S Waki

The University of Tokyo, Tokyo, Tokyo-to, Japan

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Publications (34)86.18 Total impact

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    ABSTRACT: Plasmodium berghei XAT is an irradiation-induced attenuated variant derived from the lethal strain P. berghei NK65, and its blood-stage parasites are spontaneously cleared in immune competent mice. In the present study, we studied the mechanism of host resistance to blood-stage malaria infection using P. berghei XAT. Infection enhanced Ab-dependent phagocytosis of PRBC by splenic macrophages in wild-type C57BL/6 mice. In contrast, FcR gamma-chain knockout (FcRgamma(-/-)) mice, which lack the ability to mediate Ab-dependent phagocytosis and Ab-dependent cell-mediated cytotoxicity through FcgammaRI, FcgammaRII, and FcgammaRIII, could not induce Ab-dependent phagocytic activity. These FcRgamma(-/-) mice showed increased susceptibility to the P. berghei XAT infection, with eventually fatal results, although they produced comparable amounts of IFN-gamma by spleen cells and anti-XAT Abs in serum. In addition, passive transfer of anti-XAT IgG obtained from wild-type mice that had recovered from infection into FcRgamma(-/-) mice could not suppress the increase in parasitemia, and almost all of these mice died after marked parasitemia. In contrast, passive transfer of anti-XAT IgG into control wild-type mice inhibited the increase in parasitemia. IFN-gamma(-/-) mice, which were highly susceptible to the P. berghei XAT infection, failed to induce Ab-dependent phagocytic activity and also showed reduced production of serum anti-XAT IgG2a isotype compared with control wild-type mice. These results suggest that FcR-mediated Ab-dependent phagocytosis, which is located downstream of IFN-gamma production, is important as an effector mechanism to eliminate PRBC in blood-stage P. berghei XAT infection.
    The Journal of Immunology 06/2001; 166(10):6236-41. · 5.52 Impact Factor
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    ABSTRACT: Babesia microti produces a self-limiting infection in mice, and recovered mice are resistant to reinfection. In the present study, the role of T cells in protective immunity against challenge infection was examined. BALB/c mice which recovered from primary infection showed strong protective immunity against challenge infection. In contrast, nude mice which failed to control the primary infection and were cured with an antibabesial drug did not show protection against challenge infection. Treatment of immune mice with anti-CD4 monoclonal antibody (MAb) diminished the protective immunity against challenge infection, but treatment with anti-CD8 MAb had no effect on the protection. Transfer of CD4(+) T-cell-depleted spleen cells resulted in higher parasitemia than transfer of CD8(+) T-cell-depleted spleen cells. A high level of gamma interferon (IFN-gamma), which was produced by CD4(+) T cells, was observed for the culture supernatant of spleen cells from immune mice, and treatment of immune mice with anti-IFN-gamma MAb partially reduced the protection. Moreover, no protection against challenge infection was found in IFN-gamma-deficient mice. On the other hand, treatment of immune mice with MAbs against interleukin-2 (IL-2), IL-4, or tumor necrosis factor alpha did not affect protective immunity. These results suggest essential requirements for CD4(+) T cells and IFN-gamma in protective immunity against challenge infection with B. microti.
    Infection and Immunity 09/1999; 67(8):4143-8. · 4.07 Impact Factor
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    ABSTRACT: We have examined the roles of gamma interferon (IFN-gamma), nitric oxide (NO), and natural killer (NK) cells in the host resistance to infection with the blood-stage malarial parasite Plasmodium berghei XAT, an irradiation-induced attenuated variant of the lethal strain P. berghei NK65. Although the infection with P. berghei XAT enhanced NK cell lytic activity of splenocytes, depletion of NK1.1(+) cells caused by the treatment of mice with anti-NK1.1 antibody affected neither parasitemia nor IFN-gamma production by their splenocytes. The P. berghei XAT infection induced a large amount of NO production by splenocytes during the first peak of parasitemia, while P. berghei NK65 infection induced a small amount. Unexpectedly, however, mice deficient in inducible nitric oxide synthase (iNOS-/-) cleared P. berghei XAT after two peaks of parasitemia were observed, as occurred for wild-type control mice. Although the infected iNOS-/- mouse splenocytes did not produce a detectable level of NO, they produced an amount of IFN-gamma comparable to that produced by wild-type control mouse splenocytes, and treatment of these mice with neutralizing anti-IFN-gamma antibody led to the progression of parasitemia and fatal outcome. CD4(-/-) mice infected with P. berghei XAT could not clear the parasite, and all these mice died with apparently reduced IFN-gamma production. Furthermore, treatment with carrageenan increased the susceptibility of mice to P. berghei XAT infection. These results suggest that neither NO production nor NK cell activation is critical for the resistance to P. berghei XAT infection and that IFN-gamma plays an important role in the elimination of malarial parasites, possibly by the enhancement of phagocytic activity of macrophages.
