Development of malaria vaccines that block transmission of parasites by mosquito vectors

Malaria is still one of the infectious diseases urgently requiring control and causes socioeconomic burdens on people residing in developing countries. Malaria vaccines are expected to control the disease. However, there is no effective vaccine available despite the intense efforts of malaria scientists. One strategy for a malaria vaccine is to prevent parasite spread by means of interfering with parasite development in mosquito vectors, which is the so-called transmission-blocking vaccine (TBV). We will here review the current progress of TBV

ナゼ アレルギー シッカン ワ ゾウカ シテ イルノカ : メンエキガク ノ タチバ ヨリ

Type I allergic diseases, such as rhinitis, pollinosis and bronchial asthma, are mediated by Th2-type helper T cell induction, specific IgE antibody production and mast cell activation. Increases of these allergic diseases in recent years might be caused by skewed differentiation of T cells toward Th2 cells by some environmental factors including diesel exhaust particles and decreases of virus and bacteria infection in childhood. The decrease of parasite infection is also thought to affect the susceptibility against allergic diseases by eliciting polyclonal IgE production that suppresses mast cell activation. Important clues for prevention and therapy of the allergic diseases would be derived from further investigations of the relationship between the diseases and these environmental factors

Experimental study of combined treatment with tacrolimus and donor splenocytes via the portal vein in small bowel transplantation

We previously reported that the combined treatment of perioperative administration of donor splenocytes via the recipient's portal vein (DSPV) and a short-course Tacrolimus significantly prolonged the survival of fully allogenic grafts in rat small bowel transplantation (SBTX). In the present study we examined whether this effect depended on the quantity of the administered alloantigens in DSPV. In addition, we examined the expression of the surface antigen on T cells of the splenocytes and the induced toleragenic factor, according to the tolerant recipients which in our previous report had shown the prolongation of allogenic transplant small bowel graft survival by the combined treatment of DSPV (1×108 donor splenocytes) and a short-course Tacrolimus. Donor splenocytes were prepared from Brown-Norway (BN (RT1n)) rat spleens for Lewis (LEW (RT1l)) recipients. The recipients (n=10), treated with a short course of Tacrolimus (0.5mg/kg, 0 to 3 days postoperatively) only showed graft rejection with an average of 6.3±1.0 days postoperatively. However, the combined treatment, consisting of DSPV of 1×108 donor splenocytes and a short course Tacrolimus significantly prolonged graft survival to 12.7±2.1 days (n=12, P<0.01). DSPV of less than 1×108 donor splenocytes (5×107 cells and 2.5×107) could not prolong the graft or animal survival under a short-course Tacrolimus treatment. In the tolerant recipients, the CD4 and CD8 percentages of splenocytes were not significantly different from those of control rats or recipients that were treated with short-course Tacrolimus alone. Neverthless, the percentage of Tcr-αβ+ cells expressing IL-2 receptor (R) was significantly lower than in either control rats or the recipients with short-course Tacrolimus. In the suppression assay to one-way mixed lymphocyte response, a toleragenic factor was suggested to the present in the serum of the tolerant recipients. In the present study, it was suggested that the effects of the combined treatment of DSPV and short-course Tacrolimus for the prolongation of graft survival in the rat allogenic SBTX should depended on the quantity of the antigens administered into the portal vein. The beneficial effects of this treatment were reflected in the suppression of IL-2R on the recipient's splenocytes, and tolerogenic factor(s) might subsequently be induced in the tolerant recipient's serum

Role of innate immune cells in protection against Toxoplasma gondii at inflamed site

The intraperitoneal infection with Toxoplasma gondii (T. gondii) caused accumulation of γδ T, NK, NK1.1+T-like (NKT) cells at inflamed sites. To clarify the roles of these cells in protection against T. gondii at the inflamed sites, BALB/c mice were depleted of γδ T, NK, NK and NKT cells by treatment with antibody against TCR-γδ, asialoGM1 or Interleukin-2 receptor β-chain (IL-2Rβ), respectively, prior to infection. Mice treated with anti-TCR-γδ monoclonal antibody (mAb) became more susceptible to infection, whereas mice treated with anti-IL-2Rβ mAb acquired resistance. Treatment with anti-asialoGM1 Ab showed no effect. We previously reported that heat shock protein 65 (HSP65) in macrophages induced by γδ T cells plays an essential role in protective immunity against T. gondii infection, by preventing apoptotic death of infected macrophages. In the present study, we showed that treatment with anti-IL-2Rβ mAb, but not with anti-asialoGM1 Ab, enhanced the HSP65 induction in macrophages, and inhibited Interleukin-4 (IL-4) expression in nonadherent peritoneal exudate cells. Furthermore, neutralization of endogenous IL-4 by anti-IL-4 mAb enhanced the HSP65 induction in macrophages. These findings suggest that NKT cells, but not NK cells, negatively regulate the protective immunity against T. gondii infection possibly by producing IL-4and suppressing HSP65 induction

