Immune Rejection: Principles and Mechanisms | 免疫排斥反应：原理与机制

📚 Immune Rejection: Principles and Mechanisms | 免疫排斥反应：原理与机制

The immune system is designed to defend the body against pathogens, but it can also attack transplanted organs or tissues, leading to graft rejection. Understanding the molecular and cellular mechanisms underlying this process is essential for clinical transplantation and for A Level/IB Biology students exploring the specificity of immune responses.

免疫系统的作用是抵御病原体，但它同样会攻击移植的器官或组织，导致移植物排斥。理解这一过程背后的分子与细胞机制，对临床移植至关重要，也有助于 A Level / IB 生物学生深入理解免疫应答的特异性。

1. MHC Molecules: The Basis of Self-Recognition | MHC 分子：自我识别的基础

Major histocompatibility complex (MHC) molecules are cell-surface glycoproteins that present peptide fragments to T lymphocytes. In humans, these molecules are called human leukocyte antigens (HLA). MHC class I molecules are expressed on almost all nucleated cells, while MHC class II molecules are mainly found on antigen-presenting cells such as dendritic cells, macrophages, and B cells.

主要组织相容性复合体（MHC）是细胞表面的糖蛋白，负责将肽段呈递给 T 淋巴细胞。在人类中，这些分子被称为人类白细胞抗原（HLA）。MHC I 类分子几乎表达于所有有核细胞表面，而 MHC II 类分子主要存在于树突状细胞、巨噬细胞和 B 细胞等抗原呈递细胞上。

The MHC gene family is the most polymorphic region in the human genome. Hundreds of alleles exist at the HLA-A, HLA-B, HLA-DR, and other loci, which means that two unrelated individuals rarely share identical MHC profiles. This polymorphism is the main reason why transplanted organs are recognised as foreign by the recipient’s immune system.

MHC 基因家族是人类基因组中多态性最高的区域。HLA-A、HLA-B、HLA-DR 等位点存在数百种等位基因，这意味着两个无亲缘关系的人几乎不可能拥有完全相同的 MHC 谱型。这种多态性是移植器官被受者免疫系统识别为外源异物的根本原因。

2. Allorecognition: Direct and Indirect Pathways | 同种异体识别：直接与间接途径

Allorecognition is the process by which recipient T cells detect donor MHC molecules. Two distinct pathways are involved: the direct pathway and the indirect pathway.

同种异体识别是指受者 T 细胞识别供者 MHC 分子的过程。该过程涉及两条不同途径：直接途径和间接途径。

Direct pathway: Recipient CD4⁺ or CD8⁺ T cells bind directly to intact donor MHC molecules displayed on the surface of transplanted cells. This pathway is particularly strong during acute rejection because a large number of recipient T cells cross-react with foreign MHC molecules.
间接途径：受者 CD4⁺ 或 CD8⁺ T 细胞直接结合移植细胞表面的完整供者 MHC 分子。该途径在急性排斥中尤为强烈，因为大量受者 T 细胞可与外来 MHC 分子发生交叉反应。

Indirect pathway: Donor proteins, including MHC molecules, are taken up by recipient antigen-presenting cells, processed, and presented as peptides on recipient MHC class II molecules. This pathway is believed to dominate chronic rejection.
间接途径：供者蛋白质（包括 MHC 分子）被受者抗原呈递细胞摄取，加工后以肽段形式呈递在受者 MHC II 类分子上。该途径被认为是慢性排斥反应的主要机制。

The direct pathway resembles a strong primary immune response, while the indirect pathway is similar to the conventional processing of foreign antigens. Both pathways activate distinct T cell subsets, causing a cascade of inflammatory damage within the graft.