    Infection and Immunity 06/1999; 67(5):2349-56. · 4.07 Impact Factor
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    ABSTRACT: We studied whether the infection with a blood-stage murine malaria lethal Plasmodium berghei NK65 induces IL-12 production, and if so, how the IL-12 production is involved in the protection or pathogenesis. The infection of C57BL/6 mice enhanced mRNA expression of IL-12 p40 and also IFN-gamma, IL-4, and IL-10 in both spleen and liver during the early course of the infection. It also enhanced the mRNA expression of TNF-alpha, Fas ligand, and cytokine-inducible nitric oxide synthase. Increased IL-12 p40 production was also observed in the culture supernatant of spleen cells and in sera of infected mice. In addition, the infection caused massive liver injury with elevated serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and body weight loss. Treatment of these infected mice with neutralizing mAb against IL-12 prolonged the survival and diminished the liver injury with reduced elevation of serum serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and decreased body weight loss. However, the anti-IL-12 treatment did not affect parasitemia, and all these mice eventually died. Similar results were obtained when infected mice were treated with neutralizing mAb against IFN-gamma. Moreover, anti-IL-12 treatment greatly reduced the secretion and mRNA expression of IFN-gamma in both spleen and liver. These results suggest that the lethal P. berghei NK65 infection induces IL-12 production and that the IL-12 is involved in the pathogenesis of liver injury via IFN-gamma production rather than the protection.
    The Journal of Immunology 07/1998; 160(11):5500-5. · 5.52 Impact Factor
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    ABSTRACT: The mechanism of development of host resistance to blood-stage malarial infection was studied by use of an irradiation-induced attenuated variant, Plasmodium berghei XAT, obtained from a lethal strain, P. berghei NK65. The infection enhanced mRNA expression of interleukin (IL)-12 p40 and also of interferon (IFN)-gamma, IL-4, IL-10, and cytokine-inducible nitric oxide synthase (iNOS) in spleen. Treatment of these mice with anti-IL-12 or anti-IFN-gamma led to the progression of parasitemia and fatal outcome. Anti-IL-12 treatment significantly reduced the secretion and mRNA expression of IFN-gamma and greatly diminished the augmentation of iNOS mRNA expression. In addition, recombinant IL-12 administration delayed the onset of parasitemia because of the enhanced IFN-gamma production. These results suggest that blood-stage P. berghei XAT infection induces IL-12 production, which is important for the development of host resistance via IFN-gamma production.
    The Journal of Infectious Diseases 07/1998; 177(6):1674-81. · 5.85 Impact Factor
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    ABSTRACT: To investigate the antagonistic effect of IL-12 p40 on IL-12 activity in vivo, we generated transgenic (Tg) mice in which p40 gene was regulated by a liver-specific promoter. Three Tg mouse lines were generated, and they expressed the p40 transgene predominantly in liver. Serum p40 level was extremely high, and it consisted of mainly monomer and homodimer and also of higher m.w. complexes. These Tg mice did not show any apparent phenotypic difference from control littermates in lymphoid cells. Enhancement of NK cell lytic activity in spleen by administration of rIL-12 to these mice was greatly diminished. Ag-induced cytokine production was impaired: decreased production of IFN-γ and increased production of IL-4 and IL-10. Delayed-type hypersensitivity response was also significantly reduced. Moreover, these Tg mice showed increased susceptibility to the infection with an intracellular pathogen, blood-stage Plasmodium berghei XAT, which is an irradiation-induced attenuated substrain of P. berghei NK65, presumably due to the decreased IFN-γ production. These results suggest that p40 functions as an IL-12 antagonist in vivo, and that Th1 responses in p40 Tg mice are significantly reduced. Thus, these Tg mice could be a useful model to evaluate the inhibitory effect of p40 on IL-12-mediated various immune responses in vivo.
