📚 Organ Transplantation Rejection and Immune Mechanisms | 器官移植的排异反应与免疫机制
Organ transplantation is one of the most remarkable achievements of modern medicine, yet its success is constantly challenged by the recipient's immune system. Understanding the immunological mechanisms behind transplant rejection is essential for A-Level Biology students, as it integrates core concepts of immunity, cell signalling, and clinical application.
器官移植是现代医学最杰出的成就之一，然而其成功始终面临受者免疫系统的挑战。理解移植排异背后的免疫机制，是A-Level生物学的核心考点，因为它整合了免疫学、细胞信号传导及临床应用等多方面知识。
1. Why Does Rejection Occur? | 为什么会发生排异？
The immune system is designed to distinguish "self" from "non-self". When an organ is transplanted from a donor to a recipient, the recipient's immune system recognises the donor organ as foreign because of differences in cell surface molecules, primarily the Human Leukocyte Antigen (HLA) system.
免疫系统的核心功能是区分“自身”与“非自身”。当器官从供者移植到受者体内时，受者的免疫系统会因细胞表面分子——主要是人类白细胞抗原（HLA）系统——的差异，将供体器官识别为外来物。
- HLA molecules are glycoproteins encoded by the Major Histocompatibility Complex (MHC) genes.
- HLA 分子是由主要组织相容性复合体（MHC）基因编码的糖蛋白。
- In humans, the most important transplant antigens are HLA-A, HLA-B, and HLA-DR.
- 在人类中，最重要的移植抗原是 HLA-A、HLA-B 和 HLA-DR。
- The greater the HLA mismatch, the stronger the immune response against the graft.
- HLA 错配程度越高，针对移植物的免疫反应就越强烈。
Rejection intensity ∝ degree of HLA mismatch
排异强度 ∝ HLA 错配程度
2. The Role of MHC Molecules | MHC 分子的作用
MHC molecules present antigen peptides to T lymphocytes. There are two major classes: MHC class I and MHC class II. In transplantation, recipient T cells recognise foreign MHC molecules directly — a process known as allorecognition.
MHC 分子负责将抗原肽呈递给 T 淋巴细胞。MHC 分为两大类：MHC I 类分子和 MHC II 类分子。在移植中，受者 T 细胞能直接识别外来 MHC 分子，这一过程称为同种异体识别。
| Feature | MHC Class I | MHC Class II |
| Expression | All nucleated cells | Antigen-presenting cells (APCs) |
| Presented to | CD8⁺ cytotoxic T cells | CD4⁺ helper T cells |
| Role in rejection | Direct target for CTL killing | Activates helper T cells → cytokine release |
MHC I 类分子存在于所有有核细胞表面，而 MHC II 类分子仅存在于抗原呈递细胞（APC）表面。前者将内源性抗原呈递给 CD8⁺ 细胞毒性 T 细胞，后者将外源性抗原呈递给 CD4⁺ 辅助 T 细胞。
3. Direct and Indirect Allorecognition | 直接与间接同种异体识别
Two distinct pathways explain how recipient T cells are activated by donor antigens. Both are critical for A-Level exam answers on transplant immunology.
两条不同的通路解释了受者 T 细胞如何被供者抗原激活。在考试中，这两条通路都是器官移植免疫学的重要得分点。
- Direct pathway: Recipient CD8⁺ T cells recognise intact foreign MHC molecules on donor cells.
- 直接通路：受者 CD8⁺ T 细胞直接识别供者细胞表面完整的外来 MHC 分子。
- Indirect pathway: Recipient APCs take up donor antigens, process them, and present them via self-MHC to recipient T cells.
- 间接通路：受者 APC 摄取供者抗原，经加工处理后，通过自身 MHC 分子呈递给受者 T 细胞。
- The direct pathway dominates early acute rejection; the indirect pathway contributes to chronic rejection.
- 直接通路主导早期急性排异，间接通路则与慢性排异密切相关。
4. Cellular Mechanisms: T Cell Activation | 细胞机制：T 细胞的激活
T cell activation requires two signals. Signal 1 is the binding of the T cell receptor (TCR) to the MHC-antigen complex. Signal 2 is a costimulatory signal, such as CD28 on T cells binding to B7 (CD80/CD86) on APCs.
