JPH03109328A - Transplantation rejection inhibitory agent - Google Patents
Transplantation rejection inhibitory agentInfo
- Publication number
- JPH03109328A JPH03109328A JP1246329A JP24632989A JPH03109328A JP H03109328 A JPH03109328 A JP H03109328A JP 1246329 A JP1246329 A JP 1246329A JP 24632989 A JP24632989 A JP 24632989A JP H03109328 A JPH03109328 A JP H03109328A
- Authority
- JP
- Japan
- Prior art keywords
- subunit
- toxin
- cholera toxin
- inhibitory agent
- transplantation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 230000002401 inhibitory effect Effects 0.000 title abstract 4
- 108010049048 Cholera Toxin Proteins 0.000 claims abstract description 26
- 102000009016 Cholera Toxin Human genes 0.000 claims abstract description 24
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- 239000003112 inhibitor Substances 0.000 claims description 5
- 206010052779 Transplant rejections Diseases 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 abstract description 10
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Description
【発明の詳細な説明】
巌１上匹■几分災
この発明は皮膚、骨髄、臓器を移植した場合に起きる拒
絶反応を防止するための拒絶反応抑制剤に関する。DETAILED DESCRIPTION OF THE INVENTION This invention relates to an anti-rejection agent for preventing rejection reactions that occur when skin, bone marrow, or organs are transplanted.
灸米技権
ヒトその他の哺乳動物において臓器移植を行なう場合、
移植片に対して臓器移植を行われた宿主動物の免疫反応
により、拒絶反応を生ずる場合が多い。このため移植時
においては、宿主に対して免疫抑制剤が投与される。こ
のような抑制剤として従来から種々の物質が使用されて
おり、その代表例としてサイクロスポリンＡを挙げるこ
とができる。Moxibustion Techniques When performing organ transplants in humans or other mammals,
Rejection of the transplanted organ often occurs due to the immune reaction of the host animal to which the organ has been transplanted. Therefore, at the time of transplantation, an immunosuppressant is administered to the host. Various substances have conventionally been used as such inhibitors, and cyclosporin A can be cited as a representative example.
ｌが すべき課電
しかしながら、従来の免疫抑制剤は、皮膚移植、骨髄移
植時の拒絶反応を抑制する効果が十分に満足できるもの
ではなかった。However, conventional immunosuppressants have not been sufficiently effective in suppressing rejection reactions during skin transplantation and bone marrow transplantation.
迭ｍ寵（１支犬−Δ件毛陪
本発明者らは、従来使用されている免疫抑制剤とは全く
異なるタイプの、しかも強力な免疫抑制活性を有する免
疫抑制剤を提供すべく研究を重ねた結果、コレラ菌の生
産するコレラ毒素のＢサブユニットに、このような免疫
抑制活性があることを見出し、本発明に到達したもので
ある。The present inventors have conducted research in order to provide an immunosuppressant that is completely different from conventionally used immunosuppressants and has a strong immunosuppressive activity. As a result of repeated efforts, it was discovered that the B subunit of cholera toxin produced by Vibrio cholerae has such immunosuppressive activity, and the present invention was achieved.
すなわち本発明は（１）コレラ毒素Ｂサブユニットを活
性成分とする移植拒絶反応抑制剤に関するものである。That is, the present invention relates to (1) a transplant rejection inhibitor containing cholera toxin B subunit as an active ingredient.
コレラ毒素は１分子量約２７，０００のサブユニットＡ
１個と分子量約１１ 、６００のサブユニットＢ ５個
とから成る分子量約８４ 、０００の蛋白質である。Cholera toxin is a subunit A with a molecular weight of approximately 27,000.
It is a protein with a molecular weight of about 84,000, consisting of one subunit B and five subunits B with a molecular weight of about 11.600.
