Japan Science and Technology Agency

Osaka University

Other

Nippon Zenyaku Kogyo Co., Ltd.

Tadamitsu Kishimoto

Nitto-denko Corporation

Toray Industries, Inc.

Japan Science and Technology Corporation

Dainippon Sumitomo Pharma Co., Ltd.

Independent Administrative Institution Japan Science and Technology Agency

Shizuo Akira

Ken Ishii

Osamu Takeuchi

Cevayir Coban

Masahiro Yamamoto

Toshio Hirano

Hiroshi Isshiki

Shigemi Kinoshita

Osamu Tanabe

Takuya Shimamoto

Mitsuhiko Hori

Daisuke Asari

Arimichi Okazaki

Masahiro Fukasaka

Toshihiro Tsukui

Hideki Narumi

Hideyuki Tomizawa

Takashi Yamaoka

Tomokatsu Iwamura

Hajime Masumoto

Akihito Kaneda

Yoshikatsu Igari

Akiko Soneda

Yasumasa Kano

Hiroaki Hemmi

Akina Otsuki

Kiyoshi Takeda

Taro Kawai

Kazufumi Matsushita

Keiichi Ohata

The instant invention is to provide a method for detecting and measuring malaria infection utilizing the induction by hemozoin (HZ); a method for screening a vaccine for malaria infection and a preventative or therapeutic agent for malaria infection using the method for detecting and measuring; and a means for regulating the induction of innate immunity using the HZ, synthetic HZ, or derivatives thereof as an adjuvant or immunostimulant. Malaria infection is detected and measured of by detecting and measuring HZ-induced, TLR9-mediated, and MyD88-dependent innate immune activity. The detection and measurement of malaria infection can be used to diagnose malaria infection. The method for detecting and measuring is also used for screening a vaccine for malaria infection and a preventative or therapeutic agent for malaria infection. Further, HZ, synthetic HZ, or derivatives thereof are used as an adjuvant or immunostimulant to regulate HZ-induced innate immune induction.

Detection/measurement of malaria infection disease utilizing natural immunity by hemozoin induction, screening of preventative or therapeutic medicine for malaria infection disease, and regulation of natural immunity induction

This invention provides a method of preparing a &#x3b2;-hematin crystal comprising a step of heating, the &#x3b2;-hematin crystal obtained by such method, and a vaccine adjuvant composition containing the &#x3b2;-hematin crystal. The &#x3b2;-hematin crystal has a needle-like morphology, it has an average particle size of 0.6 to 1.2 &#x3bc;m, and it exhibits main peaks characteristics for angles of diffraction (2&#x3b8;) of 7.4&#xb0;, 12.2&#xb0;, 21.6&#xb0;, and 24.1&#xb0; in an X-ray diffraction pattern obtained by powder X-ray diffractometry with Cu&#x2014;K&#x3b1; rays (with each peak including a plus-minus 0.2&#xb0; diffraction angle).

Method for producing beta-hematin crystal comprising step of heating

An intraorally administrable vaccine composition useful to be a preventive or therapeutic agent for infectious diseases, and effectively induces a systemic immune response or a mucosal immune response is provided. A vaccine composition for administration to the oral cavity of a human or an animal, the vaccine composition containing at least one antigen derived from an infectious disease, and at least one selected from the group consisting of a toll-like receptor 4 (TLR4) agonist, a toll-like receptor 2/6 (TLR2/6) agonist, and cyclic dinucleotide, or a derivative or salt thereof.

Vaccine composition

The present invention provides a vaccine adjuvant composition which is used in combination with an allergen vaccine, infection vaccine or tumor vaccine. The present invention specifically provides a vaccine adjuvant composition comprising hemozoin or &#x3b2;-hematin and being used in combination with an allergen vaccine, infection vaccine or tumor vaccine, and a vaccine composition comprising the vaccine adjuvant composition and an allergen vaccine, infection vaccine or tumor vaccine.

Adjuvant

Disclosed is a composition comprising, as an active ingredient, at least one selected from the group consisting of a Zc3h12a gene inhibitor and a Zc3h12a protein inhibitor. This composition can be used as an immunoadjuvant.

Immunoadjuvant composition and use thereof

A novel immunostimulatory oligonucleotide by which an IFN-inducing activity is enhanced and an inflammatory cytokine-inducing activity is reduced, and a pharmaceutical containing the same, and an application thereof are provided. That is, the present invention provides the immunostimulatory oligonucleotide composed of a base sequence represented by a formula: 5'-(G)PXCGYQ(G)-3&#x2032; (SEQ ID NO: 118) (X and Y are mutually independent and represent an arbitrary sequence which has a length of 0 to 10 nucleotides and does not contain 4 or more consecutive G residues, and a length of X+Y is 6 to 20 nucleotides; XCGY contains a palindrome sequence having a length of at least 8 nucleotides and has a length of 8 to 22 nucleotides; P and Q are mutually independent and represent one nucleotide other than G; M represents an integer of 6 to 10 and N represents an integer of 0 to 3) wherein a full length thereof is 16 to 37 nucleotides (except for an oligonucleotide composed of a base sequence represented by SEQ ID NO:5), the pharmaceutical application thereof.

