerance to MHC class II or Mls alloantigens.

The neonatal injection of semiallogeneic F1 spleen cells into newborn parental mice results in the induction of tolerance to the corresponding alloantigen (alloAg) and chimerism. In these F1 cell-injected mice, we have previously observed that this state of specific tolerance is associated with the development of a transient lupus-like autoimmune syndrome. In this study, we show that neonatal injection of mice with spleen cells differing from the host at major histocompatibility complex (MHC) class I, class II, class (I + II), or minor lymphocyte stimulating (Mls) alloAg induced a state of specific tolerance characterized by the absence of alloreactive CTL and/or Th cell responses in the spleen and the thymus of 6- to 12-week-old injected mice. However, in mice rendered tolerant to MHC class II or class (I + II) alloAg, the presence of high levels of IgG1 antibodies, of circulating immune complexes, of anti-ssDNA autoantibodies, and of tissue lesions were transiently observed. In these mice, an increased Ia Ag expression on lymphoid spleen cells was also detected at 1 wk. The elevated production of IgG1 and the overexpression of Ia Ag were almost completely prevented by treatment with an anti-IL-4 mAb. Such manifestations of B cell activation and autoimmunity were not observed in mice neonatally injected with F1 cells differing from the host only at MHC class I Ag. In mice neonatally tolerized to Mls Ag, a transient increase in IgG2a production and an overexpression of Ia Ag were detected without features of autoimmunity, and were prevented by anti-INF-gamma mAb treatment. In mice rendered tolerant to MHC class II, class (I + II), or Mls alloAg at birth, the manifestations of B cell activation were associated with the presence of in vivo-activated alloreactive CD4+ T cells in the spleen--but not the thymus--of 1-wk-old injected mice. Together, these results suggest that in mice neonatally injected with semiallogeneic F1 cells, the process of tolerance induction is not efficient during the early postnatal period, and could allow the maturation and peripheralization of some alloreactive CD4+ T cells, leading to transient B cell activation and, depending on the alloAg, to autoimmunity.

Animals↗
PubMed1991

Lack of anti-DNA precursors in lambda chain-bearing B lymphocytes in (NZB x NZW)F1 mice. Evidence for the contribution of V kappa genes to anti-DNA specificity.

We have analyzed by the limiting dilution assay on spleen cells from (NZB x NZW)F1 hybrid mice the repertoire of lipopolysaccharide-responsive murine kappa- and lambda 1-secreting B cells committed to the production of anti-DNA autoantibodies to determine the contribution of the heavy and light chains to anti-DNA specificities. Our results demonstrated that anti-DNA precursors were predominantly found in the kappa-secreting B cell population, but not in lambda 1-secreting B cells, while anti-hapten, dinitrophenyl, and anti-tetanus toxoid activities were distributed fairly well in both populations of B cells. This suggests that the V kappa gene segments are critically involved in the generation of anti-DNA specificities, and that at least at the germ-line gene level, the heavy chain V region genes by themselves are not able to confer the anti-DNA autoreactivity.

Animals↗
PubMed1991

Protective effect of cyclosporin A on immune abnormalities observed in the murine acquired immunodeficiency syndrome.

The murine leukemia viruses (MuLV) designated LP-BM5 induce an immunodeficiency disease in susceptible strains of mice with many features in common to human acquired immunodeficiency syndrome (AIDS), including lymphadenopathy and profound immunodeficiency associated with enhanced susceptibility to infection and terminal B cell lymphomas. The disease, termed murine AIDS (MAIDS), crucially depends on the presence of B cells and CD4+ T cells, suggesting that mutual activation of these two cell types is central in the pathogenesis of the immunodeficiency syndrome. Cyclosporin A (CsA), whose immunosuppressive effect is attributed mainly to inhibition of interleukin 2 and interferon-gamma expression, interferes in T-B cell interactions. Here we show that chronic treatment with CsA (40 or 60 mg/kg/day) before and after infection with LP-BM5 MuLV protects against the development of immunodeficiency disease as assessed by functional, serological and histopathological criteria. The protection was not complete, suggesting both CsA-sensitive and CsA-resistant components to the pathogenesis of this syndrome, and was found to be independent of ecotropic MuLV expression. These results underline immunopathological mechanisms in the progression of immune abnormalities in MAIDS that are susceptible to inhibition of CsA and may serve as an experimental basis for developing a treatment of the human disorder with immunomodulators.

Animals↗
PubMed1990

Interleukin 3 perfusion prevents death due to acute anemia induced by monoclonal antierythrocyte autoantibody.

