四君子湯為東方國家使用千年以上的補氣中藥，由人蔘、白朮、茯苓、甘草四種中藥材組成。本實驗室於1996年證實四君子湯具有免疫調節功能，因此本研究目的在透過一系列實驗，更完整探討四君子湯及單方調節免疫反應的機轉。
實驗藥材採用四君子湯及其單方之50%酒精萃取物，第一階段實驗老鼠連續三天腹腔注射藥劑，結果顯示，四君子湯及其單方都可顯著促進脾臟細胞分泌IgG及IgA，但是四君子湯及白朮、茯苓並未促進IgM的分泌。第二階段以相同方式給藥，探討四種單方對於脾臟細胞製造Th-1型（IL-2、IFN-γ）和Th-2型細胞激素 (IL-10、IL-4)的影響，結果發現四種單方對Th-1及Th-2型細胞激素的製造，皆有促進作用，影響層面包括基因表現層次及蛋白質層次，佐以IgG亞型（IgG1, IgG2a, IgG2b）分泌量改變的數據，確認四種單方藉由IFN-γ(Th-1型)及IL-4 (Th-2 型)的分泌，影響B淋巴球的抗體類型轉換（class-switching）。第三階段主要探討人蔘途徑及時間長短對其免疫調節功能所造成的影響，實驗結果發現，經由口服途徑，除了對IgA仍保持促進作用外，IgG及IgM皆呈現抑制效應，推論經由口服途徑可以增加黏膜性免疫反應，且口服人蔘會促進Th-1型細胞激素製造，但是對IL-4製造卻無顯著影響，對IL-10則有促進作用，佐以IgG亞型（IgG1, IgG2a, IgG2b）分泌量改變的數據，確認人蔘藉由IFN-γ，使 B淋巴球由IgM製造者類型轉換成IgG2a製造者，同時抑制IgM轉型為IgG1及IgG2b。口服人蔘會促進NK細胞活性，增加細胞毒殺作用，整體效應應該趨向於細胞性免疫反應的調節，但短期口服人蔘卻抑制CD3+T淋巴球的數量，伴隨抑制了CD4+ 及CD8+細胞的量，造成的原因須待進一步探討。
口服時間長短也會影響免疫調節機制，長期服用後，失去對IgA分泌的促進作用，只有IL-10維持促進效果，推測IL-10在長期口服中扮演細胞激素及抗體分泌的負面協調角色。長期口服對NK細胞活性無影響，CD3+T細胞及CD8+T細胞的比例降低，但CD4+T細胞比例與控制組無顯著差異。最後探討長期口服人蔘對抗雞卵蛋白 (ovalbumin;OVA)專一性免疫反應的調節，老鼠餵食人蔘三十天中，第一天免疫注射OVA，第十四天追加注射，第三十天測定抗OVA抗體效價，發現長期口服人蔘能增進專一性抗OVA抗體反應。總結本研究之結果，可確定以50﹪乙醇萃取之人蔘萃取物，劑量如在0.4至4 g/kg/day之間，則短期口服人蔘萃取物，有利於黏膜免疫反應及細胞性免疫反應，尤其是與NK細胞有關的防禦機轉；而長期口服人蔘對整體免疫功能無幫助，不過透過某些未知的機制，能增進專一性抗體反應。

Si-Jun-Zi-Tang is a general tonic medicine that has been used in Asian countries for more than a thousand years. It is composed of four major ingredients including Ginseng (Panax ginseng C.A Meyer), Bai-zhu (Atraclylodes macrocephala Koidz), Licorice (Glycyrrhiza uralensis Fisch) and Fu-ling (Poria cocos (Schw.) Wolf). In 1996, our research team had demonstrated that Si-Jun-Zi-Tang was a potential immunoregulatory medicine. Therefore, the research was taken through a series of carefully designed experiments to investigate closely into the mechanism by which the Si-Jun-Zi-Tang modulated the immune function. The reagents used in this study were prepared by boiling the Si-Jun-Zi-Tang and its four major ingredients separately in 50% ethanol. In the primary stage of the experiment, the mice were injected intraperitoneally (i.p.) with the extracts for three consecutive days. Results indicated that injecting the drug all significantly enhanced both IgG and IgA secretion by spleen cells, but IgM secretion was not augmented significantly by Si-Jun-Zi-Tang, Bai-zhu and Fu-ling. In the secondary stage, assayed for production of Th-1 type (IL-2, IFN-g) and Th-2 type (IL-4 and IL-10) cytokines by spleen cells cultured in vitro. Results indicated that treatment with drug all significantly enhanced both cytokine mRNA expression and cytokine secretion by spleen cells. This observation was further supported by showing that the IgG1, IgG2b (mediated by IL-4) and IgG2a (mediated by IFN-g) secretion by spleen cells were increased significantly after the drug treatments. The result also implied that antibodies production by the B-lymphocytes might undergo class-switch. In the third stage, the study was focused on the possible effects of the route and the duration of drug treatment on the Ginseng-mediated immunoregulation. Oral administration of Ginseng extract only enhanced the secretion of IgA, but showed a significantly suppressive effect on IgG and IgM secretion, suggesting that Ginseng might directly stimulate the mucosal-associated