乳酸菌用於小鼠癌症化療輔助免疫調節提升之效果評估

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標題:	乳酸菌用於小鼠癌症化療輔助免疫調節提升之效果評估 Enhancement of immunomodulation by supplementation with Lactobacillus in 5-FU administrated mice.
作者:	胡本平
貢獻者:	生物科技系王照元張竣凱
關鍵字:	5-氟尿嘧啶 5-Fluorouracil
日期:	2015
上傳時間:	2015-10-21 17:06:30 (UTC+8)
摘要:	癌症治療一直是全世界生物醫學研究的重點，化學治療更是癌症療法中非常重要的輔助療法，近年癌症藥物的開發已有長足進步，但效果仍無法讓醫師滿意。根據多年的觀察發現，多數的患者，在完成第一劑或第二劑化療後（有些免疫能力較強者，尚可撐過第三劑），即因白血球計數無法回升至醫師要求標準，而延誤下一劑化療，造成癌細胞因化療延誤又再度回復，而再進行的化療等同回到第一次化療，造成病患一直重複進行無效的化療，同時免疫能力也在藥物的摧殘下越來越低。 5-氟尿嘧啶（5-Fluorouracil，5-FU）是臨床上常用於治療上皮細胞癌的化學藥物，其作用機轉，會誘使骨髓衍生抑制細胞（Myeloid-Derived Suppressor Cell , MDSC）分泌IL-1β，抑制CD4＋ T cell的活化，直接造成白血球下降，是延誤化療療程，造成治療困難的負面因素。由比較分析發現，有90%的癌症都是屬於上皮細胞癌，同時「過敏反應」也只發生在上皮細胞，因此大膽假設，癌細胞的形成與過敏發炎有極為密切的關聯。所以依據改善過敏機制為藍本，設計一組以乳酸菌為主體的免疫營養配方-「倍立100」，希望能在癌症患者接受化學治療期間，輔助免疫功能提升，減少副作用的產生，達成改善以下問題：1. 有效誘導白血球回升，積極協助癌症患者接受每一劑化學治療，提高化療成功率。2. 有效解決腹瀉、口腔潰瘍情形，提高患者生活品質。3. 快速回復患者食慾，降低體重減輕威脅。4. 有效保護消化道黏膜，阻絕感染危機。實驗方法依據衛福部建議之健康食品之免疫調節功能評估方法為基礎，實驗結果顯示：1. 當小鼠注射5-FU後白血球數目相較於Control組別有明顯的下降，而在同時處理「5-FU+倍立100」的組別白血球數目則有回升的情形。類似的現象也顯示在血液中淋巴球的數目，在同時處理「5-FU+倍立100」的組別血液中淋巴球數目相較於只處理5-FU有明顯回升的情形。由此結果我們推測「倍立100」具有提升化療藥物5-FU處理後血液中的白血球與淋巴球數量的功能。2. 餵食小鼠「倍立100」可增加CD8細胞比例；當小鼠注射5-FU後，會降低CD8細胞比例，而同時處理5-FU與「倍立100」時則可回復其CD8細胞比例。CD40主要表現於B cells，參與發炎反應以其免疫反應活化的調控，四組中只餵食「倍立100」的小鼠CD40細胞比例有降低，而注射5-FU或同時處理「5-FU+倍立100」則無明顯變化。因此，小鼠餵食「倍立100」不影響其Helper T cells，而可增加Cytotoxic T cells及降低B cells細胞比例，推測「倍立100」可能具有降低發炎反應之效果。3. Interferon gamma (IFN-γ)為生物體內先天及後天性免疫系統重要的細胞激素(Cytokine)，主要由自然殺手細胞(Natural killer cell)、自然殺手T細胞(Nature killer T cell)、CD4第一型輔助性T細胞(CD4+ TH1 cell)、CD8細胞毒殺型T細胞 (CD8+ Cytotoxic T cell) 所分泌，用於抑制病毒於細胞內複製及細菌感染。在「5-FU+倍立100」的小鼠組別其脾臟內淋巴細胞IFN-γ表現量較5-FU alone組有些微提升。此外IL-10的主要功能是抑制活化的T細胞和B細胞，是一個抗發炎的細胞激素，在免疫系統中作調節的角色，除了Monocytes之外，免疫細胞中的Type 2 T Helper cells (TH2), Mastocytes, Regulatory T cells都會在特定環境中分泌IL-10。在「5-FU+倍立100」的小鼠組，其脾臟內淋巴細胞IL-10表現量也相較於只處理5-FU有明顯上升，這表明「5-FU+倍立100」的小鼠仍具有調節免疫細胞的功能，並非完全抑制「體液免疫路徑」的發展。因此根據以上實驗成果，我們推測「倍立100」可能具有增強「細胞免疫路徑」的能力，以及免疫調節的功能。 Cancer therapy has been the key topic of global biomedical studies, and chemotherapy is one of the critical adjuvant therapeutic regimens in cancer therapy. Recently, the development of therapeutic medicine to treat cancers has made a great progress; however, the effects are still unsatisfying to physicians. According to our observations over the past several years, we discovered that most patients are forced to postpone their course of chemotherapy after completing the first or second course of chemotherapy (some patients with better immunity can complete the third course of chemotherapy) due to the failure of white blood cell (WBC) count to reach the level requested by the physician. In this case, the patients have to suffer the relapse of cancer cells owing to the delay of chemotherapy and are required to receive the same course of chemotherapy as the first time, which leads to repeat chemotherapy courses and worsening immunity under the toxicity exposure of the drugs.5-Fluorouracil (5-FU) is a common clinical chemotherapy drug applied to epithelial carcinoma treatment. The working mechanism is to induce Myeloid-Derived Suppressor Cell (MDSC) secreting IL-1β, inhibit the activation of CD4＋ T cells, and directly reduce WBC counts. Therefore, 5-FU is a negative factor to the treatment due to its effects on delaying the progress of chemotherapy and increasing the difficulties of treatments.After comparative analyses, we discovered that 90% of cancers are epithelial carcinomas. At the same time, we also found out that “the symptoms of allergy” only occur on epithelial cells. Based on this, we hypothesize that the formation of cancer cells is closely related to inflammatory allergic reactions. In order to ameliorate allergic reactions, we have designed an immunological nutrition formula “倍立100”, to improve allergies, as the formula is based on lactic acid bacteria. We hope that this formula can help cancer patients enhance their immune functions and reduce the production of side effects during the periods of receiving chemotherapy treatments in order to improve the following issues: 1. Effectively reverse WBC count and actively assist cancer patients in receiving chemotherapy regimens, so the success rate of chemotherapy can be increased. 