閱讀筆記：免疫抑制劑於實體器官移植與骨髓移植

 免疫抑制劑於實體器官移植與骨髓移植

簡介

回顧目前於實體器官移植和骨髓移植中使用的主要免疫抑制劑種類、其作用機制、生理效應以及潛在的副作用。免疫抑制的進展顯著提升了移植的成功率，透過針對特定的免疫訊號傳遞路徑和活化機制，選擇性地抑制免疫反應，從而降低急性及慢性排斥的發生率，並減輕骨髓移植後可能發生的移植物抗宿主疾病（GVHD）。

正如文件中所述：「The success of solid organ and bone marrow transplantation (BMT) has correlated with improvements in selective immunosuppression. Immunosuppression decreases both the incidence of acute and chronic organ graft and bone marrow rejection, and a potentially life threatening complication of BMT known as graft-vs-host disease (GVHD). Selective immunosuppression targets specific pathways of immune signaling and activation, and minimizes the incidence of deleterious side effects.」

免疫抑制劑種類與作用機制

以下將詳細介紹各類免疫抑制劑的作用機制、生理效應和副作用，並引用原文中的描述。

(1) 類固醇 (Corticosteroids)

• 生化機制： 「Affect NF-AT mediated pathway of signal transduction, which results in ultimate blockade of IL-1 and IL-6 production in macrophages at the earliest stage of immune response.」類固醇影響 NF-AT 介導的訊號傳導路徑，最終阻斷巨噬細胞在免疫反應早期產生 IL-1 和 IL-6。
• 生理效應： 「Inhibits leukocyte proliferation, reduce leukocyte migration into bloodstream (by decreasing production of endothelial adhesion molecules). Steroids are non-specific and broad spectrum anti-inflammatory agents used in a large number of medical conditions.」抑制白血球增生，減少白血球遷移至血液（透過減少內皮細胞黏附分子的產生）。類固醇是非特異性且廣譜的抗發炎藥物，廣泛應用於多種醫療狀況。
• 副作用： 「Cushing’s Syndrome [hypertension, hyperglycemia, insulin resistance, weight gain, moon facies, osteoporosis, impaired wound healing, ulcers], hyperlipidemia, adrenal suppression which may result in crisis if withdrawn abruptly」包括庫欣氏症候群（高血壓、高血糖、胰島素阻抗、體重增加、月亮臉、骨質疏鬆、傷口癒合不良、潰瘍）、高血脂和腎上腺抑制（若突然停藥可能導致危機）。

(2) 環孢靈 (Cyclosporine)

• 生化機制： 「Cyclosporine complexes with immunophilin protein in T cell. The complex blocks the phosphatase calcineurin. Without calcineurin activity, NF-AT is not dephosphorylated, is not translocated to the nucleus, and cannot activate transcription.」環孢靈與 T 細胞內的免疫親和素蛋白結合，形成的複合物阻斷磷酸酶鈣調磷酸酶的活性。缺乏鈣調磷酸酶活性，NF-AT 就無法去磷酸化，無法轉位至細胞核，也無法活化轉錄。
• 生理效應： 「Transcription of cytokines, including IL-2, is blunted. Consequently, T cell proliferation is inhibited, secretion of gamma interferon declines, and macrophage activation is limited.」包括 IL-2 在內的細胞激素轉錄受到抑制，進而抑制 T 細胞增生，減少γ干擾素分泌，並限制巨噬細胞活化。
• 副作用： 「Nephrotoxicity (preventable with mannitol diuresis; chronic cyclosporine nephrotoxicity may produce irreversible interstitial fibrosis), Neurotoxicity (tremor, headache, tinnitus), Neoplasms (lymphoproliferative malignancy); Hypertension, Hyperkalemia, Hepatotoxicity, Hirsutism, Hypertrophy of gingiva, Hyperglycemia, Hyperlipidemia」包括腎毒性（可使用甘露醇利尿預防；慢性腎毒性可能導致不可逆的間質纖維化）、神經毒性（顫抖、頭痛、耳鳴）、腫瘤（淋巴增生性惡性腫瘤）、高血壓、高血鉀、肝毒性、多毛症、牙齦肥厚、高血糖、高血脂。