Immunostimulatory oligonucleotides and use thereof in pharmaceuticals

The present invention relates to provide a non-human animal model unresponsive to a synthetic compound wherein a gene function encoding TLR7 that recognizes an immunopotentiating synthetic compound such as imidazoquinoline lacks on is genomic locus. Whole or part of a gene fragment of a gene site including an intracellular region and a transmembrane region of a TLR7 gene obtained from a mouse gene library is replaced by a plasmid including poly A signal and a marker gene to construct a targeting vector. Then, this targeting vector is linearized and transferred into embryonic stem cells. The target embryonic stem cells wherein the TLR7 gene function is deleted are microinjected into a mouse blastocyst to generate a chimeric mouse. Then, this chimeric mouse is crossed with a wild-type mouse to generate a heterozygote mouse. Next, the heterozygote mice are intercrossed to obtain a TLR7 knockout mouse.

Nonhuman model animal unresponsive to immunopotentiating synthetic compound

The present invention is to provide a non-human animal model non-responsive especially to endotoxin being a Gram-negative bacteria cell wall fraction, which is useful to elucidate the function of TIR domain-containing TRIF-related adaptor molecule (TRAM); and a method for screening substances promoting or suppressing responses to ligands recognized by TLR4 with the use of the non-human animal model non-responsive to endotoxin; and the like. Mice non-responsive to the endotoxin wherein a part or a whole of Tram genes on their chromosome are deleted, the function to express TRAM which is expressed in wild-types is lacked, and the responsiveness to ligands recognized by TLR4 is specifically impaired; is used for screening substances promoting or suppressing responses to ligands recognized by TLR4.

Endotoxin-nonresponsive model animal

The present invention provides a receptor protein specifically recognizing bacterial DNA having an unmethylated CpG sequence, a genomic DNA encoding it, an experimental animal model useful for examining responsiveness of a host immune cell against a bacterial infectious disease. DNA encoding a receptor protein specifically recognizing bacterial DNA having an unmethylated CpG sequence is screened by BLAST search, a number of EST clones having high homology with various TLRs is screened, these clones are used as a probe to isolate a full-length cDNA from mouse macrophage cDNA library, and the sequence of bases of the cDNA is analyzed to confirm that it is TLR9 comprising a conserved regions such as LRR and TIR regions, and then a knockout mouse is produced to confirm that TLR9 is a receptor protein of oligonucleotides having an unmethylated CpG sequence of bacterial DNA.

Transgenic toll-like receptor 9 (TLR9) mice

An object of the present invention is to provide a non-human animal model unresponsive to a mycoplasma-derived lipoprotein/lipopeptide, and a method for screening an inhibitor or a promoter for a response to a mycoplasma-derived lipoprotein with the use of the non-human animal model. A non-human animal model whose function of a gene that encodes a protein such as TLR6 that specifically recognizes a mycoplasma-derived lipoprotein is deficient on its chromosome, for example, a TLR6 knockout mouse, is generated. With the use of the non-human animal model unresponsive to a mycoplasma-derived lipoprotein or an immune cell such as a macrophage derived from the non-human animal model, a subject material and a mycoplasma-derived lipoprotein, a response to a mycoplasma-derived lipoprotein in the non-human animal model or the immune cell is measured/evaluated, and then an inhibitor or a promoter for a response to that is screened.

Nonhuman animal model non-responsive to mycoplasma-origin lipoprotein/lipopeptide

The present invention is to provide TLR1 knockout mice specifically recognizing mycobacterial lipoproteins/lipopeptides, being useful to clarify the role of TLR1 in vivo, or a method for screening substances promoting or suppressing the response to mycobacterial lipoproteins/lipopeptides by using the same. TLR1 genes are separated from murine genomic library, the genomic part containing the intracellular and transmembrane domain of the TLR1 gene is replaced with a neomycin resistant gene, HSV-tk gene being gene encoding thymidine kinase into 3' end is introduced, ES cell clones having double resistance to G418 and Gancyclovir are screened, and ES cell clones are injected into the blastocyst of C57BL/6 mice, to generate TLR1 knockout mice through the germline.

Model animals non-responsive to mycobacterial-origin lipoprotein/lipopeptide

A knockout mouse which is unresponsive to peptidoglycan, a lipoprotein/lipopeptide and the like, and is useful for elucidating the contribution of individual members of the TLR family to a signaling stimulated with bacterial cell components in vivo, in particular, the role of TLR2 and MyD88 in vivo. A bacterial cell component-unresponsive knockout mouse is generated by a process comprising the steps of: a targeting vector is constructed by replacing a whole or a part of a gene fragment of an exon region containing a cytoplasmic region of TLR2 or MyD88 gene and the like with a plasmid having a poly A signal and a marker gene; the targeting vector is introduced into an embryonic stem cell; the targeting embryonic stem cell having a homologously recombined TLR2 or MyD88 gene is microinjected into the blastocyst of a mouse and the blastocyst is put back into the uterus of a recipient mouse.

Bacterial cell component-unresponsive model mouse

The nucleic acid sequence encoding mammalian serine/threonine protein kinase comprising a leucine zipper motif (Zip-kinase) and the corresponding amino acid sequence are disclosed. The Zip-kinase is a nuclear enzyme having activity of inducing apoptosis. A victor and a transformed cell with the nucleic acid sequence as well as recombinant method of making the Zip-kinase utilizing the transformed cell are taught.

DNA coding for serine/threonine kinase

There is provided a DNA coding for a serine/threonine kinase. Thus, the present invention provides a DNA coding for a protein (a) or (b):

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Osaka, Japan

Shizuo Akira