lymphoid tissue in gut and augmented IgA production though oral administration. Oral administration of Ginseng extract significantly enhanced Th-1 type cytokine production and IL-10 production. This observation was further supported by showing that the IgG2a secretion by spleen cells, which was induced by IFN-g, were increased significantly after the drug treatments; but IgG1 and IgG2b secretion, which was induced by IL-4, were suppressed. In addition, oral administration of Ginseng significantly increased the cytotoxic activity of natural kill cells (NK cells), suggesting that Ginseng can also induced an innate cell-mediated immune response. However, oral administration of Ginseng extract significantly reduced the percentage composition of CD3+ T-lymphocytes,CD4+8- and CD4-8+ subpopulations. The Ginseng-mediated immunoregulation was also affected by the duration of drug treatment. Long-term (30 days) oral treatment of Ginseng almost failed to modulate both immunoglobulin and cytokine productions, except that the production of IL-10 was significantly induced. Since, the major biological activity of IL-10 is to inhibit the synthesis of lymphokines and monokines. Therefore, long-term oral treatment of Ginseng extract might down-regulate the immune system by increasing IL-10 production. Finally, the effect of long-term oral treatment of Ginseng extract on the ovalbumin (OVA)-induced specific antibody response was studied. During the 30 days of treatment, the mice were primary immunized with OVA at day one and were boosted at day 14. The anti-OVA antibody titer of the mice treated with Ginseng was significantly higher than that of the control group. In conclusion, for the 50% ethanol extract of Ginseng, the dosage ranged from 0.4 g/kg/day to 4 g/kg/day, the short-term oral administration will up-regulate both MALT response and cell-mediated immune response, especially the cytotoxicity of NK cells. However, long-term oral administration will not be able to augment immune response but may have advantage in the antigen-specific antibody response.

今日中藥. 進補的理論基礎. Http://www.herbno1.com/html/herb-index.html , 2003
今日健康. 冬令進補. Http://www.foodno1.com/menu/archive/autumn/html/aw- index01.html, 2003
王筠默, 周金黃. 中國藥理學. 上海科學技術出版社. 上海. 116-117, 238-241, and 246-251, 1986.
中藥志. 中國醫學科學院藥物研究所等編. 人民衛生出版社. 北京. 152-155, 1997.
中藥理念--中醫藥在免疫學理簡介(下) Http://www.dharma.com.tw/X1Chinese /D32Health/H403Immu2.htm
中藥理念--補益類中藥簡介Http://www.dharma.com.tw/X1Chinese/D32Health
/H406WellSupply.htm
呂丹妮, 余淑絹, 曾哲明. 茯苓對人體血液淋巴球分泌免疫球蛋白的影響. 師大生物學報. 29:43-51, 1994.
呂丹妮, 陳安德, 張玉冬, 曾哲明. 補氣健脾藥四君子湯調節人體B淋巴球分泌A型免疫球蛋白. 師大生物學報. 30:83-95, 1995.
亞東紀念醫院 藥劑科 傳統中醫藥—補益藥之補氣藥Http://www.feg.hinet.net
/pharmacy/china3.htm, 2003.
常用中草藥材在生活保健上的應用-人參Http://www.sinphar.com.tw /news25-019.htm
高正釗. 新編中藥大辭典(上、中、下). 新文豐出版社. 台北. 544-550,566-570, 1592-1596 and 2798-2880, 1985.
顏正華. 中藥學. 知音出版社. 台北. 332-334,739-742 and 759-767, 1991.
劉接寶. 臨床實用彩色科學中藥大典(國際中文版2). 立得出版社. 台北. 66-68, 1982.
賴怡琪, 劉倩君, 曾哲明. 中藥茯苓對老鼠B淋巴球功能的影響. 師大生物學報28:53-63, 1993.
Abe Y., T. Ueda, T. Kato, and Y. Kohli. Effectiveness of interferon, glycyrrhizin combination therapy in patients with chronic hepatitis C. Nippon Rinsho Japanese J Clin Med 52:1817-1822, 1994.
