KR101187319B1 - Method for treating sepsis and septic shock using low dose radiation - Google Patents
Method for treating sepsis and septic shock using low dose radiation Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
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Abstract
본 발명은 저준위 방사선을 이용한 패혈증 및 패혈증성 쇼크 치료 방법에 관한 것으로, 더욱 상세하게는, 상기 저준위 방사선은 패혈증에 의해 증가한 자연살해(natural killer, NK)세포의 활성을 억제하여 과염증반응을 막아 생체 내 항상성을 유지시키는 작용을 할 뿐만 아니라, 조직 내 증가한 NK세포의 비율을 감소시켜 패혈증으로 인한 장기 손상을 방지하여 급성 염증반응을 초기에 제어함으로써 패혈증 및 패혈증성 쇼크의 치료에 유용하게 사용될 수 있다.The present invention relates to a method for treating sepsis and septic shock using low-level radiation, and more particularly, the low-level radiation inhibits the activity of natural killer (NK) cells increased by sepsis to prevent over-inflammatory reactions. In addition to maintaining homeostasis in vivo, it can be useful for the treatment of sepsis and septic shock by reducing the percentage of increased NK cells in tissues, preventing long-term damage caused by sepsis, and controlling acute inflammatory responses early. have.
저준위 방사선, 패혈증, 패혈증성 쇼크, 자연살해(natural killer, NK)세포 Low level radiation, sepsis, septic shock, natural killer (NK) cells
Description
본 발명은 저준위 방사선을 이용한 패혈증 및 패혈증성 쇼크 치료 방법에 관한 것이다.The present invention relates to a method of treating sepsis and septic shock using low level radiation.
신체가 감염균, 즉 세균, 진균 또는 바이러스에 의해 침습이 되면 이에 맞서서 면역세포와 염증성 사이토카인 등 많은 방어 시스템이 작동한다. 이러한 반응에 의해서 신체기관이 손상되거나 장애를 일으키기도 한다. When the body is invaded by infectious bacteria, such as bacteria, fungi or viruses, many defense systems work against immune cells and inflammatory cytokines. These reactions can damage or damage organs.
패혈증(sepsis)은 감염된 미생물에 대항하는 신체의 비정상적인 방어작용에 의해 발생한다. 대식세포의 활성화와 이에 따른 염증관련 인자들의 과도한 생성이 연관되어 있는데, 이로 인해 전신에 심각한 염증 반응이 나타난다. 체온이 38℃ 이상으로 올라가는 발열 증상, 36℃ 이하로 내려가는 저체온증, 분당 24회 이상의 호흡수(빈호흡), 분당 90회 이상의 심박수(빈맥), 혈액 검사상 백혈구 수의 증가 또는 현저한 감소 중 두 가지 이상의 증상을 보이는 경우, 이를 전신성염증반응증후군(systemic inflammatory response syndrome; SIRS)이라 하고, 이러한 전신성염 증반응증후군이 미생물의 감염에 의한 것일 때 패혈증이라고 한다. 패혈증은 잠재적으로 패혈증성 쇼크(septic shock)를 유발할 수 있다. 패혈증이 심해지면 신체의 여러 기관(심장, 신장, 간, 뇌, 폐 등)의 기능이 나빠지고 더욱 심해지면 쇼크 상태가 되는 것이다. 다양한 종류의 병원체로 인해 패혈증이 발병할 수 있는데, 가장 발생률이 높은 것은 박테리아에 의한 것이지만 그 외에도 바이러스나 곰팡이에 의해서도 일어날 수 있다. 폐에 감염을 일으키는 폐렴, 방광과 신장에 감염을 일으키는 요도감염, 피부에 일어나는 봉소염, 복부에 일어나는 충수염 또는 뇌에 일어나는 뇌막염 등이 있으며, 예를 들면 폐렴을 앓고 있는 환자가 패혈증에 걸리게 되면 뇌, 심장, 간, 폐 또는 신장에 손상이 일어나며 중증으로 진전되는 경우 환자의 약 20 ~ 50%는 패혈증성 쇼크에 의해 사망한다. 또한, 수술 후 감염에 의해 패혈증이 발생하기도 한다. 감염 또는 수술 후 감염에 의한 초급성 염증반응으로서 패혈증에 걸리게 되면 40 ~ 90%가 사망에 이르게 된다. Sepsis is caused by the body's abnormal defense against infected microorganisms. Activation of macrophages is associated with excessive production of inflammation-related factors, resulting in severe inflammatory responses throughout the body. Two or more of the symptoms of fever that rises above 38 ° C, hypothermia below 36 ° C, respiratory rate of at least 24 times per minute, respiratory rate of at least 90 times per minute, and an increase or significant decrease in white blood cell counts on blood tests In case of showing symptoms, it is called systemic inflammatory response syndrome (SIRS), and it is called sepsis when the systemic inflammatory response syndrome is caused by microbial infection. Sepsis can potentially cause septic shock. As sepsis worsens, the body's various organs (heart, kidneys, liver, brain, lungs, etc.) become worse, and when it gets worse, it becomes shock. Different types of pathogens can cause sepsis. The most common cause is sepsis, but can also be caused by viruses or fungi. Pneumonia, which infects the lungs, urinary tract infections that cause infections in the bladder and kidneys, cellulitis on the skin, appendicitis on the abdomen, or meningitis on the brain.For example, when a patient with pneumonia develops sepsis, Injuries to the heart, liver, lungs or kidneys and in severe cases, about 20-50% of patients die from septic shock. In addition, sepsis may be caused by postoperative infection. Infection or postoperative infection, acute inflammatory reactions caused by sepsis, 40 to 90% of deaths.