本発明の活性成分であるコレラ毒素Ｂサブユニットは分
子量約５８，０００の蛋白質であり、これらのサブユニ
ットのアミノ酸配列はクローニングされたＤＮＡの配列
に基づいて推定されている（Ｊ、Ｊ。The cholera toxin B subunit, which is the active ingredient of the present invention, is a protein with a molecular weight of approximately 58,000, and the amino acid sequences of these subunits have been deduced based on the sequence of cloned DNA (J, J.
Ｍｅｋａｌａｎｏｓ等、Ｎａｔｕｒｅ、３０６．５５１
−５５７．１９８３）。Mekalanos et al., Nature, 306.551
-557.1983).
本発明の拒絶反応抑制剤の活性成分であるコレラ毒素Ｂ
サブユニットは公知物質であるが、その免疫抑制作用に
ついては全く知られていない。Cholera toxin B, which is the active ingredient of the anti-rejection agent of the present invention
Although the subunit is a known substance, its immunosuppressive effect is completely unknown.
この物質はビブリオコレラ（Ｖｉｂｒｉｏ ｃｈｏｌｅ
ｒａｅ）によって生産されるが、本発明において使用さ
れるコレラ毒素Ｂサブユニットは、必ずしもこの菌によ
って生産されたものに限定されず、例えば常法に従う遺
伝子工学的手段によって生産されたものであってもよい
。This substance is Vibrio cholera (Vibrio cholera).
However, the cholera toxin B subunit used in the present invention is not necessarily limited to that produced by this bacterium; for example, it may be produced by genetic engineering means according to conventional methods. Good too.
本発明の実施例で用いたコレラ毒素ＢサブユニットはＲ
ａｐｐａｐｏｒｔら〔インフェクションアンドイムノロ
ジー（Ｉｎｆｅｃｔ、 ｌｌ１ｓｕｎ、）、９ ： ２
９４，１９７４）やＭａｋａｌａｎｏｓら〔インフエク
ションアンドイムノロジー０ｎｆｅｃｔ、 Ｉｎ＋ｍｕ
ｎ、）、２０ ： ５５２，１９７８）の方法を改良し
た方法で、ヴイブリオコレラタイプ（Ｖｉｂｒｉｏ ｃ
ｈｏｌｅｒａｓ ｔｙｐｅ） ５６９Ｂからコレラ毒素
を単離し、さらにＬａｉら〔ジャーナルオブインフェク
シャスデイジーズ（Ｊ、 Ｉｎｆｅｃｔ、 Ｄｉｓ、）
１３３ ：Ｓ ２３．１９７６）の方法の改良により、
Ｂサブユニットを単離し高度精製したものである。The cholera toxin B subunit used in the examples of the present invention is R
Appaport et al. [Infection and Immunology (Infect, ll1sun, ), 9:2
94, 1974) and Makalanos et al.
Vibrio cholera type (Vibrio c.
cholera toxin was isolated from C. holeras type 569B, and further reported by Lai et al.
133:S 23.1976),
The B subunit was isolated and highly purified.
また、ヴイブリオコレラタイプ（Ｖｉｂｒｉｏ ｃｈｏ
ｌｅｒａｅ ｔｙｐｅ） ５６９Ｂの染色体ＤＮＡから
コレラ毒素Ｂサブユニット遺伝子を大腸菌に一１２株の
宿主−ベクター系にクローニングし、クローニングした
ＤＮＡと化学合成りＮＡを用いて局部的変異（ｌｏｃａ
ｌｉｚｅｄ ｍｕｔａｇｅｎｓｉｓ）の方法により、Ｂ
サブユニツ１−蛋白を大腸菌中で発現させた、遺伝子工
学的手法で得られたＢサブユニットを用いた。In addition, Vibrio cholera type (Vibrio cho
The cholera toxin B subunit gene was cloned from the chromosomal DNA of 569B (E.
B by the method of B
Subunit 1 - A B subunit obtained by genetic engineering, in which the protein was expressed in Escherichia coli, was used.
本発明におけるコレラ毒素Ｂサブユニットは、その構造
が、一部アミノ酸の変更、修飾、付加。The structure of the cholera toxin B subunit in the present invention includes some amino acid changes, modifications, and additions.
