Transplantation and Immunosuppression Notes

Principles of Immunosuppression in Transplantation (移植中免疫抑制的原理)

• Immunosuppression is essential for transplant recipients to prevent the adaptive immune system from rejecting the foreign organ. (免疫抑制對於移植受者來說是必不可少的，以防止適應性免疫系統排斥外來器官。)

• The goal is to balance immune suppression to prevent rejection while minimizing the risk of infection and adverse effects. (目標是平衡免疫抑制以防止排斥反應，同時最大限度地降低感染和不良反應的風險。)
  Key Concepts of Immune Responses (免疫應答的關鍵概念)

• Innate Immunity: The body's first line of defense, providing a non-specific response. (先天免疫： 身體的第一道防線，提供非特異性反應。)

• Adaptive Immunity: A specific immune response involving lymphocytes (T and B cells) that target particular antigens. ( 適應性免疫： 一種涉及針對特定抗原的淋巴細胞（T 細胞和 B 細胞）的特異性免疫反應。)

• Antigen Specificity: The ability of the adaptive immune system to recognize and respond to specific antigens. ( 抗原特異性： 適應性免疫系統識別和回應特定抗原的能力。)

• Lymphocytes: T cells and B cells are central to adaptive immunity, mediating cellular and humoral responses. ( 淋巴細胞： T 細胞和 B 細胞是適應性免疫的核心，介導細胞和體液反應。)

• Effector Mechanisms: How the immune system eliminates pathogens or damaged cells. ( 效應機制： 免疫系統如何消除病原體或受損細胞。)
  UK Organ Transplant Statistics (Oct 2024) (英國器官移植統計（2024年10月）)

• Waiting List: 7820 people are currently on the UK Transplant Waiting List. ( 等候名單： 目前有 7820 人在英國移植等候名單上。)

• Transplants Performed: 1925 transplants have been performed since April 2024. ( 進行的移植： 自 1925 年 2024 月以來已進行了 2024 例移植。)

• Survival Rates:(存活率)

  • Kidney:(腎)

  • 1-year: 99% (living donor) / 96-97% (deceased donor) (1 年：99% （活體捐獻者） / 96-97% （已故捐獻者）)

  • 5-year: 86% (living donor) / 72-76% (deceased donor) (5 年：86%（活體捐獻者）/ 72-76%（已故捐獻者）)

  • Liver:(肝)

  • 1-year: 93% (1 年：93%)

  • 5-year: 83% (5 年：83%)

  • Lung:(肺)

  • 1-year: 83% (1 年：83%)

  • 5-year: 55% (5 年：55%)

  • Heart:(心)

  • 1-year: 85% (1 年：85%)

  • 5-year: 72% (5 年期：72%)

• Other Transplants: Include intestine, pancreas, cornea, skin grafts, and cell-based transplants (HSCT/bone marrow/stem cell transplants). ( 其他移植： 包括腸道、胰腺、角膜、皮膚移植和基於細胞的移植（HSCT/骨髓/幹細胞移植）。)
  Types of Grafts (移植物的類型)

• Autograft: From the same individual. ( 自體移植物： 來自同一個人。)

• Isograft: From a genetically identical individual. ( 等移植物： 來自基因相同的個體。)

• Allograft: From a non-genetically identical individual (most common type of transplant). ( 同種異體移植物： 來自非基因相同的個體（最常見的移植類型）。)

• Xenograft: From one species to another. ( 異種移植物： 從一個物種到另一個物種。)

• Rejection: Occurs when the recipient's immune system attacks the graft, starting within days and happening faster in subsequent transplants from the same donor (sensitization). ( 排斥反應： 當受者的免疫系統攻擊移植物時發生，在幾天內開始，並在來自同一供體的後續移植中發生得更快（致敏）。)
  Types of Rejection (拒絕的類型)

• Hyperacute Rejection:(超急性排斥反應)

  • Time: Minutes (時間： 分鐘)

  • Mechanism: Pre-existing antibodies (AB) (機制：預先存在的抗體 （AB）)

• Acute Rejection:(急性排斥反應)

  • Time: Weeks (時間： 周)

  • Mechanism: MHC I and II mismatch (機制：MHC I 和 II 錯配)

• Chronic Rejection:(慢性排斥反應)

  • Time: Years (時間：年)

  • Mechanism: MHCIII, Type II hypersensitivity, Type IV hypersensitivity (機制： MHCIII， II 型超敏反應， IV 型超敏反應)
    Hypersensitivity Classification Recap (超敏反應分類回顧)

• Type I: IgE antibody on mast cells. ( I 型： 肥大細胞上的 IgE 抗體。)

• Type II: IgM and IgG antibody mediated cell killing. ( II 型： IgM 和 IgG 抗體介導的細胞殺傷。)