    The Journal of Immunology 01/1998; 160(2). · 5.52 Impact Factor
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    ABSTRACT: To investigate the antagonistic effect of IL-12 p40 on IL-12 activity in vivo, we generated transgenic (Tg) mice in which p40 gene was regulated by a liver-specific promoter. Three Tg mouse lines were generated, and they expressed the p40 transgene predominantly in liver. Serum p40 level was extremely high, and it consisted of mainly monomer and homodimer and also of higher m.w. complexes. These Tg mice did not show any apparent phenotypic difference from control littermates in lymphoid cells. Enhancement of NK cell lytic activity in spleen by administration of rIL-12 to these mice was greatly diminished. Ag induced cytokine production was impaired: decreased production of IFN-gamma and increased production of IL-4 and IL-10. Delayed-type hypersensitivity response was also significantly reduced. Moreover, these Tg mice showed increased susceptibility to the infection with an intracellular pathogen, blood-stage Plasmodium berghei XAT, which is an irradiation-induced attenuated substrain of P. berghei NK65, presumably due to the decreased IFN-gamma production. These results suggest that p40 functions as an IL-12 antagonist in vivo, and that Th1 responses in p40 Tg mice are significantly reduced. Thus, these Tg mice could be a useful model to evaluate the inhibitory effect of p40 on IL-12-mediated various immune responses in vivo.
    The Journal of Immunology 01/1998; 160(2):588-94. · 5.52 Impact Factor
  • Journal of Infectious Diseases - J INFEC DIS. 01/1998; 177(6):1674-1681.
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    ABSTRACT: Mice treated with anti-IFN-gamma monoclonal antibodies were unable to recover from infection with an attenuated variant of P. berghei (Pb XAT) which causes non-lethal malaria in normal mice. On the other hand, treatment with anti-IL-4 monoclonal antibodies had no effect on the course of infection. IFN-gamma was produced by spleen cells in vitro during the early phase of the infection. Treatment with anti-IFN-gamma suppressed development of an anti-plasmodial IgG2a immunoglobulin isotype in the serum of infected mice whereas anti-IL-4 interfered with the IgG1 response. An IgG2a fraction of immune serum collected from mice that had recovered from Pb XAT transferred immunity to naive mice but the IgG1 fraction did not. When glutaraldehyde fixed parasitized erythrocytes were incubated with immune serum in suspension, specific IgG2a antibodies were detected by fluorescein staining on the membranes of cells infected with mature stages of parasites. These results indicate that IFN-gamma is a key to inducing B cells to produce the protective antiplasmodial IgG2a immunoglobulin isotype. Antibody-dependent cell-mediated parasite killing seems to be involved in the mechanism of recovery from infection with Pb XAT.
    Parasite Immunology 11/1995; 17(10):503-8. · 2.21 Impact Factor
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    ABSTRACT: Mice treated with anti-IFN-gamma monoclonal antibodies were unable to recover from infection with an attenuated variant of P. berghei (Pb XAT) which causes non-lethal malaria in normal mice. On the other hand, treatment with anti-lL-4 monoclonal antibodies had no effect on the course of infection. IFN-gamma was produced by spleen cells in vitro during the early phase of the infection. Treatment with anti-IFN-gamma suppressed development of an anti-plasmodial IgG2a immunoglobulin isotype in the serum of infected mice whereas anti-IL-4 interfered with the IgGl response. An lgG2a fraction of immune serum collected from mice that had recovered from Pb XA T transferred immunity to naive mice but the IgGl fraction did not. When glutaraldehyde fixed parasitized erythrocytes were incubated with immune serum in suspension, specific IgG2a antibodies were detected by fluorescein staining on the membranes of cells infected with mature stages of parasites. These results indicate that IFN-gamma is a key to inducing B cells to produce the protective anti-plasmodial IgG2a immunoglobulin isotype. Antibody-dependent cell-mediated parasite killing seems to be involved in the mechanism of recovery from infection with Pb XAT.