直接途径类似于强烈的原发性免疫应答，而间接途径则接近常规的外源抗原加工过程。这两条途径激活不同的 T 细胞亚群，在移植物内部引发级联炎症损伤。

3. T Cell Activation: Signal 1 and Signal 2 | T 细胞活化：第一信号与第二信号

Full activation of naïve T cells requires two signals. Signal 1 is provided by the binding of the T cell receptor (TCR) to the peptide-MHC complex. Signal 2, the co-stimulatory signal, is delivered by the interaction of CD28 on T cells with B7 molecules (CD80/CD86) on antigen-presenting cells.

初始 T 细胞的完全活化需要两个信号。第一信号由 T 细胞受体（TCR）与肽-MHC 复合物的结合提供。第二信号，即共刺激信号，由 T 细胞表面的 CD28 与抗原呈递细胞上的 B7 分子（CD80/CD86）相互作用传递。

TCR + peptide-MHC → Signal 1
CD28 + B7 (CD80/CD86) → Signal 2

If Signal 1 occurs without Signal 2, T cells become anergic (unresponsive) and may undergo apoptosis. In transplantation, donor-derived dendritic cells provide both signals, thereby triggering a powerful allogeneic response. Blocking the CD28-B7 interaction with agents such as belatacept has become a promising immunosuppressive strategy.

如果只有第一信号而没有第二信号，T 细胞将进入失能状态（无反应性）并可能发生凋亡。在移植中，供者来源的树突状细胞提供两个信号，从而引发强烈的同种异体应答。使用贝拉西普等药物阻断 CD28-B7 相互作用已成为一种有前景的免疫抑制策略。

4. Cellular Effectors: CD8⁺ Cytotoxic T Cells and NK Cells | 细胞效应：CD8⁺ 细胞毒性 T 细胞与 NK 细胞

CD8⁺ cytotoxic T lymphocytes (CTLs) are the principal cellular effectors of acute graft rejection. They recognise donor MHC class I molecules and release perforin and granzymes to induce apoptosis of target cells. Perforin forms pores in the target cell membrane, allowing granzymes to enter and activate caspases.

CD8⁺ 细胞毒性 T 淋巴细胞（CTL）是急性移植物排斥的主要细胞效应细胞。它们识别供者 MHC I 类分子，释放穿孔素和颗粒酶以诱导靶细胞凋亡。穿孔素在靶细胞膜上形成孔道，使颗粒酶进入并激活半胱天冬酶。

In addition, CD8⁺ T cells express Fas ligand (FasL), which binds to Fas receptors on graft cells, triggering death-receptor-mediated apoptosis. This pathway is rapid and does not require newly synthesised proteins.

此外，CD8⁺ T 细胞表达 Fas 配体（FasL），可与移植物细胞表面的 Fas 受体结合，启动死亡受体介导的凋亡。该途径快速且不需要新合成蛋白质。

Natural killer (NK) cells also contribute to rejection. Donor cells lacking recipient-matched HLA molecules fail to engage inhibitory NK receptors, so NK cells become activated and kill the graft cells through antibody-dependent cellular cytotoxicity (ADCC) or direct cytotoxic mechanisms.

自然杀伤（NK）细胞也参与排斥反应。当供者细胞缺乏与受者匹配的 HLA 分子时，无法结合抑制性 NK 受体，NK 细胞因此被激活，并通过抗体依赖的细胞介导的细胞毒性作用（ADCC）或直接细胞毒机制杀伤移植物细胞。

5. Humoral Rejection: Antibody-Mediated Damage | 体液性排斥：抗体介导的损伤

B cells and plasma cells participate in graft rejection by producing donor-specific antibodies (DSAs), which target donor HLA molecules, ABO blood group antigens, and endothelial cell antigens.

B 细胞和浆细胞通过产生供体特异性抗体（DSA）参与移植物排斥反应，这些抗体靶向供者 HLA 分子、ABO 血型抗原和内皮细胞抗原。

Hyperacute rejection: Pre-existing antibodies bind to the vascular endothelium, activating complement and triggering rapid thrombosis within minutes.
超急性排斥：预存抗体与血管内皮结合，激活补体并在数分钟内引发血栓形成。

Acute antibody-mediated rejection: De novo DSAs activate complement, recruit neutrophils and macrophages, and cause endothelial injury, usually days to weeks after transplantation.
急性抗体介导性排斥：新生 DSA 激活补体，招募中性粒细胞和巨噬细胞，导致内皮损伤，通常发生在移植后数天至数周。

Microarray detection of C4d, a stable degradation product of complement component C4, is widely used in renal transplant biopsies as a marker of antibody-mediated rejection.