패혈증 치료 방법으로는 정상 혈압을 유지하기 위한 수액과 약물 투여, 감염을 치료하기 위한 약물 투여, 산소공급, 인공호흡장치, 영양공급, 감염을 치료하기 위한 부신피질호르몬 투여 등이 있다. 패혈증의 원인이 되는 장기의 감염을 치료하는 것이 중요하고, 적절한 항생제를 사용하여 감염증을 치료한다. 또한, 혈관 수축제를 사용하여 혈압 상승을 유도하고, 심각한 패혈증으로 생명에 위협을 줄 정도의 장기 손상이 있을 경우 활성화단백질C를 처방하여 패혈증으로 인한 과도한 면역반응을 억제시킨다. 그 외에도 낮은 도수의 코르티코스테로이드, 혈당유지를 위한 인슐린, 또는 진통제나 신경안정제가 처방되기도 한다. 감염 및 수술 후의 감 염 등 초급성 중증 질환인 패혈증에 대한 약물 치료가 개선되고 있으나, 패혈증과 같은 과반응성 염증반응을 효과적이고 신속하게 치료할 수 있는 임상적인 약물 또는 치료 방법은 거의 없는 실정이다. 현재까지, 패혈증 치료와 관련된 발명으로는, 알로에 추출물(대한민국 등록특허 10-0876979), 금은화 추출물(대한민국 등록특허 10-0841408), 라이소포스파티딜콜린(lysophosphatidylcholine) 화합물 또는 홍삼 사포닌 전환체인 화학물 K(compound K)(대한민국 등록특허 10-0842160)의 패혈증 치료 효과가 보고되었고, 인터루킨 IL-18 항체 또는 IL-18 결합 단백질을 이용한 패혈증 치료용 조성물(대한민국 등록특허 10-0877033)이 보고되었으며, 종양세포장해인자(Tumor Cytotoxic Factor-II, TCF-II)를 이용한 패혈증 치료제(대한민국 등록특허 10-0572044)가 보고된 바 있다.Treatment of sepsis includes the administration of fluids and drugs to maintain normal blood pressure, drug administration to treat infections, oxygenation, ventilation, nutrition, and corticosteroids to treat infections. It is important to treat the infections of the organs that cause sepsis, and treat the infection with the appropriate antibiotic. In addition, blood vessel constrictors are used to induce an increase in blood pressure, and when there is a long-term damage to life-threatening sepsis, activating protein C is prescribed to suppress excessive immune response due to sepsis. In addition, low-frequency corticosteroids, insulin for blood sugar maintenance, or analgesics or neurostabilizers may be prescribed. Drug treatment for sepsis, acutely severe disease such as infection and postoperative infection, has been improved, but there are few clinical drugs or treatments that can effectively and promptly treat overreactive inflammatory reactions such as sepsis. To date, inventions related to the treatment of sepsis include aloe extract (Korean Patent No. 10-0876979), gold silver extract (Korean Patent No. 10-0841408), lysophosphatidylcholine compound or red ginseng saponin converting chemical K (compound) K) (Korean Patent Registration No. 10-0842160) has been reported for the treatment of sepsis, the composition for treating sepsis using interleukin IL-18 antibody or IL-18 binding protein (Korea Patent Registration 10-0877033), tumor cell disorders Sepsis treatment using a factor (Tumor Cytotoxic Factor-II, TCF-II) (Korean Patent Registration 10-0572044) has been reported.
한편, 자연면역세포와 획득면역세포는 외부병원균으로부터 인체를 보호하는 방어기전을 수행하여 건강 및 생명 유지의 역할을 담당한다. 특히, 자연살해(natural killer, NK)세포는 선천 면역을 주관하는 세포로서, 바이러스 등과 같은 외부감염균이 체내에 침입을 하였을 경우, 감염균 또는 감염균에 감염된 세포 등을 살해하는 효과를 가지고 있다. 따라서 NK세포는 초기 염증반응을 매개하지만, 활성이 지나치면 급성염증반응을 초래하여 조직손상 및 과염증반응을 일으켜 패혈증 및 패혈증성 쇼크를 유발 또는 악화시킬 수 있다. On the other hand, natural immune cells and acquired immune cells play a role in maintaining health and life by performing a defense mechanism to protect the human body from external pathogens. In particular, natural killer (NK) cells are cells that control innate immunity, and when an external infection such as a virus or the like invades the body, it has the effect of killing an infected or infected cell. Therefore, NK cells mediate the initial inflammatory response, but excessive activity can lead to acute inflammatory reactions, resulting in tissue damage and overinflammatory reactions, which can cause or worsen sepsis and septic shock.