    Parasite Immunology 09/1995; 17(10):503 - 508. · 2.21 Impact Factor
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    ABSTRACT: The distribution of Dirofilaria immitis acid proteinase in adult worm tissue was examined biochemically and immunohistochemically. About 45% of the total proteinase activity of 700g supernatant, which was obtained from the 0.25 M sucrose homogenate of live adult worms, was found in the 100,000g supernatant by subcellular centrifugation analysis. The distribution pattern of the proteinase activity observed by Percoll density gradient centrifugation coincided with that of glucose-6-phosphatase, a marker cytosolic enzyme, suggesting that the acid proteinase was present in vivo in a membrane-free form, possibly in the cytosol or secretory fluid. Immunostaining for the proteinase in the parasite tissue using the IgG1 (kappa-type) monoclonal antibody, H-1, revealed immunoreactive enzyme primarily inside the cell as small grains, but not on the cell surface, and immunoreactivity was distributed widely in worm tissues such as lateral cords, dorsal and ventral median cords, the anterior end of the parasite, and intestinal epithelial cells in granular form. In the male reproductive system, the testicular wall and germ cells were labeled with the antibody, and in the female, uterine walls, fertilized eggs, and developing eggs as well as microfilaria were labeled. In conclusion, D. immitis acid proteinase is widely distributed in the parasite tissue, possibly functioning not only in nutrition metabolism but also in production of sperm and microfilariae, etc.
    Experimental Parasitology 09/1995; 81(1):63-71. · 2.15 Impact Factor
  • S Waki
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    ABSTRACT: The effects of administrating recombinant human granulocyte colony-stimulating factor (rhG-CSF) and passively transferring immune serum on infection with an attenuated variant of Plasmodium berghei XAT (Pb XAT), in severe combined immunodeficiency (SCID) mice were examined. In immune competent (C.B-17) mice, the attenuated parasite infection was inevitably self-resolving and degenerating forms inside erythrocytes appeared, coinciding with the drop in parasitaemia, whereas SCID mice were unable to control parasite growth and all the mice died. Continuous administration with rhG-CSF caused neutrophilic granulocytosis in both SCID and C.B-17 mice. The effect of rhG-CSF on the infection in C.B-17 mice was to suppress the course of the parasitaemia at an early phase whereas it had no effect in SCID mice. When immune serum was transferred on the day of infection, the prepatent period was prolonged two days in both SCID and C.B-17 mice. When administration with rhG-CSF was combined with transfer of immune serum, SCID mice showed four days delay in patency and degenerating parasites were seen during the course of parasitaemia, although the infection was ultimately fatal. C.B-17 mice similarly treated showed a seven day delay in the onset of the patent parasitaemia which was of a lesser magnitude and shorter in duration compared with control mice. On the other hand, when C.B-17 mice were splenectomized three weeks before infection and then treated with rhG-CSF and immune serum, no degenerating parasites were seen during the infection and all mice died with high parasitaemias.(ABSTRACT TRUNCATED AT 250 WORDS)
    Parasite Immunology 12/1994; 16(11):587-91. · 2.21 Impact Factor
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    ABSTRACT: All CBA mice that had been immunised by means of four successive inoculations of Plasmodium berghei NK65, each inoculation being followed by chemotherapy, survived an intravenous challenge inoculation of parasite, with 4/12 mice developing patent parasitaemia that resolved within 2 weeks. In contrast, all non-immunised control mice died before the 10th day post-challenge. Examination of sera for antibodies revealed that the immunised mice, all of which survived the challenge, had significantly high anti-plasmodial whole IgG, IgG1, and IgG2a titres before the challenge. A 16-fold rise in IgG2a titre alone was recorded on the 5th day post-challenge, with a further boosting of the titre to 4096 being observed on day 10. In comparison, the titres of Ig isotypes in the non-immunised control mice that succumbed to the challenge remained below 4. Specific IgG subclasses, in particular IgG2a, could be involved in the humoral immune protection against this rodent parasite.
    Parasitology Research 02/1994; 80(8):638-41. · 2.85 Impact Factor
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    ABSTRACT: The effect of repeated subcutaneous injections of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on the attenuated Plasmodium berghei XAT infection in CBA mice was examined. When mice were injected with rhG-CSF daily beginning 2 days before infection, the neutrophil count in the peripheral blood increased 5 times higher than that of control mice and the development of parasitaemia was suppressed significantly during the early phase of the infection. This suppressive effect of rhG-CSF was reduced by treatment of the mice with either anti-interferon (IFN)-gamma or anti-tumour necrosis factor (TNF)-alpha immunoglobulins. These results suggest that neutrophils may have a role in immunity against the parasites and that IFN-gamma and TNF-alpha are possibly involved.