We have evaluated the therapeutic activity of rIL-3, in comparison with recombinant granulocyte-macrophage CSF (rGM-CSF) and recombinant erythropoietin (rEpo), on a lethal form of acute anemia induced by a single injection of a monoclonal IgG1 anti-mouse RBC (MRBC) autoantibody. Continuous perfusion of rIL-3 before the administration of anti-MRBC mAb prevented animals from the death due to anemia with a rapid recovery in greater than 90% of the cases, while only partial protection (one third of the cases) was obtained by rEpo perfusion, and no protection by rGM-CSF. Since the anti-MRBC mAb induced a marked agglutination of RBC in spleens and livers, and subsequent hemodynamic failure may be an additional contributing factor to the animals' death, the activation of Fc gamma receptor-dependent phagocytosis by rIL-3, as well as the increased number of monocytes/macrophages resulting from rIL-3 perfusion, may also facilitate rapid elimination of these agglutinated RBC, resulting in the further amelioration of the animals' survival. Our results suggest that the therapeutic effect of rIL-3 on anti-MRBC autoantibody-induced anemia is achieved by: (a) its activity to promote the growth and differentiation of erythroid progenitors responsive to Epo and of monocyte/macrophage lineage; and (b) its activity to enhance the phagocytic activity of macrophages to efficiently eliminate agglutinated RBC in spleens and livers.

Acute Disease↗
PubMed1990

Variable region sequences of pathogenic anti-mouse red blood cell autoantibodies from autoimmune NZB mice.

New Zealand Black (NZB) mice spontaneously develop a severe autoimmune hemolytic anemia due to the production of anti-mouse red blood cell (MRBC) autoantibodies. The contribution of variable region genes and somatic mutations in the pathogenicity of anti-MRBC autoantibodies was investigated by mRNA sequencing of eight NZB anti-MRBC monoclonal autoantibodies, among which five are capable of inducing anemia in BALB/c mice. Here we report that at least three VH gene families (J558, J606 and 3609) and five Vchi subgroups (V chi 8, 9, 19, 21 and 28), in combination with several D, JH and Jchi gene segments, encode anti-MRBC autoantibodies. Thus, the NZB anti-MRBC autoantibodies, whether pathogenic or not, are encoded by a large number of immunoglobulin gene elements and by members of known VH and Vchi gene families with preferential usage of VH gene families most distal to the D regions. The presence of several mutations in the JH gene segments of both IgM and IgG anti-MRBC autoantibodies, whether pathogenic or not, strongly suggests that their VH regions may be highly mutated and that the mechanism of somatic diversification might be important in the generation of anti-MRBC autoantibodies. Our results support the idea that anti-MRBC autoimmune responses are likely to be generated by an antigen-driven mechanism.

Amino Acid Sequence↗
PubMed1990

5-Azacytidine inhibits the lpr gene-induced lymphadenopathy and acceleration of lupus-like syndrome in MRL/MpJ-lpr/lpr mice.

MRL/MpJ-lpr/lpr mice spontaneously develop a lupus-like autoimmune disorder characterized by massive proliferation of T cells and rapidly fatal immune complex glomerulonephritis. We evaluated the therapeutic effect of 5-azacytidine (5AC), a cytidine analogue known as an inhibitor of DNA methylation, in MRL/MpJ-lpr/lpr mice. Intraperitoneal injection of 5AC (50 micrograms, twice a week) starting from 6 weeks of age retarded the development of lymphadenopathy and autoimmune syndrome. Its beneficial effects included: (a) increased life-span, (b) diminution of lymphadenopathy and splenomegaly, (c) reduction in circulating levels of autoantibodies such as anti-DNA and rheumatoid factors, and (d) suppression of lupus glomerulonephritis. However, similar treatment in BALB/c mice did not affect the development of IgG anti-human IgG antibody responses. These results suggest that the protective effect of 5AC is related to the inhibition of the lpr gene-induced T cell proliferation, thereby suppressing the autoimmunity-accelerating effect mediated by the lpr gene.

Animals↗
PubMed1990

Spontaneous production of anti-mouse red blood cell autoantibodies is independent of the polyclonal activation in NZB mice.

New Zealand Black (NZB) mice spontaneously develop an autoimmune hemolytic anemia together with a markedly increased production of polyclonal antibodies. The spontaneous generation of anti-mouse red blood cells (MRBC), anti-bromelain-treated MRBC (BrMRBC) and anti-DNA autoantibodies was compared to the polyclonal antibody formation in irradiated (800 rad) 2-month-old NZB mice reconstituted with bone marrow cells (BMC) from 2- or 10-month-old NZB mice. The injection of 10-month-old NZB BMC markedly accelerated the mortality rate in parallel with the progressive increase of anti-MRBC and anti-BrMRBC autoantibody production, but the spontaneous production of polyclonal IgM antibodies and anti-DNA autoantibodies was completely abolished down to the levels of non-autoimmune mice. In contrast, mice reconstituted with 2-month-old NZB BMC exhibited neither the acceleration of anemia nor the lack of polyclonal antibody production. These results strongly suggest that the spontaneous production of anti-MRBC autoantibodies, including anti-BrMRBC autoantibodies, in the NZB mouse occurs independently of the polyclonal B cell activation, and that they result from a specific immune stimulation, while the anti-DNA autoantibody production is a consequence of polyclonal antibody formation.

Anemia, Hemolytic, Autoimmune↗