(3) 他克莫司 (Tacrolimus)

• 生化機制： 「Binds to FK506 Binding Protein (FKBP). The Tacrolimus- FKBP complex inhibits calcineurin. The mechanism is therefore the same as that of cyclosporine.」與 FK506 結合蛋白（FKBP）結合，形成的複合物抑制鈣調磷酸酶，作用機制與環孢靈相似。
• 生理效應： 「10-100 times more potent than cyclosporine, but similar mechanism: decreased production of IL-2」效力比環孢靈強 10-100 倍，但機制相似，均減少 IL-2 的產生。
• 副作用： 「Similar to cyclosporine. Do not use with cyclosporine!」副作用與環孢靈相似，且不應與環孢靈同時使用。

(4) 細胞週期抑制劑 (Cell Cycle Inhibitors)

• 硫唑嘌呤 (Azathioprine)： 「Azathioprine is metabolized in vivo to 6-mercaptopurine (6MP). 6MP is a purine anti-metabolite that prevents DNA and RNA synthesis which inhibits proliferation of lymphocytes. Side effects include pancytopenias, gastrointestinal symptoms, and hepatic dysfunction (hepatitis).」在體內代謝為 6-巰基嘌呤 (6MP)，6MP 是一種嘌呤抗代謝物，可阻止 DNA 和 RNA 的合成，從而抑制淋巴細胞增生。副作用包括全血球減少症、腸胃道症狀和肝功能障礙（肝炎）。
• 麥考酚酸莫替酯 (Mycophenolate mofetil, MMF)： 「MMF is a prodrug of mycophenolic acid (MPA), which is an inhibitor of inosine monophosphate dehydrogenase (IMPDH). Inhibition of IMPDH limits production of guanosine nucleotides required for nucleic acid synthesis, and thus exerts a potent, selective cytostatic effect on B- and T- lymphocytes (decreased antibody production and generation of cytotoxic T-cells). Side effects include pancytopenias, infections and malignancies, and gastrointestinal symptoms.」是麥考酚酸 (MPA) 的前驅藥，MPA 是次黃嘌呤核苷酸脫氫酶 (IMPDH) 的抑制劑。抑制 IMPDH 會限制鳥嘌呤核苷酸的產生，這些核苷酸是核酸合成所需的，因此對 B 細胞和 T 細胞具有強效且選擇性的細胞靜態作用（減少抗體產生和細胞毒性 T 細胞的生成）。副作用包括全血球減少症、感染和惡性腫瘤以及腸胃道症狀。
• 來氟米特 (Leflunomide)： 「Leflunomide inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis); as a result, nucleic acid synthesis and lymphocyte proliferation are inhibited. Side effects include pancytopenias, hepatotoxicity, risk of lymphoproliferative disorders, and rare cases of Stevens- Johnson syndrome and toxic epidermal necrolysis.」抑制二氫乳清酸脫氫酶（一種參與從頭合成嘧啶的酶），導致核酸合成和淋巴細胞增生受到抑制。副作用包括全血球減少症、肝毒性、淋巴增生性疾病的風險以及罕見的史蒂芬強森症候群和毒性表皮溶解症。
• 環磷醯胺 (Cyclophosphamide)： 「Cyclophosphamide is an extremely potent alkylating agent which destroys proliferating lymphoid cells. Cyclophosphamide causes pancytopenias, hemorrhagic cystitis, alopecia, and infertility.」是一種極強效的烷化劑，可破壞增殖的淋巴細胞。環磷醯胺會引起全血球減少症、出血性膀胱炎、脫髮和不孕。