补体成分 C4 的稳定降解产物 C4d 的微阵列检测，广泛应用于肾移植活检中，作为抗体介导性排斥的标志物。

6. Classification of Graft Rejection | 移植物排斥的分类

Graft rejection is broadly classified by its timing and pathological mechanism into hyperacute, acute, and chronic rejection.

移植物排斥按发生时间和病理机制，大致可分为超急性、急性和慢性排斥三种类型。

Type	Time	Mechanism	Prevention/Treatment
Hyperacute	Minutes to hours	Pre-existing anti-donor antibodies, complement activation, thrombosis	Cross-match before transplant
Acute cellular	Days to months	CD4⁺ and CD8⁺ T cell infiltration	Immunosuppressive drugs
Acute humoral	Days to weeks	DSA, complement, endothelial injury	Plasmapheresis, anti-CD20 therapy
Chronic	Months to years	Indirect allorecognition, fibrosis, arteriosclerosis	Long-term maintenance immunosuppression

Hyperacute rejection is now rare due to mandatory ABO and cross-match testing. Acute rejection, particularly cellular rejection, is often reversible with high-dose corticosteroids. Chronic rejection remains the leading cause of late graft loss and is difficult to treat effectively.

由于 ABO 血型配型和交叉配血试验的常规开展，超急性排斥目前已很罕见。急性排斥尤其是细胞性排斥，通常可通过大剂量糖皮质激素逆转。慢性排斥仍是移植物远期丢失的主要原因，且难以有效治疗。

7. Graft-Versus-Host Disease (GVHD) | 移植物抗宿主病（GVHD）

In bone marrow or haematopoietic stem cell transplantation, donor immune cells contained in the graft may recognise recipient tissues as foreign and attack them. This condition is known as graft-versus-host disease (GVHD), which is the reverse of host-versus-graft rejection.

在骨髓或造血干细胞移植中，移植物中含有的供者免疫细胞可能将受者组织识别为外来物并加以攻击。这种情况称为移植物抗宿主病（GVHD），与宿主抗移植物排斥相反。

GVHD can be acute or chronic and primarily affects the skin, liver, and gastrointestinal tract. The pathophysiology involves donor T cells recognising recipient HLA differences, followed by inflammatory cytokine release and tissue injury. Prophylaxis typically includes methotrexate and calcineurin inhibitors such as cyclosporine A.

GVHD 可分为急性与慢性，主要影响皮肤、肝脏和胃肠道。其病理生理过程包括供者 T 细胞识别受者 HLA 差异，随后释放炎性细胞因子并造成组织损伤。预防措施通常包括甲氨蝶呤和钙调神经磷酸酶抑制剂（如环孢素 A）。

8. Immunosuppressive Therapy and Tolerance Induction | 免疫抑制治疗与耐受诱导

Immunosuppressive drugs are essential to prevent and treat graft rejection, but they carry risks of infection and malignancy. Common agents target different stages of the immune response.