• Type III: IgG antibody immune complexes. ( III 型： IgG 抗體免疫複合物。)

• Type IV: T cells. ( IV 型： T 細胞。)
  Matching Donor and Recipient (匹配的供體和受體)

• ABO Blood Group Matching: Requires donor-recipient compatibility. ( ABO 血型匹配： 需要供體-受體相容性。)

• MHC Matching: Determined by tissue typing and MHC locus sequencing. ( MHC 匹配： 通過組織分型和 MHC 基因座測序確定。)

• Importance of MHC Compatibility:(MHC 兼容性的重要性)

  • TH and TC cells recognize non-self molecules (alloreactivity). (TH 和 TC 細胞識別的非自身分子（同種異體反應）.)

  • Parents or siblings are often the first choice due to closer MHC compatibility. (由於 MHC 相容性更強，父母或兄弟姐妹通常是首選。)

• Crossmatching: Determines if the recipient has pre-existing antibodies against donor MHC proteins. ( 交叉配型： 確定受體是否具有預先存在的針對供體 MHC 蛋白的抗體。)
  Rejection Direction: Host vs Graft and Graft vs Host (排斥方向：宿主 vs 移植物和移植物 vs 宿主)

• Host vs Graft: The recipient's immune system attacks the donor organ. ( 宿主與移植物： 受體的免疫系統攻擊供體器官。)

• Graft vs Host: The donor's immune cells attack the recipient's tissues. ( 移植物抗宿主： 供體的免疫細胞攻擊受體的組織。)

• Bone Marrow Transplantation: Particularly relevant as the immune system is being transplanted. ( 骨髓移植： 由於免疫系統正在被移植，因此尤其相關。)

  • MHC mismatched bone marrow transplants may contain donor lymphocytes that recognize the recipient's tissues as foreign, leading to graft-versus-host disease (GVHD). (MHC 錯配骨髓移植可能包含供體淋巴細胞，這些淋巴細胞將受者的組織識別為外來組織，從而導致移植物抗宿主病 （GVHD）。)

  • GVHD is treated with steroids and sometimes ciclosporin. (GVHD 使用類固醇治療，有時使用環孢素治療。)
    Allorecognition (同種異體識別)

• Transplanted organs have a profoundly different T cell antigen profile. (移植器官具有截然不同的 T 細胞抗原譜。)

• MHC differences between individuals lead to random activation of a significant percentage (up to 10%+) of CD8 and CD4 T lymphocytes. (個體之間的 MHC 差異導致 CD8 和 CD4 T 淋巴細胞的很大百分比（高達 10%+）隨機啟動。)

• Many of these lymphocytes are memory and effector cells already programmed to defend against pathogens. (這些淋巴細胞中有許多是記憶細胞和效應細胞，已經被程式設計來抵禦病原體。)
  Major Histocompatibility Complex (MHC) aka HLA (主要組織相容性複合體 （MHC） 又名 HLA)

• Contains a large number of immune-related genes, including MHC class I and class II molecules. (包含大量免疫相關基因，包括 MHC I 類和 II 類分子。)

• MHC class I presents endogenous antigens. (MHC I 類呈遞內源性抗原。)

• MHC class II presents exogenous antigens. (MHC II 類呈外源性抗原。)

• MHC diversity is critical for the adaptive immune system to recognize a wide range of pathogens. (MHC 多樣性對於適應性免疫系統識別多種病原體至關重要。)
  Mechanisms of Transplant Rejection: Allorecognition Host vs Graft (移植排斥反應的機制：同種異體識別宿主 vs 移植物)

• The recipient's T cells recognize the donor's MHC molecules as foreign, initiating an immune response. (受體的 T 細胞將供體的 MHC 分子識別為外來分子，從而啟動免疫反應。)
  Transplantation Interventions (移植干預)

• Ideal Cure: Remove the antigen by achieving a perfect MHC match between donor and recipient. ( 理想治癒： 通過在供體和受體之間實現完美的 MHC 匹配來去除抗原。)

• Matching MHC (HLA) Complex:(符合的 MHC （HLA） 複合物)

  • MHC-I and MHC-II are most important for transplantation. (MHC-I 和 MHC-II 對移植最重要。)

  • Match up to 6 different (major) genes. (匹配多達 6 個不同的（主要）基因。)

  • 2 alleles of each DPa and b subunits, DQa and b, DRa and b (multiple). (每個 DPa 和 b 亞基的 2 個等位基因，DQa 和 b，DRa 和 b（多個）。)

  • MHC diversity is driven by the need to present as many different peptide antigens as possible. (MHC 多樣性是由呈現盡可能多的不同肽抗原的需求驅動的。)
    HLA Matching (HLA 匹配)