    Parasitology Research 02/1993; 79(8):703-5. · 2.85 Impact Factor
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    ABSTRACT: T-cell-mediated immunity to a virulent strain of Plasmodium berghei NK65 (Pb NK65) and to an attenuated derivative (Pb XAT) of the strain were examined in CBA mice by the administration of monoclonal antibodies against T-cell subsets or interferon-gamma (IFN-gamma). The injection of anti-CD8+ or anti-IFN-gamma delayed the mortality of mice infected with Pb NK65, although it did not affect the parasitaemia. In the late stage of PB NK65 infection, T cells, especially CD8+ T cells, were increased in number in the liver at the expense of splenic CD8+ T cells. These CD8+ T cells released IFN-gamma in culture without antigen stimulation and were thought to induce tumour necrosis factor-alpha (TNF-alpha) production by the cells in the liver. In mice infected with Pb XAT, or mice primed with Pb XAT and then challenged with Pb NK65, CD4+ T cells had a crucial role in preventing parasite growth and in protective immunity. IFN-gamma was again the key molecule in protective immunity. These results suggest that T cells stimulated with malaria antigen play important roles both in protective immunity and pathogenesis depending upon their subsets; CD8+ T cells in pathogenesis, and CD4+ T cells in protective immunity. These apparently contradictory responses may be mediated by the same cytokine, IFN-gamma.
    Immunology 05/1992; 75(4):646-51. · 3.71 Impact Factor
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    ABSTRACT: A deoxyribonucleic acid (DNA) hybridization technique was applied to in vitro drug sensitivity testing of P. falciparum using a synthetic 21-mer oligonucleotide coupled to alkaline phosphatase (PFR1-AP) to monitor development of parasite stages in culture. The density of the coloured spot clearly distinguished schizonts from ring forms. This assay system was applied in the field on Hainan Island, China. Blood samples obtained from patients were cultivated in the presence of antimalarial drugs and the minimum drug concentration required to inhibit development of parasites was determined by the DNA hybridization assay and by microscopical observation of Giemsa-stained blood smears. The 2 methods yielded identical results, indicating that the DNA hybridization assay can be used for in vitro drug sensitivity testing under field conditions.
    Transactions of the Royal Society of Tropical Medicine and Hygiene 01/1992; 86(3):227-8. · 1.82 Impact Factor
  • S Waki, T Takagi, M Suzuki
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    ABSTRACT: In virulent Plasmodium berghei infection, mice showed suppressive responses to sheep red blood cells SRBC (PFC) as well as the parasite antigen (DTH) and developed autoantibodies against homologous lymphocytes. On the other hand, mice infected with an attenuated variant derived from P. berghei did not show these responses but developed solid protective immunity against parent parasite infection accompanied by high antibody titre. When such an immune serum was transferred into mice, attenuated parasite infection was completely eliminated. These results show that an attenuated variant stimulates antibody production, which contributes to protection against the parasites. In contrast, in virulent P. berghei infections harmful immunopathological responses against the host are more prominent than protective immune responses against the parasites.
    Parasitology Research 02/1989; 75(8):614-8. · 2.85 Impact Factor
  • Transactions of the Royal Society of Tropical Medicine and Hygiene 01/1989; 83(2):165-6. · 1.82 Impact Factor
  • Zhongguo yao li xue bao = Acta pharmacologica Sinica 04/1988; 9(2):160-3.
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    ABSTRACT: Plasmodium berghei XAT is an irradiation-induced, permanent attenuated derivative from high-virulence P. berghei NK65. Monoclonal antibodies against XAT were developed. By immunofluorescence screening, one monoclonal antibody was identified that was reactive with XAT at the schizont stage but not with NK65 nor with any other stage of intra-erythrocytic development of either parasite. The monoclonal antibody precipitated a 240-kD molecule from metabolically labeled XAT antigens. This molecule was thought to be a marker epitope of the attenuated parasite.
    Parasitology Research 02/1988; 74(5):436-40. · 2.85 Impact Factor