脱離等で部分的に変形されたものをも、コレラ毒素Ｂサ
ブユニットと同等の免疫抑制効果を有する限りその範囲
に包含するものである。またコレラ毒素Ｂサブユニット
とほぼ類似のアミノ酸枯造を有する大腸菌エンテロトキ
シンＢサブユニソ１−も同様の作用効果を奏し得るもの
で、同様に用いることができる。Those that have been partially modified by detachment or the like are also included within the scope as long as they have an immunosuppressive effect equivalent to that of the cholera toxin B subunit. Furthermore, Escherichia coli enterotoxin B subunit 1-, which has an amino acid structure almost similar to that of the cholera toxin B subunit, can exhibit similar effects and can be used in the same manner.
本発明の免疫抑制剤は、各種の臓器移植において拒絶反
応を除去または緩和するために有用であり１例えば皮膚
移植、腎移植、心移植、肝移植、骨髄移植等において使
用することができる。The immunosuppressive agent of the present invention is useful for eliminating or alleviating rejection reactions in various organ transplants, and can be used, for example, in skin transplants, kidney transplants, heart transplants, liver transplants, bone marrow transplants, and the like.
この発明の移植拒絶反応抑制剤は、移植前または移植と
同時に投与され、必要によりさらに複数回にわたって投
与される。投与経路は非経腸的経路が好ましく、例えば
静脈、腹腔内、筋肉内、皮下注射等により投与される。The transplant rejection inhibitor of the present invention is administered before or at the same time as transplantation, and if necessary, administered multiple times. The administration route is preferably a parenteral route, such as intravenous, intraperitoneal, intramuscular, or subcutaneous injection.
投与に回数、投与期間は移植臓器や移植部位、患者の状
態により異なり、具体的には臨床例ごとに医者の判断に
より適宜決定される。１回の投与量も同様に医師により
判断されるが通常１２０μｇ／ｋｇである。The number of times of administration and the duration of administration vary depending on the organ to be transplanted, the site of transplantation, and the condition of the patient, and are specifically determined as appropriate by the doctor's judgment for each clinical case. The dosage per dose is similarly determined by a physician, but is usually 120 μg/kg.
コレラ毒素Ｂサブユニットの哺乳動物に対する毒性はほ
とんどないが、例えばマウスではＬＤ５０が４０． Ｏ
ＯＯμｇ／ｋｇテｔｏル。Cholera toxin B subunit has almost no toxicity to mammals, but for example, the LD50 in mice is 40. O
OOμg/kg tetol.
本発明の免疫抑制剤は活性成分たるコレラ毒素Ｂサブユ
ニットの外に副成分を、その剤の形態に応じて包含する
がその例としては次のようなものがある。In addition to the cholera toxin B subunit as an active ingredient, the immunosuppressant of the present invention may contain subcomponents depending on the form of the drug, examples of which are as follows.
投与形ｆルにおいて、非口紅投与の場合、例えば注射剤
、或いは直腸坐剤等であり、これらの製剤のいずれも常
法で調製できる。注射用としては。In the case of non-lipstick administration, for example, injections, rectal suppositories, etc. can be used as the dosage form, and any of these preparations can be prepared in a conventional manner. For injection.
注射用蒸留水のようなベヒクル中に、或いは、ゴム油、
ヤシ油、落花生油、綿実油等のような天然植物油又はエ
チルオレート等のような合成樹脂ベヒクルに溶解又はｌ
！ｌ濁させる通常の製剤化に従って処方できる。緩衝剤
、防腐剤、酸化防止剤等も必要に応じて添加できる。in a vehicle such as distilled water for injection, or in rubber oil,
Dissolved or dissolved in natural vegetable oils such as coconut oil, peanut oil, cottonseed oil, etc. or synthetic resin vehicles such as ethyl oleate, etc.
! It can be formulated according to conventional formulations. Buffers, preservatives, antioxidants, etc. can also be added as necessary.