• Match the correct alleles for as many as possible of the 12 genes. (匹配12個基因中盡可能多的正確等位基因。)

• Genes are polymorphic and expression is co-dominant. (基因是多態性的，表達是共顯性的。)

• Specific alleles/genes are more important (e.g., HLA-DR). (特異性等位基因/基因更重要（例如 HLA-DR）。)

• HLA-A, -B, -C, -DRB1, and -DQB1’s ‘perfect match’ is seen as 10/10. (HLA-A、-B、-C、-DRB1 和 -DQB1 的“完美匹配”被視為 10/10。)

• Mismatch number is linked to poorer outcomes, making isografts or autografts the best option, followed by genetic relatives. (錯配數量與較差的結果有關，使同種移植物或自體移植物成為最佳選擇，其次是遺傳親屬。)

• HLA match is more important in Hematopoietic Stem Cell (HSC) transplants (bone marrow). (HLA 匹配在造血幹細胞 （HSC） 移植（骨髓）中更為重要。)

• Less important for liver transplants. (對於肝移植來說不太重要。)
  Inhibitors of the Adaptive Immune System (適應性免疫系統的抑製劑)
  一. Anti-proliferative Drugs:(抗增殖藥物)
  o Methotrexate, azathioprine (甲氨蝶呤、硫唑嘌呤)
  二. Calcineurin Inhibitors:(鈣調磷酸酶抑製劑)
  o Ciclosporin, tacrolimus (環孢素、他克莫司)
  三. Biologic Inhibitors of Lymphocyte Signalling:(淋巴細胞信號傳導的生物抑製劑)
  o Abatacept (binds CD80/86 on APCs, blocking T cell priming) (阿巴西普（與 APC 上的 CD80/86 結合，阻斷 T 細胞啟動）)

• These drugs block all lymphocyte activity, inhibiting ongoing and new adaptive immune responses rather than targeting specific autoantigens. (這些藥物阻斷所有淋巴細胞活性，抑制正在進行的和新的適應性免疫反應，而不是靶向特定的自身抗原。)
  Transplant Immune-Targeted Interventions (移植免疫靶向干預)
  一. Anti-proliferative Drugs:(抗增殖藥物)
  o Azathioprine, mycophenolate mofetil, cyclophosphamide (硫唑嘌呤、嗎替麥考酚酯、環磷醯胺)
  二. Calcineurin Inhibitors:(鈣調磷酸酶抑製劑)
  o Ciclosporin, tacrolimus (環孢素、他克莫司)
  三. Non-Calcineurin Inhibitors:(非鈣調磷酸酶抑製劑)
  o Sirolimus, everolimus (西羅莫司、依維莫司)
  四. Biologic Inhibitors of Lymphocyte Signalling:(淋巴細胞信號傳導的生物抑製劑)
  o Belatacept (binds CD80/86 on APC, blocking T cell priming) (Belatacept（與 APC 上的 CD80/86 結合，阻斷 T 細胞啟動）)
  o Basiliximab (mAb against IL-2R, preventing lymphocyte activation) (巴厘昔單抗（抗 IL-2R 的 mAb，阻止淋巴細胞活化）)

• Glucocorticoids can also inhibit lymphocyte activation. (糖皮質激素還可以抑制淋巴細胞活化。)
  Anti-Proliferative Drugs (抗增殖藥物)

• Mycophenolate Mofetil (MMF):(嗎替麥考酚酯 （MMF）) Used in prophylaxis of acute rejection, inhibits inosine-5’-monophosphate dehydrogenase, depleting guanosine nucleotides, inhibiting DNA/RNA synthesis, and thus inhibiting proliferation. (用於預防急性排斥反應，抑制肌苷-5'-單磷酸脫氫酶，消耗鳥苷核苷酸，抑制 DNA/RNA 合成，從而抑制增殖。)

• Azathioprine:(硫唑嘌呤) Used in transplant rejection, inhibits purine synthesis, and has other mechanisms that contribute to lymphocyte reduction. (用於移植排斥反應，抑制嘌呤合成，並具有其他有助於淋巴細胞減少的機制。)
  Calcineurin Inhibitors (鈣調磷酸酶抑製劑)

• Ciclosporin and tacrolimus inhibit lymphocyte signalling by blocking the calcineurin pathway. (環孢素和他克莫司通過阻斷鈣調磷酸酶途徑來抑制淋巴細胞信號傳導。)

• Require interactions for naïve T-cell activation. (需要相互作用才能啟動幼稚 T 細胞。)

• Ciclosporin may be an alternative to tacrolimus. (環孢素可能是他克莫司的替代品。)
  Non-Calcineurin Inhibitors (非鈣調磷酸酶抑製劑)