저준위 방사선(low dose radiation, LDR)은 강도가 낮은 방사선을 가리키며 자연에 가까운 보통의 것을 말한다. 다량의 방사선은 생물체에 해를 줄 수 있지만 이러한 소량의 저준위 방사선은 오히려 생명체의 생리활동이 촉진되어 수명이 연장되거나 성장촉진 또는 종양 발생율이 저하되는 등 유익한 효과를 준다고 보고되고 있다. 이를 방사선 호메시스(radiation hormesis)라 한다. 밀리그레이(milligray, mGy) 범위의 저준위 방사선은 고준위 방사선과는 달리 질병에 대한 저항성을 유발하고 적응 보호(adaptive protection) 효과를 나타낸다고 보고되었고(Sakai K., et al., Dose Response, 2006, 4(4):327~332; Sakai K., et al, Int . J. Low Radiat ., 2003, 1(1):142~146; Scott BR., Dose Response, 2008, 6(3):299~318), 당뇨병 유전인자를 가진 실험 생쥐에 일정량의 저준위 방사선을 조사하였더니 병세가 호전되었다는 보고가 있다(Sakai K., et al., Dose Response, 2006, 4(4):327~332). 0.25 Gy 이하의 방사선은 DNA 손상를 방어하고 손상된 DNA를 복구하는 효과(Le XC., et al., Science, 1998, 280(5366):1066~1069)가 있으며, 저준위 방사선은 면역증강효과(Nogami M., et al., Int . J. Radiat . Biol ., 1993, 63(6):775~783; Nogami M., et al., Radiat . Res ., 1994, 139(1):47~52)를 나타낸다고 알려졌다. 그러나 저준위 방사선 조사가 과염증반응을 억제하여 패혈증 치료에 관여한다고 보고된 바는 없다.Low dose radiation (LDR) refers to radiation that is low in intensity and usually close to nature. Large amounts of radiation can harm organisms, but such low levels of radiation have been reported to have beneficial effects, such as promoting the physiological activity of living organisms, prolonging their life, promoting growth, or decreasing the incidence of tumors. This is called radiation hormesis. Low-level radiation in the milligray (mGy) range, unlike high-level radiation, has been reported to induce disease resistance and to have an adaptive protection effect (Sakai K., et al., Dose Response , 2006, 4 (4): 327-332; Sakai K., et al, Int . J. Low Radiat . , 2003, 1 (1): 142-146; Scott BR., Dose Response , 2008, 6 (3): 299 ~ 318), There was a report that the condition improved after irradiation of a certain amount of low-level radiation in experimental mice with diabetic genetic factors (Sakai K., et al., Dose Response , 2006, 4 (4): 327-332). Radiation below 0.25 Gy protects DNA damage and repairs damaged DNA (Le XC., Et al., Science , 1998, 280 (5366): 1066 ~ 1069). ....., et al , Int J. Radiat Biol, 1993, 63 (6):... 775 ~ 783; Nogami M., et al, Radiat Res, 1994, 139 (1): 47 ~ 52) It is known to indicate. However, low-level irradiation has not been reported to be involved in the treatment of sepsis by inhibiting over-inflammatory responses.
이에, 본 발명자들은 초급성 중증 질환인 패혈증의 과염증반응을 신속하게 치료할 수 있는 효과적인 기술에 관하여 연구하던 중, 0.2 Gy 이하의 저준위 방사선(low dose radiation)의 조사가 패혈증에 의해 증가한 NK세포의 활성을 억제하여 과염증반응을 막아 생체 내 항상성을 유지시키는 작용을 하고, 조직 내 증가한 NK세포의 비율을 감소시켜 패혈증으로 인한 장기 손상을 방지하여 급성 염증반응을 초기에 제어함으로써 패혈증 및 패혈증성 쇼크의 치료를 위해 유용하게 사용될 수 있음을 밝힘으로써 본 발명을 완성하였다. Therefore, while the present inventors are researching an effective technique for rapidly treating the hyperinflammatory reaction of sepsis, which is a severe acute disease, the irradiation of low dose radiation of 0.2 Gy or less of NK cells increased by sepsis Suppresses activity and prevents over-inflammatory reactions to maintain homeostasis in vivo, and decreases the percentage of increased NK cells in tissues to prevent long-term damage caused by sepsis, thereby controlling acute inflammatory reactions early to prevent sepsis and septic shock. The present invention has been completed by revealing that it can be usefully used for the treatment of.
본 발명의 목적은 저준위 방사선을 이용한 패혈증 및 패혈증성 쇼크 치료 방법을 제공하는 것이다.It is an object of the present invention to provide a method for treating sepsis and septic shock using low level radiation.
상기 목적을 달성하기 위하여, 본 발명은 패혈증에 걸린 인간을 제외한 포유류에 저준위 방사선을 조사하는 단계를 포함하는 패혈증 치료 방법을 제공한다.In order to achieve the above object, the present invention provides a method for treating sepsis, which comprises irradiating low-level radiation to a mammal other than a human suffering from sepsis.
또한, 본 발명은 패혈증에 걸린 인간을 제외한 포유류에 저준위 방사선을 조사하는 단계를 포함하는 패혈증성 쇼크 예방 및 치료 방법을 제공한다.In addition, the present invention provides a method for preventing and treating sepsis, including irradiating low-level radiation to a mammal other than a human suffering from sepsis.
또한, 본 발명은 과반응성 염증 질환에 걸린 인간을 제외한 포유류에 저준위 방사선을 조사하는 단계를 포함하는 과반응성 염증 질환 치료 방법을 제공한다.The present invention also provides a method for treating overreactive inflammatory disease comprising irradiating low-level radiation to a mammal other than a human suffering from a hyperreactive inflammatory disease.