T 细胞的完全激活需要双信号。第一信号是 T 细胞受体（TCR）与 MHC-抗原复合物的结合；第二信号是共刺激信号，例如 T 细胞表面的 CD28 与 APC 表面的 B7（CD80/CD86）结合。
Signal 1: TCR–MHC/peptide + Signal 2: CD28–B7 → Full T cell activation
信号 1：TCR–MHC/肽 + 信号 2：CD28–B7 → T 细胞完全激活
Without costimulation, T cells become anergic (unresponsive), a concept exploited in immunotherapy. Cytokines such as IL-2 promote T cell proliferation and differentiation into effector cells.
若无共刺激信号，T 细胞会进入无反应状态（失能），这一原理已被用于免疫治疗。IL-2 等细胞因子可促进 T 细胞增殖并分化为效应细胞。
5. Types of Graft Rejection: Hyperacute | 超急性排异
Hyperacute rejection occurs within minutes to hours after transplantation. It is mediated by pre-existing antibodies in the recipient against donor ABO blood group antigens or HLA molecules.
超急性排异发生在移植后数分钟至数小时内，由受者体内预先存在的抗体介导，这些抗体针对供者的 ABO 血型抗原或 HLA 分子。
- Pre-formed antibodies bind to vascular endothelium → complement activation → thrombosis.
- 预formed抗体与血管内皮结合 → 补体激活 → 血栓形成。
- The graft becomes cyanotic, mottled, and fails rapidly.
- 移植物出现发绀、斑驳外观，并迅速衰竭。
- Prevention is achieved through ABO and cross-match testing before transplantation.
- 术前通过 ABO 配型和交叉配型试验进行预防。
6. Acute Rejection | 急性排异
Acute rejection typically occurs days to weeks after transplantation and is primarily T-cell mediated. It is the most common form of rejection and can be reversed with immunosuppressive drugs.
急性排异通常发生在移植后数天至数周，主要由 T 细胞介导。它是最常见的排异类型，可通过免疫抑制药物逆转。
- CD4⁺ helper T cells are activated by donor MHC class II antigens.
- CD4⁺ 辅助 T 细胞被供者 MHC II 类抗原激活。
- Activated CD4⁺ cells secrete cytokines (e.g., IL-2, IFN-γ), activating CD8⁺ cytotoxic T cells and macrophages.
- 激活的 CD4⁺ 细胞分泌细胞因子（如 IL-2、IFN-γ），进而激活 CD8⁺ 细胞毒性 T 细胞和巨噬细胞。
- Cytotoxic T cells release perforin and granzymes, inducing apoptosis of graft cells.
- 细胞毒性 T 细胞释放穿孔素和颗粒酶，诱导移植物细胞凋亡。
- Macrophages contribute to delayed-type hypersensitivity (DTH) responses within the graft.
- 巨噬细胞在移植物内引发迟发型超敏反应（DTH）。
7. Chronic Rejection | 慢性排异
Chronic rejection develops over months to years and is characterised by fibrosis, intimal thickening of blood vessels, and progressive organ dysfunction. It involves both cellular and antibody-mediated mechanisms.
慢性排异在数月到数年内缓慢发展，以纤维化、血管内膜增厚和进行性器官功能障碍为特征，涉及细胞免疫和抗体介导的多种机制。
- Repeated or low-level acute rejection episodes can lead to chronic damage.
- 反复或低水平的急性排异发作可导致慢性损伤。
- Chronic antibody-mediated rejection involves donor-specific antibodies (DSA) against HLA.
- 慢性抗体介导的排异涉及针对 HLA 的供体特异性抗体（DSA）。
- IFN-γ from activated T cells stimulates smooth muscle proliferation → vessel occlusion.
- 激活 T 细胞分泌的 IFN-γ 刺激平滑肌增殖 → 血管闭塞。
- The only definitive treatment for chronic rejection is re-transplantation.
- 慢性排异的最终治疗方法只能是再次移植。
8. Immunosuppressive Drugs | 免疫抑制药物
Immunosuppressive therapy aims to inhibit T cell activation and proliferation while minimising side effects. A combination of drugs is often used to target different stages of the immune response.