(5) 抗 TCR/CD3 抗體藥劑 (Anti-TCR/CD3 antibody agents)

• 抗淋巴球球蛋白 (ALG) 和抗胸腺細胞球蛋白 (ATG)： 「anti-lymphocyte globulin (ALG) and anti-thymocyte globulin (ATG) both inactivate peripheral lymphocytes and impair cellular immunity. These antibodies are used for induction of immunosuppression, treating initial rejection, and treating steroid resistant rejection. Side effects include anaphylactic response (because these antibodies are foreign proteins), serum sickness, antigen-antibody induced glomerulonephritis, reactivation of latent viral infections, post transplant lymphoproliferative disease, and development of human anti(mouse) antibodies.」ALG 和 ATG 均可使周邊淋巴細胞失活並損害細胞免疫。這些抗體用於誘導免疫抑制、治療初期排斥反應和治療類固醇抵抗性排斥反應。副作用包括過敏性反應（因為這些抗體是外來蛋白質）、血清病、抗原-抗體誘導的腎絲球腎炎、潛伏病毒感染的再活化、移植後淋巴增生性疾病以及產生人類抗（鼠）抗體。原文亦提及：「ALG/ATG can deplete the」。
• OKT3： 「OKT3 is a murine monoclonal antibody that blocks the binding of the TCR to antigen, thus downregulating the activity of the entire TCR/CD3 receptor complex. Compared to ALG and ATG, there are fewer serum proteins associated with OKT3 preparations than with those polyclonal antibody preparations (which may result in a more specific effect and fewer side effects). Side effects of OKT3 include fever, myalgias, arthralgias, CNS symptoms, GI irritation, and B-cell lymphoproliferative disorders.」OKT3 是一種鼠單株抗體，可阻斷 TCR 與抗原的結合，從而下調整個 TCR/CD3 受體複合物的活性。與 ALG 和 ATG 相比，OKT3 製劑中相關的血清蛋白較少（可能導致更特異性的作用和更少的副作用）。副作用包括發燒、肌肉痛、關節痛、中樞神經系統症狀、腸胃道刺激和 B 細胞淋巴增生性疾病。

(6) 西羅莫司 (Sirolimus)

• 生化機制： 「Inhibits IL-2 mediated signaling by inhibiting Target of Rapamycin (TOR), an enzyme active in IL-2 cascades in proliferating lymphocytes.」透過抑制哺乳類雷帕黴素標靶蛋白 (TOR)（一種在增殖淋巴細胞 IL-2 級聯反應中活躍的酶）來抑制 IL-2 介導的訊號傳遞。
• 生理效應： 「Cell cycle progression from G1 to S is blocked; T- cell and B- cell proliferation is limited, and B-cell antibody production is inhibited.」細胞週期從 G1 期到 S 期的進程被阻斷；T 細胞和 B 細胞的增殖受到限制，B 細胞抗體的產生也受到抑制。
• 副作用： 「Hyperlipidemia, Hypertension, Hypokalemia, Pancytopenias, decreased GFR / increased Serum Creatinine, metallic taste in mouth」包括高血脂、高血壓、低血鉀、全血球減少症、腎絲球過濾率下降/血清肌酸酐升高、口中有金屬味。

(7) 新型藥劑 (Newer agents)