CD8+ T-cell Activation in Mice Injected with a Plasmid DNA Vaccine Encoding AMA-1 of the Reemerging Korean Plasmodium vivax

Relatively little has been studied on the AMA-1 vaccine against Plasmodium vivax and on the plasmid DNA vaccine encoding P. vivax AMA-1 (PvAMA-1). In the present study, a plasmid DNA vaccine encoding AMA-1 of the reemerging Korean P. vivax has been constructed and a preliminary study was done on its cellular immunogenicity to recipient BALB/c mice. The PvAMA-1 gene was cloned and expressed in the plasmid vector UBpcAMA-1, and a protein band of approximately 56.8 kDa was obtained from the transfected COS7 cells. BALB/c mice were immunized intramuscularly or using a gene gun 4 times with the vaccine, and the proportions of splenic T-cell subsets were examined by fluorocytometry at week 2 after the last injection. The spleen cells from intramuscularly injected mice revealed no significant changes in the proportions of CD8+ T-cells and CD4+ T-cells. However, in mice immunized using a gene gun, significantly higher (P<0.05) proportions of CD8+ cells were observed compared to UB vector-injected control mice. The results indicated that cellular immunogenicity of the plasmid DNA vaccine encoding AMA-1 of the reemerging Korean P. vivax was weak when it was injected intramuscularly; however, a promising effect was observed using the gene gun injection technique

Species-Specific Immunity Induced by Infection with Entamoeba histolytica and Entamoeba moshkovskii in Mice

Entamoeba histolytica, the parasitic amoeba responsible for amoebiasis, causes approximately 100,000 deaths every year. There is currently no vaccine against this parasite. We have previously shown that intracecal inoculation of E. histolytica trophozoites leads to chronic and non-healing cecitis in mice. Entamoeba moshkovskii, a closely related amoeba, also causes diarrhea and other intestinal disorders in this model. Here, we investigated the effect of infection followed by drug-cure of these species on the induction of immunity against homologous or heterologous species challenge. Mice were infected with E. histolytica or E. moshkovskii and treated with metronidazole 14 days later. Re-challenge with E. histolytica or E. moshkovskii was conducted seven or 28 days following confirmation of the clearance of amoebae, and the degree of protection compared to non-exposed control mice was evaluated. We show that primary infection with these amoebae induces a species-specific immune response which protects against challenge with the homologous, but not a heterologous species. These findings pave the way, therefore, for the identification of novel amoebae antigens that may become the targets of vaccines and provide a useful platform to investigate host protective immunity to Entamoeba infections

マラリア原虫の免疫回避メカニズム

感染症の経過は宿主と病原微生物との間の相互作用によって決定される.宿主は進化に伴い病原体を排除するために免疫系を主体とする高度な生体防御システムを構築している.生体防御系により容易に排除されるものは宿主に定着すらできずに病原性を発揮するに至らない.一方,宿主防御システムを回避する手段を獲得したものは宿主内で定着,増殖に成功し,宿主を死に至らしめることすらある.このように感染症では宿主と病原体の激しいせめぎ合いが行われている.マラリアはPlasmodium属の原虫による熱性感染症で,年間3億人の患者,250万人もの死者を出す世界最大規模の感染症である.現在においてもマラリアが猛威を奮っている原因は,特効薬であったクロロキンに耐性を獲得した原虫が拡大したことに加え,いまだに有効なワクチンが開発されていないこと,ヒトにおいてマラリア原虫に対する終生免疫が得られにくいことも挙げられる.これらの事実はマラリア患者においては宿主防御システムが充分に機能していないことを示唆している.実際にマラリア原虫は多様な免疫回避機構を備えていることが多くの研究者により報告されてきている.今後マラリアの撲滅を目指すうえにおいて,まずマラリア原虫の免疫応答系からの回避機構を解明することが先決であると思われる.本稿ではマラリア原虫の宿主免疫制御のメカニズムについて,我々の知見も交えて総説する