直腸坐剤を調製する場合には、溶血連鎖球菌製剤に賦形
剤、更には必要に応じて、界面活性剤を加えた後、常法
により坐剤とすることができる。When preparing rectal suppositories, after adding excipients and, if necessary, a surfactant to the hemolytic streptococcus preparation, suppositories can be prepared by a conventional method.
経口投与の場合には、例えば、錠剤、被覆錠剤、顆粒剤
、散剤、カプセル剤等の経口用固形製剤。In the case of oral administration, for example, oral solid preparations such as tablets, coated tablets, granules, powders, and capsules.
シロップ剤、ドライシロップ剤、エリキシル剤等の経口
用液状製剤であり、これらの製剤はいずれも常法で調製
できる。These are oral liquid preparations such as syrups, dry syrups, and elixirs, and all of these preparations can be prepared by conventional methods.
より具体的には、錠剤、カプセル剤等の経口用固形製剤
には、トラガカントゴム、アラビアゴム。More specifically, oral solid preparations such as tablets and capsules include gum tragacanth and gum arabic.
コーンスターチ又はゼラチン等の結合剤、微品性セルロ
ース等の賦形剤、コーンスターチ、前ゼラチン化デンプ
ン、アルギン酸等の膨化剤、ステアリン酸マグネシウム
等の潤滑剤、シヨ糖、乳糖又はアスパルテートのような
甘味剤、ペパーミント、アカモノ油又はチェリー等の香
味剤、調剤単位形態がカプセルである場合には更に油脂
のような液状担体をも含めることができる０種々の他の
材料を被覆剤として、又は製剤単位の物理的形態を別の
方法で変化させるために存在させることができる６例え
ば１錠剤はシェラツク、砂糖又はその両方で被覆するこ
とができる。シロップ剤、ドライシロップ剤、エリキシ
ル剤等の経口液状製剤には、甘味剤としてのシヨ糖等、
防腐剤としてのメチル又はプロピルパラベン等１色素及
びチェリー又はオレンジ香味等の香味剤を含めることが
できる。Binders such as corn starch or gelatin, excipients such as microcellulose, leavening agents such as corn starch, pre-gelatinized starch, alginic acid, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or aspartate. flavoring agents such as peppermint, redberry oil, or cherry; and when the dosage unit form is a capsule, it may also contain a liquid carrier such as an oil or fat; various other materials may be used as coatings; For example, one tablet may be coated with shellac, sugar or both. Oral liquid preparations such as syrups, dry syrups, and elixirs contain sweeteners such as sucrose, etc.
Dyes such as methyl or propyl parabens as preservatives and flavoring agents such as cherry or orange flavor may be included.
走携
本発明の移植拒絶反応抑制剤は皮膚、骨髄、臓器を移植
する際に投与することにより、宿主の生体拒絶反応を抑
制することができ、臓器移植の延命効果を大幅に増大さ
せるものである。By administering the transplant rejection inhibitor of the present invention at the time of skin, bone marrow, or organ transplantation, it is possible to suppress the host's biological rejection response and greatly increase the survival effect of organ transplantation. be.
夫立涯
次に、実施例により、この発明の拒絶反応抑制剤の効果
を具体的に説明する。Next, the effects of the anti-rejection agent of the present invention will be specifically explained with reference to Examples.
実施例１．皮膚移植に対する効果
マウスＣ３Ｈ／Ｈｅ （Ｈ−２ｋ）系を受容体動物とし
て使用し、マウスＣ３ＤＢＬ／６ （Ｈ−２ｂ）系を供
給体動物として使用して移植片の生着日数を求めた。実
験群として受容体マウスに移植前日、同日、移植の１日
後、２日後、５日後のいずれかに１２０μｇ／ｋｇのコ
レラ毒素Ｂサブユニットを含む０．２ｍｌのリン酸緩衝
液を静脈内注射した。他方、比較のため、マウスに１日
当り１５μｇ／ｋｇのサイクリスポリンＡを、オリーブ
油に溶解して移植日から１４日間連続経口投与した。Example 1. Effect on Skin Grafts The survival time of the grafts was determined using the mouse C3H/He (H-2k) strain as the recipient animal and the mouse C3DBL/6 (H-2b) strain as the donor animal. As an experimental group, recipient mice were intravenously injected with 0.2 ml of phosphate buffer containing 120 μg/kg of cholera toxin B subunit on the day before, on the same day, or 1, 2, or 5 days after transplantation. . On the other hand, for comparison, 15 μg/kg of Cyclisporin A per day was dissolved in olive oil and orally administered to mice continuously for 14 days from the day of transplantation.