• 抗 TNF 藥物 (Anti-TNF agents)： 包括依那西普 (etanercept) 和英夫利昔單抗 (infliximab)。「By limiting TNF activity, the generation of pro-inflammatory cytokines IL-1 and IL-6 are diminished.」透過限制 TNF 的活性，減少了促發炎細胞激素 IL-1 和 IL-6 的產生。此外，還有阿那白滯素 (anakinra)，是人類 IL-1 受體拮抗劑的重組版本，透過阻斷其受體來抑制 IL-1。
• 達克珠單抗 (Daclizumab)： 「Daclizumab is a humanized monoclonal murine IgG1 antibody that binds to a subunit of the IL-2 (CD25) receptor on the surface of activated lymphocytes. Daclizumab thereby functions as an IL-2 inhibitor. Side effects include hypersensitivity, cellulitis, and wound infection.」是一種人源化鼠單株 IgG1 抗體，可與活化淋巴細胞表面 IL-2 (CD25) 受體的一個亞單位結合，從而作為 IL-2 抑制劑發揮作用。副作用包括過敏反應、蜂窩性組織炎和傷口感染。
• 巴利昔單抗 (Basiliximab)： 「Basiliximab is a chimeric murine/human monoclonal IgG1 antibody that blocks the alpha chain of the IL-2 (CD25) receptor on the surface of activated T-cell lymphocytes. Basiliximab is indicated for the prophylaxis of acute organ rejection in renal transplantation. Side effects include hypersensitivity and gastrointestinal disorders.」是一種嵌合鼠/人單株 IgG1 抗體，可阻斷活化 T 細胞淋巴細胞表面 IL-2 (CD25) 受體的 α 鏈。巴利昔單抗適用於腎臟移植中急性器官排斥的預防。副作用包括過敏反應和腸胃道疾病。

免疫抑制的歷史進展

文件簡述了免疫抑制在移植領域的發展歷程：「1960s: Introduction of effective immunosuppressive drugs. Steroids, ATG, azathioprine」、「1970s: Cyclosporine introduced」、「1980s: OKT3, tacrolimus, mycophenolate mofetil introduced」、「1990s: Leflunomide, TNF antagonists, and selective mAbs introduced; additional mAb therapies expected in future」。這些進展顯著改善了移植的成功率，例如：「In 1988 1 year renal cadaver graft survival was 76% and 1 year renal living donor graft survival was 89% ▫ By 1995, graft survival rates improved to 87% and 93% respectively」。

免疫抑制的益處與風險

• 益處： 「Immunosuppression decreases risks of both acute and chronic organ graft and bone marrow rejection, and GVHD」。免疫抑制降低了急性及慢性器官移植和骨髓移植排斥的風險，以及 GVHD 的發生率。
• 風險： 「Immunosuppression poses risk of several types of side effects to the patient: Acute effects: gastrointestinal upset; Opportunistic infection because patient is immunocompromised: CMV, Candida,Pneumocystis carinii, etc.; Malignancies (lymphomas, skin cancer, etc.); Toxicities specific to particular immunosuppressive agent: steroids, etc.」免疫抑制也帶來多種副作用的風險，包括急性腸胃不適、機會性感染（如 CMV、念珠菌、卡氏肺囊蟲等）、惡性腫瘤（如淋巴瘤、皮膚癌等）以及特定免疫抑制劑的毒性。

器官移植排斥的類型

• 超急性排斥 (Hyperacute)： 「Occurs within minutes after transplant. Mediated by preformed anti- donor antibodies in recipient. Involves small vessel thrombosis and graft infarction.」移植後數分鐘內發生，由受者體內預先存在的抗供體抗體介導，涉及小血管血栓形成和移植體梗塞。
• 急性排斥 (Acute)： 「Occurs weeks after transplant. Delayed-type hypersensitivity / Cell mediated response of cytotoxic T lymphocytes reacting against the foreign MHC molecules of the graft. Histologically characterized by mononuclear infiltrate, hemorrhage, and edema in graft. Reversible with immunosuppressive therapy.」移植後數週發生，是細胞毒性 T 淋巴細胞對移植體外來 MHC 分子產生延遲型過敏反應/細胞介導反應。組織學特徵是移植體內單核細胞浸潤、出血和水腫，可透過免疫抑制治療逆轉。
• 慢性排斥 (Chronic)： 「Occurs months to years post transplant. Results from antibody mediated vascular damage (fibrinoid necrosis) and is irreversible. Vascular damage results in vascular cell wall proliferation which may occlude vessel lumen resulting in graft ischemia and fibrosis. Can progress insidiously despite increased immunosuppressive therapy.」移植後數月至數年發生，由抗體介導的血管損傷（纖維蛋白樣壞死）引起，是不可逆的。血管損傷導致血管壁細胞增生，可能阻塞血管腔，進而導致移植體缺血和纖維化。即使增加免疫抑制治療，也可能隱匿性地進展。