Alberola-Ila J., J. Takaki, D. Kerner, and R. M. Perlmutter. Differential signaling by
lymphocyte antigen receptors. Annu Rev Immunol 15:125-162, 1997.
Avni O., and A. Rao. T cell differentiation:a mechanistic view. Curr Opin Immunol 12:654-659, 2000.
Bach E. A., M. Agust, and R. D. Schreiber. The IFN-γ receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 15:563-602, 1997.
Briere F., C. Servet-Delprat, J. M. Bridon, J. M.Saint-Remy, and J. Banchereau . Human interleukin 10 induces naïve sIgD B cells to secrete IgG1 and IgG3.
J Exp Med 179:757–762, 1994.
Carter L. L., and R.W. Dutton. Type 1 and type 2:a fundamental dichotomy for all T cell. Curr Opin Immunol 8:336-342, 1996.
Cheng T. O., and M. D. Cooper. Panax.(Ginseng) is not a panacea. Arch Inter Med 160:3329-3335, 2000.
Chien Y. H., R. Jores, and M. P. Crowely. Recognizition by gamma/delta T cell. Annu Rev Immunol 14:511-542, 1996.
Coffman R. L., D. A. Lebman, and B. Shrader. Transforming growth factor b specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med 170:1039-1044, 1989
Constant S. L., and K. Bottomly. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol 15:297–322, 1997.
Curfs J. H. A. J., J. F. G. N. Meis, and J. A. Hoogkamp-Korstanje. A primer on cytokines: Sources,receptors,effects,and inducers. Clin Microbiol Rev 10:742-780, 1997
Defrance T., B.Vanbervliet, F. Briere, and I. Durand. Interleukin 10 and transforming growth factor b cooperate to induce anti-CD40-activated naive human B cell to secrete immunoglobulin A. J Exp Med 175: 671-682, 1992
Ezekowitz B. A. B., and J. Hoffman. Innate immunity. Curr Opin Immunol 10:9-53, 1998.
Fiorentino D. F., M. W. Bond, and T. R. Mosmann. Two type of mouse helper T cells.IV.Th2 clones secret a factor that inhibits cytokine production by Th1 clones. J Exp Med 170:2081-2095, 1989.
Gao H., F. Wang, E. J. Lien, and M. D. Thousdale. Immunostimulating polysaccharides from Panax notoginseng. Pharm Res 13:1196-1200, 1996.
Gillis C. N., Panax ginseng pharmacology: a nitric oxide link? Biochem Pharmacol
54:1-8, 1997
Hardy R. R., and K. Hayakawa. B cell development pathways. Annu Rev Immunol
19:595-621, 2001.
Huang H., and W. E. Paul. Impaired interleukin 4 signaling in T helper type 1 cells.
J Exp Med 187:1305-1313, 1998.
Huang M. X., S. X. Chen, and T. O. Cheng. Herbal pharmacology in cardiovascular therapeutics. The International Textbook of Cardiology. New York, NY: Pergamon Press Inc. 1060-1071, 1987.
Ihle J. N. Signaling through the hematopoientic cytokine receptprs. Annu Rev Immunol 13:369-412, 1995.
Itoh K., and S. Hirohata. The role of IL-10 in human B cell activation, proliferation, and differentiation. J Immunol 154:4341–4350, 1995.
Jie, Y.H., S. Cammisuli and M. Baggiolini. Immunodulatory effects of panax ginseng C. A. Meyer in the mouse. Agent. Action. 15:386-391, 1984
June C. H., A. B. Jeffery, M. N. Lee, and C. B. Thompson. The B7 and CD28 receptor families. Immuno Today 15:321-331, 1994.
Kaneko M., T. Kawakita, Y. Kumazawa, H. Takimoto, K. Nomoto, and T. Yoshikawa. Accelerated recovery from cyclophosphamide-induced leukopenia in mice administered a Japanese ethical herbal drug, Hochu-ekki-to. Immunopharmacol 44:223-231, 1999.
Kim, Y.W., D.K. Song, W. H. Kim, K. M. Lee, M. B. Wie, Y. H. Kim, S. H. Kee, and M. K. Cho. Long-term oral administration of ginseng extract decreases serum gamma-globulin and IgG1 isotype in mice. J. Ethnopharma. 58:55-58, 1997.
Kim K. H., Y. S. Lee, I. S. Jung, S. Y. Park, H. Y. Chung, I. R. Lee, and Y. S. Yun . Acidic polysaccharide from Panax ginseng, ginsan, induces Th1 cell and macrophage cytokines and generates LAK cells in synergy with rIL-2. Planta Medica 64:110-115, 1998.
