Transplant Immunology

The contract between this chapter and the reader.

1. 1. Explain why a transplanted kidney triggers an immune response.
2. 2. Describe the HLA system and its class I and class II molecules.
3. 3. Explain why HLA polymorphism and mismatch drive rejection.
4. 4. Distinguish the direct and indirect pathways of allorecognition.
5. 5. Describe the three signals of T-cell activation.
6. 6. Distinguish the cellular and humoral effector arms.
7. 7. Explain sensitization and its consequences.
8. 8. Define immune tolerance and why lifelong immunosuppression is needed.
9. 9. Outline the types of rejection by mechanism and timing.

A sixty-second reading. Each bullet stands alone.

• A transplanted kidney carries foreign antigens — mainly HLA — that trigger an alloimmune response and rejection unless suppressed.
• HLA, the human major histocompatibility complex, is highly polymorphic, and donor–recipient mismatch drives rejection.
• Class I HLA (A, B, C) is on all nucleated cells and presents to CD8 T cells; class II (DR, DQ, DP) is on antigen-presenting cells and presents to CD4 T cells.
• In direct allorecognition, recipient T cells see intact donor HLA on donor cells — dominant in early acute rejection.
• In indirect allorecognition, recipient antigen-presenting cells process donor antigen — important in chronic rejection and donor-specific antibody.
• T-cell activation needs three signals: antigen (signal 1), costimulation (signal 2), and cytokines (signal 3).
• These three signals are the targets of the immunosuppressive drugs.
• The cellular arm (T cells) drives T-cell-mediated rejection; the humoral arm (B cells and antibody) drives antibody-mediated rejection.
• Sensitization from prior transplant, pregnancy, or transfusion produces anti-HLA antibodies and a harder-to-match, higher-risk recipient.
• Tolerance is immune acceptance of the graft; durable drug-free tolerance is rare, so immunosuppression is lifelong.
• HLA matching — especially at DR — reduces rejection and improves outcomes.
• Rejection is classified by mechanism (cellular versus antibody) and timing (hyperacute, acute, chronic).

The medical core. An expert should agree transplant immunology is fully covered here.

Why it matters at the bedside

Every other chapter in this book is, at bottom, a response to one fact: the recipient's immune system recognises the graft as foreign and tries to destroy it. Immunosuppression, matching, crossmatching, rejection, and even the infections and cancers that follow all flow from this single alloimmune response. Understand it once, and the rest of transplantation becomes consequence.

Self and non-self

• The immune system is built to distinguish self from non-self, and a transplanted kidney is non-self. Its foreign antigens — chiefly the human leukocyte antigens — provoke an alloimmune response that, unchecked, causes rejection. The entire enterprise of transplantation is the management of this response.

The HLA system

• HLA is the human major histocompatibility complex, encoded on chromosome 6, whose job is to present peptides to T cells. Class I molecules (HLA-A, -B, -C) sit on all nucleated cells and present intracellular peptides to CD8 T cells; class II molecules (HLA-DR, -DQ, -DP) sit on antigen-presenting cells and present extracellular peptides to CD4 T cells. These are the molecules the recipient's immune system reads as ‘foreign.’

Polymorphism, mismatch, and matching

• HLA is the most polymorphic system in the genome — thousands of alleles — so two unrelated people almost never share a full set. The degree of donor–recipient mismatch drives the strength of the alloresponse, and minimising mismatch, especially at HLA-DR, reduces rejection and improves graft survival. (Minor histocompatibility antigens contribute a lesser part.)

Allorecognition: direct and indirect

• Recipient T cells recognise the graft by two routes. In the direct pathway they see intact donor HLA displayed on donor antigen-presenting cells carried in the graft — a powerful response that dominates early and drives acute cellular rejection. In the indirect pathway, recipient antigen-presenting cells take up and process donor antigen and present it to recipient T cells — a slower route that underlies chronic rejection and the generation of donor-specific antibody. A semi-direct pathway (recipient cells acquiring donor HLA) also contributes.