骨髓移植後的移植物排斥與 GVHD

• 移植物排斥 (Graft rejection)： 「Graft rejection occurs uncommonly (<1%) after conventional myeloablative bone marrow/stem cell transplantation, with increased incidence (1-15%) after HLA- mismatched BMT/cord blood transplantation. The rate of graft rejection is higher after nonmyeloablative preparative therapy for BMT」。在傳統骨髓消融性骨髓/幹細胞移植後不常見（<1%），但在 HLA 不合的骨髓移植/臍帶血移植後發生率增加（1-15%）。非骨髓消融性骨髓移植預處理後，移植物排斥的發生率更高。
• 急性 GVHD (Acute GVHD)： 「Acute GVHD, which is usually evident before day 100 post-transplant, occurs in 1/3 of HLA matched transplants and 2/3 of HLA-mismatched transplants. Acute GVHD affects predominantly skin, the GI tract, and liver. Tissue injury involves effector cells (initiated by T-cells), particularly of the TH1 subset, and cytokines (e.g. TNF-alpha, interferon-gamma, and interleukin-1).」通常在移植後 100 天內出現，在 HLA 相合的移植中發生率為 1/3，在 HLA 不合的移植中為 2/3。急性 GVHD 主要影響皮膚、腸胃道和肝臟。組織損傷涉及效應細胞（由 T 細胞啟動，尤其是 TH1 子集）和細胞激素（如 TNF-α、γ-干擾素和白介素-1）。
• 慢性 GVHD (Chronic GVHD)： 「Chronic GVHD (>day 100) occurs in approximately 1⁄2 of transplants. Chronic GVHD may affect almost any organ/tissue and often mimics a collagen vascular disease in its clinical presentation.」在約一半的移植病例中發生於移植後 100 天以上。慢性 GVHD 可能影響幾乎所有器官/組織，其臨床表現通常類似於膠原血管疾病。

免疫反應與免疫抑制的分子基礎

文件詳細描述了免疫反應的細胞和分子機制，以及免疫抑制劑的作用位點。關鍵在於對主要組織相容性複合體 (MHC) 分子和 T 細胞受體 (TCR) 之間相互作用的理解：「In the context of an MHC mismatched organ or bone marrow transplant, the MHC molecules of the cells of the organ (or bone marrow) graft are recognized by the host TCR not as self-MHC molecules, but rather in the same manner as a self-MHC plus the foreign peptide it is presenting. The immunologic response to the foreign MHC molecules is a major cause of most graft rejection. Conversely the donor immune system may recognize disparate MHC antigens in the host and initiate an immunologic response in the form of GVHD.」異體 MHC 分子被宿主 TCR 視為非自身 MHC 分子加上外來胜肽，從而引發排斥反應。相反，供體的免疫系統也可能識別宿主體內不同的 MHC 抗原，進而引發 GVHD。

因此，「Minimization of the antigenic differences between donor and recipient, by matching their MHC alleles, has decreased rejection and GVHD and improved graft survival.」透過配對供體和受者的 MHC 等位基因，最大限度地減少抗原差異，可以降低排斥和 GVHD 的發生率，並提高移植體的存活率。

結論

免疫抑制劑的發展和應用是提高實體器官移植和骨髓移植成功率的關鍵。理解不同免疫抑制劑的作用機制和副作用，以及免疫排斥和 GVHD 的分子基礎，對於臨床上選擇合適的免疫抑制方案至關重要。隨著對免疫系統更深入的了解，未來有望開發出更具選擇性、更有效且副作用更小的免疫抑制療法。