Koh Y. Y., Y. Park, H. J. Lee, and C. K. Kim. Levels of interleukin-2, interferon
-[gamma] , and interleukin-4 in bronchoalveolar lavage fluid from patients with mycoplasma pneumonia: implication of tendency toward increased immunoglobulin E production. Pediatrics 107:39-68, 2001.
Kramer D. R., R. M. Sutherland, S. Bao, and A. J. Husband. Cytokine mediated effects in moscosal immunity. Immunol Cell Biol 73:389-396, 1995.
Laurat, E., B. Poirier, E. Tupin, G.. Caligiuri, G.. K. Hansson, J. Bariety, and A. Nicoletti. In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation 104: 197-202, 2001.
Lee Y. S., I. S. Chung, I. R. Lee, K. H. Kim, W. S. Hong , and Y. S. Yun. Activation of multiple effector pathways of immune system by the antineoplastic immunostimulator acidic polysaccharide ginsan isolated from Panax ginseng. Anticancer Research 17:323-31, 1997.
Lenschow D. J., T. L. Walunas, and J. A. Bluestone. CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233-258, 1996.
Liu M., and J. T. Zhang. Immunoregulatory effects of ginsenoside Rg1 in aged rats. Yao Hsueh Hsueh Pao - Acta Pharmaceutica Sinica 30:818-823, 1995
Liu M., and J. T. Zhang. Studies on the mechanisms of immunoregulatory effects of ginsenoside Rg1 in aged rats. Yao Hsueh Hsueh Pao - Acta Pharmaceutica Sinica 31:95-100, 1996.
Malefyt R. de W., J. Abrams, B. Bennett, C. G. Figdor and J. E.de Vries.
Interkeukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 174:1209-1215, 1997.
Ma L., Z. L. Zhou , and Q. Yang. Study on effect of polysaccharides of ginseng on
peripheral blood mononuclear cell induced interleukin-2 production and activity
of its receptors in vitro. Chung-Kuo Chung Hsi i Chieh Ho Tsa Chih 15:411-413, 1995.
Mossman T. R., H. Cherwinski, M. W. Bond, M. A. Gledlin, and R. L. Coffman. Tow type of murine helper T cell clone.I. Definition according to profiles of lymphokine activies and secreted proteins. J Immunol 136:2348-2354, 1986.
Moore K. W., P. Vieira, D. F. Fiorentino, M. L. Trounstine, T. A. Khan, and T. R.
Mosmann. Homology of cytokines synthesis inhibitory factor (IL-10) to the
Epstein-Barr virus gene BCRFI. Science 248:1230, 1990.
Moore K.W., A. O'Garra, R. de W. Malefyt, P.Vieira, and T.R. Mosmann. Interleukin-10. Annu Rev Immunol 11:165-190, 1993.
Moore K.W., R. de Waal Malefyt, R. L. Coffman, and A. O'Garra.. Interleukin-10 and Interleukin-10 receptor. Annu Rev Immunol 19: 683-765, 2001.
Nakajima N., T. Utsunomiya , M. Kobayashi , D. N. Herndon , R. B. Pollard, and F. Suzuki. In vitro induction of anti-type 2 T cells by glycyrrhizin. Burn 22:612-617, 1996.
Nakanishi K., T. Yoshimoto, H. Tsutsui, and H. Okamura. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol 19: 423-474, 2001.
O`Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275-284, 1998.
Opal A. M., and V. A. DePalo. Anti-inflammatory cytokines. Chest 17:1162-1172, 2000.
Park Y. C., C. H. Lee, H. S. Kang, K. W. Kim, H. T. Chung, and H. D. Kim. Ginsenoside-Rh1 and Rh2 inhibit the induction of nitric oxide synthesis in murine peritoneal macrophages. Biochem Mol Biol 40:751-757, 1996 .
Raghupathy R. Pregnancy:success and failure within the Th1/Th2/Th3 paradigm.
Seminars Immunol. 13:219-227, 2001.
Ritter G., and E. L. Dembicki. The variable effects of whole-leaf digitalis is a paradigm of the glycemic effects of ginseng. Arch Internal Med 160:3330-3331, 2000.
Rousset F. E., G. T. Defrance, C. Peronne, N. Vezzio, D. H. Hsu, R. Kastelein, K. W. Moore, and J. Banchereau. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci USA. 89:1890-1895, 1992.
Scaglione F., G. Cattaneo, M. Alessandria, and R. Cogo. Efficacy and safety of the standardised ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold. Drug Exp Clinal Res 22:65-72, 1996.
Schatz D. G., and B. Malissen. Lymphocyte development. Curr Opin Immunol 14:183-185, 2002.