対照マウスには免疫抑制剤を投与することなく皮膚移植
を行なった。移植は供給体マウスの躯幹部から１ ａｓ
Ｘ １ ｅｒａの全層皮膚移用を採取し、これを受容
体マウスの胸部背側に縫着することにより行なった。Control mice underwent skin grafting without administering immunosuppressants. The transplant was carried out from the trunk of the donor mouse at 1 as
A full-thickness skin transfer of X 1 era was performed by harvesting and suturing it to the dorsal thorax of the recipient mouse.
コレラ毒素Ｂサブユニットは遺伝子工学的手法により得
たコレラ毒素Ｂサブユニット遺伝子発現大腸菌を８時間
３７℃でプレインハートインフュージョン培地中で培養
し、増殖した大腸菌を０゜１％トリプシンで溶解し、大
ｆｍ菌内に産生されたＢサブユニットを回収し、ＳＤＳ
で精製したものを用いた。Cholera toxin B subunit is obtained by culturing Escherichia coli expressing the cholera toxin B subunit gene obtained by genetic engineering in plain heart infusion medium at 37°C for 8 hours, and lysing the grown Escherichia coli with 0°1% trypsin. The B subunit produced in E.fm bacteria was collected and SDS
The purified product was used.
この結果、コレラ毒素Ｂサブユニットを皮膚移植の前日
または同日に静脈内注射した場合、顕著な生着日数延命
効果が生じた。すなねち、コレラ毒素Ｂサブユニット投
与群では平均生着日数は〉２０５．２±７．２ （ｎ
＝１０）で、これに対してサイクロスポリンＡ投与群に
おいては２１．４±３．２であり、無処理群においては
１６．１±１．２であった。As a result, when cholera toxin B subunit was intravenously injected on the day before or on the same day as skin transplantation, a remarkable survival effect was produced. In other words, in the cholera toxin B subunit administration group, the average survival time was >205.2±7.2 (n
= 10), whereas in the cyclosporine A administration group it was 21.4±3.2, and in the untreated group it was 16.1±1.2.
受容体マウス Ｃ３Ｈ／ Ｈｅ （Ｈ−２ｋ ）供給体
マウス Ｃ３ＤＢＬ／６ （Ｈ−２ｂ）実施例２゜
コレラ毒素Ｂサブユニット１２０μｇ／ｋｇを含有した
リン酸緩衝液０．２ｍｌを実験マウスである８週令のＣ
３Ｈ／ Ｈｅマウスの尾静脈内に、移植前日に注射した
。移植方法は骨髄細胞２ＸＩＯ７個を実験マウスに６０
０ｒａｄ ａＸ線照射後直ちに静脈内注射した。骨髄
移植の生着の有無は、実験マウスの生死あるいは皮膚移
植により判定した。Receptor mouse C3H/He (H-2k) Provider mouse C3DBL/6 (H-2b) Example 2 0.2 ml of phosphate buffer containing 120 μg/kg of cholera toxin B subunit was added to experimental mouse 8. Weekly C
3H/He mice were injected into the tail vein the day before transplantation. The transplantation method is to transplant 2XIO7 bone marrow cells into experimental mice at 60
Immediately after 0 rad aX-ray irradiation, intravenous injection was given. The survival of bone marrow transplants was determined by whether the experimental mice were alive or dead or by skin transplantation.