2. Effectively ameliorate diarrhea and oral ulcers in order to enhance patient’s quality of life.3. To restore patient’s appetite rapidly and reduce the danger of weight loss.4. Effectively protect gastrointestinal tract mucosa from bacterial infection risks.The experimental methodology was based on the recommendation from the Ministry of Health and Welfare for the functional assessment of health food about its immunity regulation. The study results indicated that: 1. Compared with control group, WBC count of mice in the group with 5-FU injection decreased significantly, but the WBC count in the group with simultaneous treatment of “5-FU plus倍立100” was reversed. Similar reaction was observed in lymphocyte count. Compared with the group only treated with 5-FU, the count of lymphocyte in the blood stream of the group with simultaneous treatment of “5-FU plus倍立100” was significantly increased. Based on the results, we speculate that “倍立100” has the ability to enhance WBC and lymphocyte counts in the blood stream after the treatment of chemotherapy drug 5-FU.2. Feeding mice with “倍立100” can increase the ratio of CD8 lymphocyte. The ratio of CD8 lymphocyte in mice was decreased after receiving 5-FU, but the ratio could be reversed in the group with simultaneous treatment of “5-FU and 倍立100”. CD40 majorly expressed on B cell, participates in inflammatory reactions and regulates the activation of immune responses. Among four mice groups, the ratio of CD40 expressing cells decreased in the group fed merely with “倍立100”, however, the ratios in the group with 5-FU injection or in the group simultaneously treated with “5-FU plus 倍立100” had no significant changes. Therefore, mice fed with “倍立100” would not affect the level of helper T cell, but it could increase cytotoxic T cell amount and reduce the ratio of B cells. So we conclude that “倍立100” may possess the function of reducing inflammatory reactions. 3. Interferon gamma (IFN-γ) is an important cytokine of innate and adaptive immune systems in organisms. It is secreted by natural killer cells, nature killer T cells, CD4+ TH1 cells and CD8+ cytotoxic T cells, and is applied to the inhibition of virus replication in the cells and bacterial infections. In the “5-FU plus 倍立100” mice group, the expression of IFN-γ from lymphocytes in the spleen was slightly increased compare to the group with 5-FU treatment alone. In addition, the primary function of IL-10, as an anti-immunological cytokine and a regulator in immune system, is to inhibit activated T cells and B cells. Except monocytes, immune cells such as type 2 T helper cells (TH2), mastocytes and regulatory T cells all can secrete IL-10 at a certain environment. In the “5-FU plus 倍立100” mice group, the expression of IL-10 from lymphocytes in the spleen was also significantly increased compare to the group with 5-FU treatment alone. This indicated that mice in the “5-FU plus 倍立100” group were still equipped with the function of regulating immune cells instead of inhibiting the development of “humoral immunity pathway” completely. In summary, according to aforementioned study results, we conclude that “倍立100” may have the ability to potentiate “cellular immunity pathway” and to regulate the immune system.
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