Sharpe A.H., and J. G. Freeman. The B7-CD28 superfamily. Nature immunol Rev 2:116-126, 2002.
Shinada M., M. Azuma , H. Kawai , K. Sazaki, I. Yoshida , T. Yoshida , T. Suzutani, and T, Sakuma. Enhancement of interferon-gamma production in glycyrrhizin-treated human peripheral lymphocytes in response to concanavalin A and to surface antigen of hepatitis B virus. Exp Biol Med 181:205-210, 1986.
Song Z., H. K. Johansen, V. Fabber, C. Moser, A. Kharazmi, J. Rygaard, and N. Hoiby. Ginseng treatment reduces bacterial load and lung pathology in chronic Pseudomonas aeruginosa pneumonia in rats. Antimicrob Agent Chemother 41:961-964, 1997.
Song, Z., H.K. Johansen, V. Fabber, C. Moser, A. Kharazmi, J. Rygaard, and N. Høiby. Ginseng treatment reduces bacterial load and lung pathology in chronic pseudomonas aeruginosa pneumonia in rats. Antimicrob. Agent. Chemother. 41:961-964, 1997.
Song, Z. J., H. K. Johansen, V. Faber, and N. Høiby. Ginseng treatment enhances
bacterial clearance and decreases lung pathology in athymic rats with chronic
Pseudomonas aeruginosa pneumonia. APMIS. 105:438-444, 1997.
Song, Z., A. Kharazmi, H. Wu, V. Faber, C. Moser, H.K. Johansen, J Rygaard, and N Høiby. Effects of ginseng treatment on neutrophil chemiluminescence and immunoglobulin G subclasses in a rat model of chronic pseudomonas aeruginosa pneumonia. Clin. Diagn. Lab. Immunol. 5:882-887, 1998.
Stephanie L. C., and B. Kim. Induction of Th1 and Th2 CD4+ T cell responses: The alternative approaches. Annu Rev Immunol 15: 297-322, 1997
Tseng J., and T. L. Li. Si-Jun-Zi-Tang regulates granulocyte macrophage colony-stimulating factor secretion by human peripheral blood mononuclear cells. Am J Chinese Med 24: 45-52, 1996.
Trinchieri G. Cytokines acting on or secreted by macrophages during intracellular infection IL-10,IL-12,IFN-γ. Curr Opin Immunol 9:17-23, 1997.
Utsunomiya T., M. Kobayashi, R. B. Pollard , and F. Suzuki. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrobial Agents Chemotherapy. 41:551-556, 1997.
Vaishnaw A. K., J. R. Orlinick, J. L. Chu, P. H. Krammer, M. V. Chao, and K. B. Elkon. The molecular basis for apoptotic defects in patients with CD95(Fas/Apo-1) mutations. J Clin Invest 103:355-361, 1999.
Wang M., L. J. Guilbert, L. Ling, J. Li, Y. Wu, S. Wu, P. Pang, and J. J Shan.
Immunomodulating activity of CVT-E002, a proprietary extract from North American ginseng(Panax quinquefolium). J Pharmacy Pharmacol 53:1515-1523, 2001.
Yang G., and Y.Yu. Immunopotentiating effect of traditional Chinese drugs-ginsenoside and glycyrrhiza polysaccharide. Proceedings of the Chinese Academy of Medical Sciences & the Peking Union Medical College 5:188-193, 1990.
Yoshikaw M., T. Morikawa, K. Yashiro, T. Murakami, and H. Matsuda. Bioactive Saponins and Glycosides. XIX.1) Notoginseng (3):Immunological Adjuvant Activity of Notoginsenosides and Related Saponins: Structures of Notoginsenosides-L, -M, and -N from the Roots of Panax notoginseng (BURK.)
F. H. CHEN. Chem Parm Bull 49:1452-1456, 2001.
Yun Y. S., Y. S. Lee, S. K. Jo, and I. S. Jung. Inhibition of autochthonous tumor by ethanol insoluble fraction from Panax ginseng as an immunomodulator. Planta Medica 59:521-524, 1993.
Yu S. J., and J. Tseng. Fu-Ling, a Chinese herbal drug, modulates cytokine secretion by human peripheral blood monocytes. Inter J Immunopharmac 18:37-44, 1996.
Zan H, A. Cerutti, P. Dramitinos, A. Schaffer, and P. Casali. CD40 engagement triggers switching to IgA1 and IgA2 in human B cells through induction of endogenous TGF-beta: evidence for TGF-beta but not IL-10-dependent direct S mu→S alpha and sequential S mu→S gamma, S gamma→S alpha DNA recombination. J Immunol 161:5217–5225, 1998.