The three signals of T-cell activation

• A T cell is fully activated only by three signals: signal 1, the T-cell receptor engaging the MHC–peptide complex; signal 2, costimulation (CD28 binding B7); and signal 3, cytokines — above all interleukin-2 — driving proliferation. This three-signal model is not academic: each signal is a drug target, and the immunosuppression chapters are organised around blocking them.

The effector arms: cellular and humoral

• Two effector arms do the damage. The cellular arm — CD8 cytotoxic and CD4 helper T cells — produces T-cell-mediated rejection. The humoral arm — B cells maturing into plasma cells that secrete donor-specific antibody — produces antibody-mediated rejection. The two are distinct in mechanism, diagnosis, and treatment, which is why later chapters address them separately.

Innate immunity and reperfusion

• The adaptive alloresponse does not start in a vacuum. Ischemia-reperfusion injury at implantation and complement activation engage the innate immune system, releasing danger signals that prime antigen-presenting cells and amplify the adaptive response that follows — one reason the early peri-transplant period matters so much.

Sensitization

• A patient previously exposed to foreign HLA — through a prior transplant, pregnancy, or blood transfusion — may carry preformed anti-HLA antibodies. Such a sensitized recipient (with a high panel-reactive antibody level) is harder to match to a compatible donor and is at higher risk of antibody-mediated rejection, which is why their antibody status is measured carefully (the histocompatibility chapter).

Tolerance and the need for lifelong immunosuppression

• Tolerance is the immune system's acceptance of the graft without attacking it — maintained normally by thymic deletion of self-reactive T cells (central) and by regulatory T cells and anergy (peripheral). True operational tolerance, in which a graft survives without any immunosuppression, is the field's holy grail but remains largely experimental. Because durable drug-free tolerance is rare, immunosuppression is lifelong: stop it and the alloresponse resumes.

Types of rejection

• Rejection is classified two ways at once — by mechanism and by timing. By mechanism it is cellular (T-cell-mediated) or humoral (antibody-mediated). By timing it is hyperacute (minutes to hours, from preformed antibody, now rare), acute (days to months, cellular or antibody), or chronic (months to years, with interstitial fibrosis and transplant glomerulopathy). These categories frame the rejection chapters that follow.

Five fully-built tables.

Table A — HLA class I versus class II

Table B — Allorecognition pathways

Table C — The three signals of T-cell activation

Table D — The effector arms

Table E — Types of rejection

Visualise & Map

Causal chains, each ending in a named action.

Chain 1 — The alloresponse

Foreign HLA → allorecognition → T-cell activation (three signals) → effector response → rejection → ACTION: immunosuppress the signals.

Chain 2 — The direct pathway

Donor APCs in the graft → recipient T cells see intact donor MHC → strong early response → acute cellular rejection → ACTION: target T-cell activation, especially early.

Chain 3 — The indirect pathway

Recipient APCs process donor antigen → B-cell help → donor-specific antibody → chronic antibody-mediated rejection → ACTION: prevent sensitization and de novo DSA.

Chain 4 — Sensitization

Prior HLA exposure → anti-HLA antibodies → sensitized recipient → matching difficulty and AMR risk → ACTION: assess panel-reactive antibody and the crossmatch.

Chain 5 — No durable tolerance

Immunosuppression withdrawn → alloresponse re-emerges → rejection → ACTION: maintain lifelong immunosuppression.

Numbered rules. These numbers are the cross-reference handle for the cases and flowcharts.

Clinical Reasoning

Four cases. Each stops you at a decision before it answers it.

Every mechanism from Level 3 earns a bedside consequence and an action.

Exhaustive. Every rule in the chapter is here.

Safety & Evidence

Panel A — Conceptual red flags

Panel B — NEVER DO

Anti-patterns clinicians fall into. Each becomes a Level 22 distractor.

The grade reflects strength of evidence, not importance.

Apply & Test

Pre-rounds compression. Principles only.

Active recall. At least one card per objective.

Micro-teaching for rounds. Two scenarios, five steps each.

Nine items, each anchored in this chapter. At least one per objective.