免疫抑制药物是预防和治疗移植排斥的核心手段，但也伴随着感染和恶性肿瘤风险。常用药物靶向免疫应答的不同阶段。

Calcineurin inhibitors (cyclosporine A, tacrolimus): Block IL-2 transcription in T cells, reducing T cell activation.
钙调神经磷酸酶抑制剂（环孢素 A、他克莫司）：阻断 T 细胞中 IL-2 的转录，减少 T 细胞活化。

Antiproliferative agents (azathioprine, mycophenolate mofetil): Inhibit purine synthesis, suppressing lymphocyte proliferation.
抗增殖药物（硫唑嘌呤、吗替麦考酚酯）：抑制嘌呤合成，从而抑制淋巴细胞增殖。

Corticosteroids: Broad anti-inflammatory effects, reducing cytokine production and immune cell migration.
糖皮质激素：具有广泛的抗炎作用，减少细胞因子产生和免疫细胞迁移。

Biologics (basiliximab, belatacept): Monoclonal antibodies or fusion proteins that block IL-2 receptor or co-stimulatory pathways.
生物制剂（巴利昔单抗、贝拉西普）：单克隆抗体或融合蛋白，用于阻断 IL-2 受体或共刺激通路。

Transplantation tolerance, defined as the absence of rejection without ongoing immunosuppression, remains a major research goal. Approaches include mixed chimerism, regulatory T cell therapy, and co-stimulation blockade, all of which aim to re-educate the recipient’s immune system.

移植耐受，即在持续免疫抑制下仍无排斥反应的状态，仍是重要的研究目标。主要策略包括混合嵌合、调节性 T 细胞治疗和共刺激阻断，这些方法都旨在重塑受者的免疫系统。

9. HLA Typing and Clinical Practice | HLA 配型与临床应用

Before transplantation, HLA typing and cross-match tests are performed to reduce the risk of rejection. HLA typing identifies the alleles of HLA-A, HLA-B, HLA-DR, and sometimes HLA-C and HLA-DQ loci in both donor and recipient.

移植前需进行 HLA 配型和交叉配血试验以降低排斥风险。HLA 配型用于鉴定供者和受者在 HLA-A、HLA-B、HLA-DR 以及有时还包括 HLA-C 和 HLA-DQ 位点的等位基因。

A positive T-cell cross-match indicates that the recipient has pre-formed antibodies against donor cells, and transplantation is generally contraindicated. Flow cytometry and Luminex bead arrays provide sensitive detection of donor-specific antibodies, allowing clinicians to stratify immunological risk.

T 细胞交叉配型阳性提示受者体内存在预存的抗供者细胞抗体，此时一般禁止移植。流式细胞术和 Luminex 微珠阵列可以高灵敏度地检测供体特异性抗体，帮助临床医生进行免疫风险分层。

Even with perfect matching, immunosuppression is still necessary because minor histocompatibility antigens can also trigger rejection. Thus, the balance between adequate immunosuppression and avoiding excessive immune deficiency is the central clinical challenge.

即使配型完美，仍需要免疫抑制治疗，因为次要组织相容性抗原同样可引发排斥。因此，在充足的免疫抑制与避免过度免疫缺陷之间取得平衡，是临床面临的核心挑战。

10. Exam Focus and Key Takeaways | 考点总结与核心要点

For examinations, students should be able to explain the difference between MHC class I and II, outline the direct and indirect allorecognition pathways, and compare the mechanisms of acute and chronic rejection.

应对考试时，学生应能够解释 MHC I 类和 II 类分子的区别，概述直接与间接同种异体识别途径，并比较急性和慢性排斥的发生机制。

Key memory points: MHC → TCR recognition → co-stimulation → CTL/antibody effectors → graft injury

核心记忆链：MHC → TCR 识别 → 共刺激 → CTL/抗体效应 → 移植物损伤

Remember that hyperacute rejection is mediated by pre-existing antibodies, acute rejection by T cells and de novo antibodies, and chronic rejection by persistent inflammation, fibrosis, and vascular occlusion. Linking each rejection type to its corresponding timing, cellular players, and pathological features will solidify your understanding.

请记住：超急性排斥由预存抗体介导，急性排斥由 T 细胞和新生抗体介导，慢性排斥由持续炎症、纤维化和血管闭塞导致。将每种排斥类型与其发生时间、参与细胞和病理特征联系起来，能帮助你牢固掌握该知识点。

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Immune Rejection: Principles and Mechanisms | 免疫排斥反应：原理与机制