본 발명의 저준위 방사선(low dose radiation)의 조사는 패혈증에 의해 증가한 NK세포의 활성을 억제하고 조직 내 증가한 NK세포의 비율을 감소시켜 패혈증으로 인한 장기 손상을 방지하여 급성 염증반응을 초기에 제어함으로써 급성 감염 면역반응에 따른 과도한 면역관련물질의 분비에 의한 돌연사망을 방지하고 생체 내 항상성을 유지하여, 패혈증 및 패혈증성 쇼크의 치료를 위해 유용하게 사용될 수 있다.Irradiation of low dose radiation of the present invention inhibits the activity of NK cells increased by sepsis and reduces the percentage of increased NK cells in tissues, thereby preventing organ damage caused by sepsis, thereby controlling the acute inflammatory response early. It can be useful for the treatment of sepsis and septic shock by preventing sudden death by excessive secretion of immune-related substances due to an acute infectious immune response and maintaining homeostasis in vivo.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 패혈증에 걸린 개체에 저준위 방사선을 조사하는 단계를 포함하는 패혈증 치료 방법을 제공한다.The present invention provides a method for treating sepsis, comprising irradiating low-level radiation to an individual suffering from sepsis.
또한, 본 발명은 패혈증에 걸린 개체에 저준위 방사선을 조사하는 단계를 포함하는 패혈증성 쇼크 예방 및 치료 방법을 제공한다.The present invention also provides a method for preventing and treating septic shock, comprising irradiating low-level radiation to an individual suffering from sepsis.
상기 저준위 방사선은 알파선, 베타선, 감마선, 전자선, 자외선 및 X선으로 구성된 군으로부터 선택된 어느 하나인 것이 바람직하고 감마선인 것이 더욱 바람직하나 이에 한정하지 않는다.The low level radiation is preferably any one selected from the group consisting of alpha rays, beta rays, gamma rays, electron rays, ultraviolet rays and X-rays, and more preferably gamma rays, but not always limited thereto.
상기 저준위 방사선의 원하는 효과를 나타낼 수 있는 바람직한 범위는 0.01 내지 0.5 Gy이며, 0.1 ~ 0.3 Gy인 것이 더욱 바람직하고, 0.2 Gy인 것이 가장 바람직하나 이에 한정하지 않는다.The preferred range that can exhibit the desired effect of the low level radiation is 0.01 to 0.5 Gy, more preferably 0.1 to 0.3 Gy, most preferably 0.2 Gy, but is not limited thereto.
상기 개체는 척추동물이고 바람직하게는 포유동물이며, 그보다 바람직하게는 쥐, 토끼, 기니아피그, 햄스터, 개, 고양이와 같은 실험동물이고, 가장 바람직하게는 침팬지, 고릴라와 같은 유인원류 동물이다.The subject is a vertebrate and preferably a mammal, more preferably an experimental animal such as a rat, rabbit, guinea pig, hamster, dog, cat, and most preferably an ape-like animal such as a chimpanzee or gorilla.
상기 저준위 방사선은 패혈증으로 인한 면역세포의 활성 증가를 억제하는 것이 바람직하고, 상기 면역세포는 NK세포인 것이 바람직하나 이에 한정하지 않는다. The low-level radiation is preferably to suppress the increase of the activity of immune cells due to sepsis, the immune cells are preferably NK cells, but is not limited thereto.
상기 저준위 방사선은 패혈증으로 인한 장기 손상을 억제하는 것이 바람직하 고, 상기 장기는 간, 폐, 신장, 비장, 림프절, 심장 및 뇌로 이루어진 군으로부터 선택되는 어느 하나 이상의 장기인 것이 바람직하나 이에 한정하지 않는다.The low level radiation preferably inhibits organ damage caused by sepsis, and the organ is preferably one or more organs selected from the group consisting of liver, lung, kidney, spleen, lymph node, heart and brain, but is not limited thereto. .
본 발명자들은 저준위 방사선의 패혈증 및 패혈증성 쇼크의 예방 또는 치료 효과를 확인하기 위하여, 독소로 작용하여 과도한 면역반응에 의해 패혈증을 일으키는 세포벽 성분인 리포폴리사카라이드(lipopolysaccharide, LPS)로 생쥐에 패혈증을 유발하였다. 패혈증 모델 생쥐 또는 정상 생쥐에 저준위 방사선을 4.3 mGy/hour의 조건에서 2일 동안 연속조사하여 총 0.2 Gy 선량의 방사선을 조사하였다(도 1 참조). 저준위 방사선을 조사한 후, 패혈증에서 과도한 활성을 보이는 비장조직에서의 NK세포의 활성 및, 간 조직에서의 NK세포 및 T세포의 분포를 확인하였다. In order to confirm the prevention or treatment effect of sepsis and septic shock of low-level radiation, the present inventors induce sepsis in mice with lipopolysaccharide (LPS), a cell wall component that acts as a toxin and causes sepsis by an excessive immune response. Induced. The sepsis model mice or normal mice were irradiated with a total of 0.2 Gy doses by continuous irradiation for 2 days at a level of 4.3 mGy / hour (see Fig. 1). After irradiation with low-level radiation, the activity of NK cells in spleen tissues showing excessive activity in sepsis and the distribution of NK cells and T cells in liver tissues were confirmed.
패혈증을 유발하지 않은 정상 생쥐에 저준위 방사선을 조사한 결과, 저준위 방사선이 건강한 개체에서는 비장 NK세포의 활성에 영향을 주지 않는 것으로 나타났다(도 2 참조). 반면에, LPS 또는 자가면역세포 활성을 증가시킨 모델{폴리이노신산:폴리시티딜산(polyinosinic:polycytidylic acid, poly IC 복강주사}에 저준위 방사선을 조사한 경우가 방사선을 조사하지 않은 개체에 비해 비장 NK세포의 활성이 현저히 감소한 것으로 나타났다(도 3 참조). 이는 과도한 면역반응에 따른 NK세포의 활성화가 저준위 방사선에 의해 억제되어, 저준위 방사선의 조사가 생체 내에서 면역체계의 항상성을 유지시키는 작용을 함을 나타낸다.As a result of irradiating low-level radiation to normal mice that did not cause sepsis, low-level radiation did not affect the activity of spleen NK cells in healthy individuals (see FIG. 2). On the other hand, low-level radiation in LPS or a model with increased autoimmune cell activity (polyinosinic: polycytidylic acid, poly IC intraperitoneal injection) of spleen NK cells compared to non-irradiated individuals The activity was found to be markedly reduced (see Figure 3), indicating that activation of NK cells due to excessive immune response is inhibited by low-level radiation, so that irradiation of low-level radiation acts to maintain homeostasis of the immune system in vivo. .