コレラ毒素Ｂサブユニットを投与することによって無投
与の場合（２６±２．２）と比べ、マウスの生存日数が
延長した（）２００） 、又移植後２０口目に移植され
た皮膚の生着日数が著しく延長した。By administering cholera toxin B subunit, the survival time of mice was prolonged (200) compared to the case without administration (26 ± 2.2), and the survival of the transplanted skin at the 20th mouth after transplantation. The number of days has increased significantly.
受容体マウス Ｃ３Ｈ／ Ｈｅ
骨髄供与体マウス Ｃ５７ＢＬ／６
〉２１０
サイ９０人ボリンＡ投与 １８、 １９
、 １９、 １９、２０、２０、２３．２３．２５．２
８
無投与
１４．１５．１５．１６．１６．１６．１７．１７．１
７．１８
＞１７０．＞１７０、〉１７０
＞２００．＞２００．＞２００
無投与
２０．２１．２２．２８．３０．３０
実施例３゜
コレラ毒素Ｂサブユニット１２０μｇ／ｋｇを８週令の
ルイスラットの尾静脈内に移植前日に投与した場合、顕
著な生着延長効果を認めた。すなわち、コレラ毒素Ｂサ
ブユニット投与群では平均生着日数は〉１２４±１０で
これに対してサイクロスポリンＡ投与群においては１６
．２±１１であり、無処理群においては１０，０であっ
た。Recipient mouse C3H/He Bone marrow donor mouse C57BL/6 〉210 Rhinoceros 90 bolin A administration 18, 19
, 19, 19, 20, 20, 23.23.25.2
8 No administration 14.15.15.16.16.16.17.17.1
7.18 >170. >170, >170 >200. >200. >200 No administration 20.21.22.28.30.30 Example 3 When 120 μg/kg of cholera toxin B subunit was administered into the tail vein of 8-week-old Lewis rats on the day before transplantation, significant engraftment was observed. A prolonging effect was observed. In other words, the average number of engraftment days in the cholera toxin B subunit-treated group was >124 ± 10 days, compared to 16 days in the cyclosporin A-treated group.
．． 2±11, and 10.0 in the untreated group.
受容体ラット ルイスラット
腎供与体ラット フィッシャーラット生着日数
〉１３５、〉１３５、〉１３４，１２０，１００実験群
コレ５１ＪｔＩ３サブユニツト授与
するものよりもはるかに優れた拒絶反応抑制効果を奏し
得るものである。Recipient rats Lewis rats Kidney donor rats Fischer rats .
Claims (1)
拒絶反応抑制剤(1) Transplant rejection inhibitor containing cholera toxin B subunit as an active ingredient
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1246329A JP2891485B2 (en) | 1989-09-25 | 1989-09-25 | Transplant rejection inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1246329A JP2891485B2 (en) | 1989-09-25 | 1989-09-25 | Transplant rejection inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03109328A true JPH03109328A (en) | 1991-05-09 |
| JP2891485B2 JP2891485B2 (en) | 1999-05-17 |
Family
ID=17146947
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1246329A Expired - Fee Related JP2891485B2 (en) | 1989-09-25 | 1989-09-25 | Transplant rejection inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2891485B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998047529A1 (en) * | 1997-04-23 | 1998-10-29 | Zymogenetics, Inc. | Combinations of antigen and mucosal binding component for inducing specific immunological tolerance |
-
1989
- 1989-09-25 JP JP1246329A patent/JP2891485B2/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998047529A1 (en) * | 1997-04-23 | 1998-10-29 | Zymogenetics, Inc. | Combinations of antigen and mucosal binding component for inducing specific immunological tolerance |
| JP2001523249A (en) * | 1997-04-23 | 2001-11-20 | ザイモジェネティクス，インコーポレイティド | Combination of antigen and mucosal binding component to induce specific immune tolerance |
| US7097845B2 (en) | 1997-04-23 | 2006-08-29 | Jacob Sten Petersen | Combinations of antigen and mucosal binding component for inducing specific immunological tolerance |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2891485B2 (en) | 1999-05-17 |
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