• Sirolimus and everolimus bind FKBP and inhibit the mTOR pathway, downstream of IL-2 signalling, inhibiting lymphocyte activation. (西羅莫司和依維莫司結合 FKBP 並抑制 IL-2 信號轉導下游的 mTOR 通路，從而抑制淋巴細胞活化。)

• Sirolimus used in immunosuppression for kidney transplant, everolimus used in heart, liver, and renal transplant (safer). (西羅莫司用於腎移植的免疫抑制，依維莫司用於心臟、肝臟和腎臟移植 （更安全）。)
  Glucocorticoids (糖皮質激素)

• Often used in immunosuppressive maintenance regimens for organ transplants (e.g., prednisolone). (常用於器官移植的免疫抑制維持方案（例如潑尼松龍）。)

• Regimens can reduce and then stop corticosteroids after several weeks depending on factors including level HLA mismatch. (治療方案可以減少皮質類固醇的使用，然後在幾周后停止使用皮質類固醇，具體取決於包括 HLA 水準不匹配在內的因素。)
  Therapeutic Antibodies (治療性抗體)

• Induction therapy precedes maintenance immunosuppression in some transplants (e.g., kidney). (在一些移植物（例如腎臟）中，誘導治療先於維持免疫抑制。)

• Given around the time of the transplant procedure as intensive, short-term therapy using polyclonal or monoclonal antibodies. (在移植手術前後使用多克隆或單克隆抗體進行強化、短期治療。)

• Basiliximab:(巴厘昔單抗) Monoclonal Ab antagonist IL-2R, preventing lymphocyte activation. (單克隆抗體拮抗劑 IL-2R，可防止淋巴細胞活化。)

• Rabbit Anti-human Thymocyte Immunoglobulin (r-ATG):(兔抗人胸腺細胞免疫球蛋白 （r-ATG)) Antibodies that target a range of antigens, leading to T-cell depletion. (靶向一系列抗原的抗體，導致 T 細胞耗竭。)

• Belatacept:(Belatacept) Fusion protein of IgG1 Fc with CTLA-4, blocking CD80/86 co-stimulation and T cell activation. (IgG1 Fc 與 CTLA-4 的融合蛋白，阻斷 CD80/86 共刺激和 T 細胞活化。)
  Immunosuppression Consequences (免疫抑制的後果)

• General suppression of the adaptive immune system increases sensitivity to infection. (適應性免疫系統的普遍抑制會增加對感染的敏感性。)

• Antibody is long-lived, and many adults have encountered important pathogens. (抗體壽命長，許多成年人都遇到過重要的病原體。)

• Adverse effects of drugs (e.g., corticosteroids) (藥物（例如皮質類固醇）的不良反應)

• Adjuvant treatments may include anti-virals, anti-fungal, and anti-biotic therapy due to the risk of infection. (由於存在感染風險，輔助治療可能包括抗病毒、抗真菌和抗生素治療。)
  Adjuvant Antimicrobial Therapy (輔助抗菌治療)

• Antimicrobials are often prescribed initially with immunosuppression regimens. (抗菌藥物通常最初與免疫抑制方案一起開具。)

• Typical examples:(典型範例)

  • Anti-viral therapy: valganciclovir (prophylaxis for CMV disease). (抗病毒治療：纈更昔洛韋（CMV 疾病的預防）。)

  • Anti-fungal therapy: nystatin (prophylaxis for oropharyngeal fungal infections). (抗真菌治療：制黴菌素（預防口咽真菌感染）。)

  • Anti-bacterial: co-trimoxazole (prophylaxis against bacterial infections such as PCP pneumonia). (抗菌：復方新諾明（預防細菌感染，如PCP肺炎）。)

Comparison of Allergy, Autoimmunity, and Transplantation

過敏、自身免疫和移植的比較

Summary of Inhibition

Antigen-specific priming and effector functions are targeted. (抗原特異性啟動和效應子功能是靶向的。)

Anti-histamines, glucocorticoids, and biopharmaceuticals block inflammatory signals. (抗組胺葯、糖皮質激素和生物製藥可阻斷炎症信號。)

Multiple classes of immunosuppressant drugs block adaptive immune priming: (多類免疫抑製藥物阻斷適應性免疫啟動：)

Calcineurin (and non-calcineurin) inhibitors (鈣調磷酸酶（和非鈣調磷酸酶）抑製劑)

Proliferation blockers (anti-proliferatives) (增殖阻滯劑（抗增殖藥）)

mAbs (and polyclonal - rATG) block signals or kill lymphocytes (mAb（和多克隆 - rATG）阻斷信號或殺死淋巴細胞)

Antimicrobials help protect against infection due to increased risk due to immunosuppression. (由於免疫抑制導致風險增加，抗菌劑有助於預防感染。)