한편, 패혈증으로 인한 장기 손상에 대한 저준위 방사선의 억제 효과를 확인한 결과, 역시 LPS 또는 poly IC를 주사한 생쥐에 저준위 방사선을 조사한 경우에, 방사선을 조사하지 않은 개체에 비해 간 조직의 NK세포의 비율이 현저히 감소한 것으로 나타났다(도 4 참조). 이는 저준위 방사선의 조사에 의해 장기의 과도한 면역반응이 억제되어, 패혈증에 의한 장기 손상을 막는 작용을 함을 나타낸다.On the other hand, as a result of confirming the inhibitory effect of low-level radiation on organ damage caused by sepsis, when low-level radiation was irradiated to mice injected with LPS or poly IC, the ratio of NK cells in liver tissue was higher than that of the non-irradiated individuals. Showed a significant decrease (see FIG. 4). This indicates that an excessive immune response of the organ is suppressed by irradiation of low-level radiation, thereby preventing the organ damage caused by sepsis.
따라서, 저준위 방사선은 패혈증에 의해 증가한 NK세포의 활성을 억제하여 과염증반응을 막아 생체 내 항상성을 유지시키는 작용을 할 뿐만 아니라, 조직 내 증가한 NK세포의 비율을 감소시켜 패혈증으로 인한 장기 손상을 방지하여 급성 염증반응을 초기에 제어함으로 패혈증 및 패혈증성 쇼크의 예방 또는 치료에 유용하게 사용될 수 있다.Therefore, low-level radiation inhibits the activity of NK cells increased by sepsis, prevents over-inflammatory responses and maintains homeostasis in vivo, and decreases the percentage of increased NK cells in tissues to prevent long-term damage caused by sepsis. By early control of the acute inflammatory response can be useful for the prevention or treatment of sepsis and septic shock.
또한, 본 발명은 과반응성 염증 질환에 걸린 개체에 저준위 방사선을 조사하는 단계를 포함하는 과반응성 염증 질환 치료 방법을 제공한다.In addition, the present invention provides a method for treating an overreactive inflammatory disease comprising irradiating a low level radiation to a subject having an overreactive inflammatory disease.
상기 저준위 방사선은 알파선, 베타선, 감마선, 전자선, 자외선 및 X선으로 구성된 군으로부터 선택된 어느 하나인 것이 바람직하고, 감마선인 것이 더욱 바람직하나 이에 한정하지 않는다.The low level radiation is preferably any one selected from the group consisting of alpha rays, beta rays, gamma rays, electron rays, ultraviolet rays and X-rays, and more preferably gamma rays, but is not limited thereto.
상기 저준위 방사선의 원하는 효과를 나타낼 수 있는 바람직한 범위는 0.01 내지 0.5 Gy이며, 0.1 ~ 0.3 Gy인 것이 더욱 바람직하고, 0.2 Gy인 것이 가장 바람직하나 이에 한정하지 않는다.The preferred range that can exhibit the desired effect of the low level radiation is 0.01 to 0.5 Gy, more preferably 0.1 to 0.3 Gy, most preferably 0.2 Gy, but is not limited thereto.
상기 개체는 척추동물이고 바람직하게는 포유동물이며, 그보다 바람직하게는 쥐, 토끼, 기니아피그, 햄스터, 개, 고양이와 같은 실험동물이고, 가장 바람직하게는 침팬지, 고릴라와 같은 유인원류 동물이다.The subject is a vertebrate and preferably a mammal, more preferably an experimental animal such as a rat, rabbit, guinea pig, hamster, dog, cat, and most preferably an ape-like animal such as a chimpanzee or gorilla.
상기 과반응성 염증 질환은 류마티스 관절염, 다발성 경화증, 전신성 홍반성 낭창증, 건선, 염증성 대장질환, 자가면역 간염, 알레르기성 비염, 알레르기성 결막염, 알레르기성 천식, 아토피성 피부염, 과민성 폐렴, 급성 사구체신염, 인슐린 의존성 당뇨병, 만성 갑상선염, 빈혈, 강직 척추염, 습진, 루푸스, 쇼그렌 증후군, 패혈증 및 장기이식 거부반응으로 이루어진 군으로부터 선택된 어느 하나인 것이 바람직하나 이에 한정하지 않는다.The hyperreactive inflammatory diseases include rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, autoimmune hepatitis, allergic rhinitis, allergic conjunctivitis, allergic asthma, atopic dermatitis, irritable pneumonia, acute glomerulonephritis , Insulin dependent diabetes mellitus, chronic thyroiditis, anemia, ankylosing spondylitis, eczema, lupus, Sjogren's syndrome, sepsis and organ transplant rejection is preferably any one selected from, but is not limited thereto.