免疫抑制治疗旨在抑制 T 细胞的激活和增殖，同时尽量减少副作用。临床上常联合使用多种药物，针对免疫反应的不同阶段进行干预。
| Drug | Mechanism | Target |
| Cyclosporin A | Inhibits calcineurin → blocks NFAT → reduces IL-2 transcription | T cell activation |
| Tacrolimus (FK506) | Similar to cyclosporin; binds FKBP12 | T cell activation |
| Corticosteroids | Inhibit cytokine gene expression; suppress inflammation | APCs and T cells |
| Azathioprine | Inhibits purine synthesis → blocks DNA replication | Dividing lymphocytes |
| Mycophenolate mofetil | Inhibits IMPDH → blocks guanine synthesis | Dividing lymphocytes |
副作用包括感染风险增加、肾功能毒性和长期肿瘤风险。环孢素和他克莫司直接阻断钙调磷酸酶通路，从而抑制 IL-2 的转录，是最常用的钙调磷酸酶抑制剂。
9. Graft-versus-Host Disease (GVHD) | 移植物抗宿主病
In bone marrow or haematopoietic stem cell transplantation, the graft may contain immunocompetent donor T cells that attack the recipient's tissues. This is called graft-versus-host disease (GVHD).
在骨髓或造血干细胞移植中，移植物中可能含有具有免疫活性的供者 T 细胞，它们会攻击受者的组织，这就是移植物抗宿主病（GVHD）。
- GVHD mainly affects the skin, liver, and gastrointestinal tract.
- GVHD 主要累及皮肤、肝脏和胃肠道。
- Acute GVHD occurs within 100 days; chronic GVHD later.
- 急性 GVHD 发生在 100 天内，慢性 GVHD 发生较晚。
- Treatment includes T-cell depletion from the graft and intensive immunosuppression.
- 治疗方法包括从移植物中去除 T 细胞以及加强免疫抑制。
10. Induction of Immune Tolerance | 免疫耐受的诱导
Immune tolerance refers to the specific unresponsiveness of the recipient's immune system to donor antigens while preserving responses to other pathogens. Achieving tolerance is the "holy grail" of transplantation.
免疫耐受是指受者免疫系统对供者抗原产生特异性无反应性，同时保留对其他病原体的正常免疫应答。实现免疫耐受是移植领域的“圣杯”。
- Chimerism: Mixed donor–recipient haematopoietic cells can promote tolerance.
- 嵌合状态：供者与受者造血细胞混合存在可促进耐受。
- Regulatory T cells (Tregs): Suppress effector T cell responses via IL-10 and TGF-β.
- 调节性 T 细胞（Tregs）：通过 IL-10 和 TGF-β 抑制效应 T 细胞反应。
- Costimulation blockade: Inhibiting CD28–B7 signals induces T cell anergy.
- 共刺激阻断：抑制 CD28–B7 信号可诱导 T 细胞失能。
- PD-L1/PD-1 pathway: Promotes T cell exhaustion and protects the graft.
- PD-L1/PD-1 通路：促进 T 细胞耗竭，从而保护移植物。
11. Exam-Style Summary Points | 考试要点总结
For A-Level examinations, focus on the following high-yield points:
针对 A-Level 考试，应重点关注以下高频考点：
- MHC/HLA molecules are the main triggers of rejection; MHC I → CD8⁺ T cells, MHC II → CD4⁺ T cells.
- MHC/HLA 分子是排异的主要触发因素；MHC I 类→CD8⁺ T 细胞，MHC II 类→CD4⁺ T 细胞。
- Hyperacute rejection is antibody-mediated; acute rejection is T-cell-mediated; chronic rejection involves both.
- 超急性排异由抗体介导；急性排异由 T 细胞介导；慢性排异则由两者共同参与。
- T cell activation requires TCR–MHC binding plus costimulatory signals.
- T 细胞激活需要 TCR–MHC 结合以及共刺激信号。
- Cyclosporin and tacrolimus block IL-2 production by inhibiting calcineurin.
- 环孢素和他克莫司通过抑制钙调磷酸酶来阻断 IL-2 的产生。
- GVHD is a special complication of bone marrow transplantation.
- GVHD 是骨髓移植的特殊并发症。
12. Why This Matters | 为什么这很重要
Transplant immunology is a perfect example of how basic biology translates into life-saving clinical practice. It demonstrates the balance between protective immunity and pathological immune responses, and highlights the challenges of manipulating the immune system safely.
移植免疫学是基础生物学转化为拯救生命之临床实践的完美例证。它展示了保护性免疫与病理性免疫反应之间的平衡，并揭示了安全调控免疫系统所面临的巨大挑战。
By mastering these mechanisms, you not only prepare for exam questions but also gain a deeper appreciation of how the immune system works in health and disease.
掌握这些机制，不仅能帮助你应对考试题目，更能让你深入理解免疫系统在健康和疾病中如何发挥作用。
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