본 발명의 저준위 방사선은 NK세포의 활성을 억제하여 과염증반응을 막아 생체 내 항상성을 유지시키는 작용을 할 뿐만 아니라, 조직 내 증가한 NK세포의 비율을 감소시켜 염증으로 인한 장기 손상을 방지하여 급성 염증반응을 초기에 제어함으로 과반응성 염증 질환의 치료에 유용하게 사용될 수 있다.Low-level radiation of the present invention inhibits the activity of NK cells to prevent over-inflammatory reactions to maintain homeostasis in vivo, as well as to reduce the percentage of increased NK cells in tissues to prevent organ damage due to inflammation acute inflammation Early control of the response can be useful for the treatment of hyperreactive inflammatory diseases.
또한, 본 발명은 과반응성 염증 질환에 걸린 개체에 저준위 방사선을 조사하는 단계를 포함하는 면역세포 억제 방법을 제공한다.The present invention also provides a method for inhibiting immune cells comprising the step of irradiating a low-level radiation to a subject with a hyperreactive inflammatory disease.
상기 면역세포는 NK세포인 것이 바람직하나 이에 한정하지 않는다.The immune cell is preferably an NK cell, but is not limited thereto.
상기 저준위 방사선은 알파선, 베타선, 감마선, 전자선, 자외선 및 X선으로 구성된 군으로부터 선택된 어느 하나인 것이 바람직하고, 감마선인 것이 더욱 바람직하나 이에 한정하지 않는다.The low level radiation is preferably any one selected from the group consisting of alpha rays, beta rays, gamma rays, electron rays, ultraviolet rays and X-rays, and more preferably gamma rays, but is not limited thereto.
상기 저준위 방사선의 원하는 효과를 나타낼 수 있는 바람직한 범위는 0.01 내지 0.5 Gy이며, 0.1 ~ 0.3 Gy인 것이 더욱 바람직하고, 0.2 Gy인 것이 가장 바람직하나 이에 한정하지 않는다.The preferred range that can exhibit the desired effect of the low level radiation is 0.01 to 0.5 Gy, more preferably 0.1 to 0.3 Gy, most preferably 0.2 Gy, but is not limited thereto.
상기 개체는 척추동물이고 바람직하게는 포유동물이며, 그보다 바람직하게는 쥐, 토끼, 기니아피그, 햄스터, 개, 고양이와 같은 실험동물이고, 가장 바람직하게는 침팬지, 고릴라와 같은 유인원류 동물이다.The subject is a vertebrate and preferably a mammal, more preferably an experimental animal such as a rat, rabbit, guinea pig, hamster, dog, cat, and most preferably an ape-like animal such as a chimpanzee or gorilla.
상기 과반응성 염증 질환은 류마티스 관절염, 다발성 경화증, 전신성 홍반성 낭창증, 건선, 염증성 대장질환, 자가면역 간염, 알레르기성 비염, 알레르기성 결막염, 알레르기성 천식, 아토피성 피부염, 과민성 폐렴, 급성 사구체신염, 인슐린 의존성 당뇨병, 만성 갑상선염, 빈혈, 강직 척추염, 습진, 루푸스, 쇼그렌 증후군, 패혈증 및 장기이식 거부반응으로 이루어진 군으로부터 선택된 어느 하나인 것이 바람직하나 이에 한정하지 않는다.The hyperreactive inflammatory diseases include rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, autoimmune hepatitis, allergic rhinitis, allergic conjunctivitis, allergic asthma, atopic dermatitis, irritable pneumonia, acute glomerulonephritis , Insulin dependent diabetes mellitus, chronic thyroiditis, anemia, ankylosing spondylitis, eczema, lupus, Sjogren's syndrome, sepsis and organ transplant rejection is preferably any one selected from, but is not limited thereto.
본 발명의 저준위 방사선은 NK세포의 활성을 억제하여 과염증반응을 막아 생체 내 항상성을 유지시키는 작용을 할 뿐만 아니라, 조직 내 증가한 NK세포의 비율을 감소시켜 염증으로 인한 장기 손상을 방지하여 급성 염증반응을 초기에 제어함으로 과반응성 염증 질환에 걸린 개체에서 과다한 활성을 나타내는 면역세포의 억제에 유용하게 사용될 수 있다.Low-level radiation of the present invention inhibits the activity of NK cells to prevent over-inflammatory reactions to maintain homeostasis in vivo, as well as to reduce the percentage of increased NK cells in tissues to prevent organ damage due to inflammation acute inflammation Early control of the response can be useful for the suppression of immune cells exhibiting excessive activity in individuals with hyperreactive inflammatory diseases.
<< 실시예Example 1> 정상동물모델에서 저준위 방사선( 1> Low-level radiation in normal animal models lowlow dosedose radiationradiation , , LDRLDR ) 조사가 ) Investigator NKNK 세포 활성에 미치는 영향 확인Determine the effect on cell activity
<1-1> 저준위 방사선의 조사<1-1> Low level radiation
C57BL/6 암컷 생쥐는 중앙실험동물(주) 업체로부터 구입하여 사용하였다. 총 18 마리의 생쥐 중 9마리는 감마선을 조사하였고(실험군, LDR 그룹), 나머지 9마리는 감마선을 조사하지 않았다(음성대조군, sham 그룹). 이때, 감마선의 선원은 137Cs이었고, 생쥐 케이지는 선원으로부터 일정한 거리를 두어 감마선의 세기가 4.3 mGy/hour의 조건이 되도록 하였으며, 2일 동안 연속적으로 조사하여 총 200 mGy(0.2 Gy) 선량의 방사선을 조사받도록 하였다.C57BL / 6 female mice were purchased from a central laboratory company. Nine out of a total of 18 mice were irradiated with gamma rays (experimental group, LDR group) and the remaining nine were not irradiated with gamma rays (negative control, sham group). At this time, the source of gamma ray was 137 Cs, and the mouse cage was placed at a certain distance from the source so that the intensity of gamma ray was 4.3 mGy / hour, and it was irradiated continuously for 2 days and the total dose of 200 mGy (0.2 Gy) dose To be investigated.
<1-2> 비장 <1-2> spleen NKNK 세포의 세포 살상활성 확인Confirmation of cell killing activity of cells
상기 실시예 <1-1>의 생쥐에서 비장 세포를 적출하여 세포수를 측정하였고, 서울대병원 암연구소에서 입수한 YAC-1 암세포를 대상으로, E:T ratio를 300:1, 100:1 또는 30:1로 하여, 통상적으로 사용하는 세포살상방법인 51Cr release assay를 수행하여 비장 NK세포의 암세포 살상활성을 알아보았다. 그 결과, 방사선 조사된 생쥐와 조사되지 않은 생쥐의 비장 NK세포의 암세포 살상활성은 거의 동일하게 나타났다(도 2). 이에, 저준위 방사선의 조사는 염증이 유발되지 않은 정상 생쥐에서 NK세포의 활성에 영향을 미치지 않는 것으로 확인되었다. Spleen cells were extracted from the mice of Example <1-1> to measure the number of cells, and E: T ratios of 300: 1, 100: 1 or YAC-1 cancer cells obtained from Seoul National University Cancer Institute As a 30: 1, 51 Cr release assay, a commonly used cell killing method was performed to determine the cancer cell killing activity of spleen NK cells. As a result, the cancer cell killing activity of the spleen NK cells of the irradiated and non-irradiated mice was almost the same (Fig. 2). Thus, irradiation of low-level radiation did not affect the activity of NK cells in normal mice that did not cause inflammation.
<< 실시예Example 2> 패혈증동물모델에서 저준위 방사선 조사가 2> Low-level irradiation in sepsis animal model NKNK 세포 활성에 미치는 영향 확인Determine the effect on cell activity
<2-1> 패혈증이 유발된 생쥐모델 제작 및 저준위 방사선의 조사 <2-1> Sepsis-Induced Mouse Model and Low-level Radiation
패혈증 상태를 인위적으로 유발한 생쥐모델에 대한 저준위 방사선의 효과를 알아보기 위해, 각각의 C57BL/6 암컷 생쥐에 자연면역세포 활성을 증가시키는 물질인, 폴리이노신산:폴리시티딜산(polyinosinic:polycytidylic acid, poly IC)을 개체 당 0.5 ㎎으로 복강내 주사하였고, 패혈증을 유도시키는 물질인, 리포폴리사카라이드(lipopolysaccharide, LPS)를 개체 당 0.4 ㎎으로 각각 복강내 주사하여 패혈증이 유발된 모델을 제작하였다. 저준위 방사선은 선원이 137Cs인 감마선을 사용하여 4.3 mGy/hour의 조건에서 연속적으로 2일 동안 총 0.2 Gy를 조사하였다(도 1). 이때, 음성대조군(sham), poly IC 주사한 생쥐(sham+poly IC), LPS 주사한 생쥐(sham+LPS), 저준위 방사선 조사한 생쥐(LDR), 저준위 방사선 조사+poly IC 주사한 생쥐(LDR+poly IC) 및 저준위 방사선 조사+LPS 주사한 생쥐(LDR+LPS)의 그룹(n=3)으로 각각 나누어 실시하였다. To investigate the effect of low-level radiation on an artificially induced sepsis state, polyinosinic: polycytidylic acid, a substance that increases natural immune cell activity in each C57BL / 6 female mouse, poly IC) was injected intraperitoneally at 0.5 mg per individual, and sepsis-induced model was prepared by intraperitoneally injecting lipopolysaccharide (LPS), a substance inducing sepsis, at 0.4 mg per individual, respectively. Low-level radiation was irradiated with a total of 0.2 Gy for 2 consecutive days under conditions of 4.3 mGy / hour using gamma rays with a source of 137 Cs (FIG. 1). At this time, negative control group (sham), poly IC injection mice (sham + poly IC), LPS injection mice (sham + LPS), low-level irradiation mice (LDR), low-level irradiation + poly IC injection mice (LDR + poly IC) and low-level irradiation + LPS-injected mice (LDR + LPS) group (n = 3), respectively.
<2-2> 비장 <2-2> spleen NKNK 세포의 세포 살상활성 확인Confirmation of cell killing activity of cells
상기 실시예 <2-1>의 각 그룹의 생쥐에서 비장을 적출하여 세포수를 측정하였고, 서울대학교 암연구소에서 입수한 RMA/S 암세포를 대상으로 E:T ratio를 300:1, 100:1 또는 30:1로 하여, 통상적으로 사용하는 세포살상방법인 51Cr release assay를 수행하여 비장 NK세포의 암세포 살상활성을 알아보았다.The spleens were extracted from the mice of each group of Example <2-1> to measure the number of cells, and the E: T ratios of the RMA / S cancer cells obtained from the Seoul National Cancer Institute were 300: 1 and 100: 1. Or 30: 1, by performing a 51 Cr release assay, a commonly used cell killing method to determine the cancer cell killing activity of spleen NK cells.
그 결과, 저준위 방사선을 조사하지 않은, poly IC 주사한 생쥐(sham+poly IC) 또는 LPS 주사한 생쥐(sham+LPS) 그룹에 비해, 저준위 방사선을 조사한, poly IC 주사한 생쥐(LDR+poly IC) 또는 LPS 주사한 생쥐(LDR+LPS)에서 암세포에 대한 세포 살상활성이 현저히 감소한 것으로 나타났다(도 3). 상기 실시예 <1-2>에서 확인한 바와 같이, 저준위 방사선 자체가 비장 NK세포의 세포 살상활성에는 영향을 미치지 않으므로, 이는 저준위 방사선의 조사가 패혈증에 의한 NK세포의 활성화를 조절하여 생체 내 항상성을 유지하려고 하는 것을 나타낸다. As a result, compared to the group of poly IC injected mice (sham + poly IC) or LPS injected mice (sham + LPS), which did not receive low level radiation, poly IC injected mice (LDR + poly IC) irradiated with low level radiation. Or LPS-injected mice (LDR + LPS) showed a significant decrease in cytotoxic activity against cancer cells (FIG. 3). As confirmed in Example <1-2>, low-level radiation itself does not affect the cell killing activity of spleen NK cells, which means that irradiation of low-level radiation modulates the activation of NK cells by sepsis, resulting in homeostasis in vivo. Indicates what you want to keep.
<2-3> 간에서의 <2-3> in the liver NKNK 세포 및 T세포의 분포 확인Confirmation of Cell and T Cell Distribution
LPS 주사 시, 간(liver) 조직에서의 NK세포의 활성화와 이에 따른 과염증반응(cytokine storm)에 의해 생쥐가 패혈증으로 죽게 되는데, 이때 저준위 방사선을 조사함으로써 이를 방지하는지 알아보기 위해, 상기 실시예 <2-1>의 각각 그룹의 생쥐에서 간을 적출하여 유세포분석법(flow cytometry)을 사용하여 간 조직에 분포하는 NK세포의 비율을 측정하였다. In LPS injection, mice are killed by sepsis due to activation of NK cells in liver tissue and the resulting cytokine storm, in which case the irradiation with low-level radiation prevents them. Liver was extracted from the mice in each group of <2-1> and flow cytometry was used to measure the percentage of NK cells distributed in liver tissue.
그 결과, LPS를 처리한 생쥐(sham+LPS 또는 LDR+LPS)가 처리하지 않은 생쥐(sham 또는 LDR)보다 NK세포의 비율이 증가하였고, 저준위 방사선을 조사하지 않고 LPS를 주사한 생쥐(sham+LPS)의 경우는 NK세포의 비율이 현저히 증가한 것에 비해, 저준위 방사선을 조사한 LPS 주사 생쥐(LDR+LPS)는 NK세포의 증가폭이 현저히 감소하였다. T세포 분포의 경우에는 sham+LPS와 비교하여, LDR+LPS에서 유의성 있는 감소가 나타나지 않았다(도 4). 이에, 저준위 방사선은 자연면역세포인 NK세포의 활성화를 억제함으로써 생체 내 항상성을 유지하는 작용을 가지는 것으로 나타났다.As a result, the percentage of NK cells increased in mice treated with LPS (sham + LPS or LDR + LPS) (sham or LDR), and mice injected with LPS without irradiating low-level radiation (sham + In the case of LPS), the percentage of NK cells decreased significantly in LPS-injected mice (LDR + LPS) irradiated with low-level radiation. In the case of T cell distribution, there was no significant decrease in LDR + LPS compared to sham + LPS (FIG. 4). Thus, low-level radiation has been shown to have the effect of maintaining homeostasis in vivo by inhibiting the activation of NK cells, which are natural immune cells.
상기와 같이, 본 발명의 저준위 방사선은 패혈증으로 인한 과면역반응을 조절하여 생체 내 항상성 유지 작용을 하므로, 자연면역세포 활성의 조절을 통하여 감염 또는 수술 후의 급성 염증반응으로 인한 패혈증 또는 과반응성 염증 질환의 치료를 위한 치료용 장치 및 치료법의 개발에 유용하게 이용할 수 있다. As described above, since the low-level radiation of the present invention regulates the hyperimmune response due to sepsis and maintains homeostasis in vivo, the sepsis or hyperreactive inflammatory disease caused by an acute inflammatory response after infection or surgery through the regulation of natural immune cell activity It can be usefully used in the development of therapeutic devices and therapies for treatment.
도 1은 저준위 방사선의 조사 프로토콜을 나타낸 그림이다.1 is a diagram showing the irradiation protocol of low-level radiation.
도 2는 정상 생쥐에 저준위 방사선을 조사한 직후의 비장 NK세포의 세포살상활성을 나타낸 그래프이다.Figure 2 is a graph showing the cytotoxic activity of spleen NK cells immediately after low-level irradiation to normal mice.
도 3은 poly IC에 의해 자연면역세포 활성이 증가된 생쥐 및 LPS에 의해 패혈증이 유발된 생쥐에 저준위 방사선을 조사한 직후의 비장 NK세포의 세포살상활성을 나타낸 그래프이다. Figure 3 is a graph showing the cytotoxic activity of spleen NK cells immediately after low-level radiation to mice with increased natural immune cell activity by poly IC and mice with sepsis induced by LPS.
도 4는 LPS에 의해 패혈증이 유발된 생쥐에 저준위 방사선을 조사한 직후의 간 조직에서의 NK세포 및 T세포의 분포 변화를 나타낸 그래프이다. Figure 4 is a graph showing the distribution of NK cells and T cells in liver tissue immediately after irradiation with low-level radiation to mice induced sepsis by LPS.
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