Transplant Immunology and Tumour Immunology

Two Opposite Problems

Transplant: immune response = barrier → suppress immunity. Cancer: suppressed immunity = tumor opportunity → enhance immunity.

Transplant Classification

By site: Orthotopic (normal site, e.g. skin graft) vs Heterotopic (abnormal site, e.g. thyroid in subcutaneous pocket). By function: Vital (live, functions — kidney/heart) vs Static (nonliving scaffold — bone/artery). By genetic relationship:

• Autograft — self to self
• Isograft/syngeneic — genetically identical (monozygotic twins)
• Allograft — same species, non-identical (COMMONEST clinical type — kidney/heart)
• Xenograft — different species

Histocompatibility

Histocompatible (antigenically similar) → accepted. Autograft/isograft = histocompatible. Histoincompatible → rejected. Allograft/xenograft = histoincompatible (usually).

Transplantation antigens: MHC (most important), ABO/Rh blood group, Minor histocompatibility antigens (MHA — weaker response, less rejection).

Exception: male donor → female recipient = H-Y antigen (Y-chromosome specific) absent in recipient → MORE rejection than reverse direction. = Eichwald-Silmser effect.

Graft Rejection Types

Hyperacute: preexisting Ab (prior transfusion/pregnancy/transplant) → binds graft endothelium → complement → intravascular thrombosis + vessel necrosis. Avoidable by cross-match + HLA typing → NOW UNCOMMON clinically.

Acute: active response to alloantigen. Cytotoxic T cell direct kill + TH cytokine inflammation. Antibody → vascular injury (classical complement). Immunosuppressive Rx targets THIS stage.

Chronic: fibrosis + graft arteriosclerosis. Cytokine-driven fibroblast/SMC proliferation = specialized chronic DTH + alloantibody contribution. Refractory to Rx. LEADING cause of long-term graft failure.

Factors Affecting Rejection Rate

Tissue type (skin rejects fastest, faster than kidney/heart). Genetic distance (↑distance = ↑rejection speed; autograft/isograft = well tolerated). Immunological memory (2nd graft from same donor rejected FASTER — memory cells → rapid effector differentiation).

Skin graft patterns:

• Autograft: revascularize d3-7 → heal d7-10 → accept d12-14
• First-set rejection: revascularize d3-7 → cellular infiltrate → ↓vascularization d7-10 → necrosis d10 → rejection d12-14
• Second-set rejection: vascularization starts but quickly interrupted → early necrosis → sloughs by DAY 6 (accelerated)

Mechanism of Rejection

Sensitization phase — 2 pathways:

• Direct: donor APC (carried with graft) → recipient TH directly. Responsible for most ACUTE (cytotoxic T cell) rejection.
• Indirect: recipient APC ingests graft, presents via own MHC → recipient TH. Responsible for most CHRONIC (DTH) rejection.

Effector phase — 3 mechanisms:

• DTH: TH→TDTH, IFN-γ activates macrophage → lytic enzymes destroy graft
• Cytotoxic T cell: CD8+ TC recognizes allogeneic MHC-I → direct kill
• Antibody: complement-mediated lysis + ADCC (NK/macrophage). DOMINATES hyperacute; MINOR role in acute/chronic.

Prevention

Pretransplant: ABO cross-match + HLA typing. HLA typing methods: Phenotypic (OLD — serology/microcytotoxicity, mixed lymphocyte reaction) vs Genotypic (CURRENT, high-resolution — PCR-SSOP, PCR-SSP, PCR-DNA sequencing).

Immunosuppression by stage:

• Hyperacute: immediate graft removal (irreversible pharmacologically)
• Chronic: irreversible, retransplant only option
• Acute: DRUG TARGET. Corticosteroids (prednisolone), Calcineurin inhibitors (cyclosporine, tacrolimus), Mitotic inhibitors (azathioprine, cyclophosphamide, methotrexate), Antiproliferatives (mycophenolic acid), mTOR inhibitors (sirolimus, everolimus), mAbs (anti-CD2/3/4; anti-IL2Rα = basiliximab/daclizumab; anti-CD20 = rituximab; anti-TNFα = infliximab; ATG/ALG)

Graft-versus-Host (GVH) Reaction

Reverse direction: GRAFT attacks HOST (not host rejects graft). 3 conditions: (1) graft has immunocompetent T cells (bone marrow/stem cell/thymus transplant) (2) recipient has Ag graft lacks (3) recipient immunosuppressed (can’t counter-respond).

Acute GVH: <100 days post-transplant. Major bone marrow transplant complication. Hepatomegaly, skin rash, mucosal damage, diarrhea. Animal model = Runt disease. Chronic GVH: >100 days. Less severe. Same organs + connective tissue + exocrine gland damage. Treatment: IV glucocorticoids (both types).

Tumor Antigens

TSTA (tumor-specific transplantation antigen): ONLY on tumor cells, never normal cells. From mutated proteins → novel MHC-I peptide → tumor-specific CTL response.

• Chemical/physical carcinogen (methylcholanthrene, UV) induced: UNIQUE per tumor even if same carcinogen
• Virus-induced: VIRUS-SPECIFIC — all tumors from same virus share same antigen (EBV → nasopharyngeal Ca, lymphoma)

TATA (tumor-associated transplantation antigen): NOT unique, also on normal cells at LOW level, dramatically elevated in tumor.

• Oncofetal antigens: normally fetal-only, reactivated in tumor. AFP (hepatoma, testicular Ca), CEA (GI, lung, ovarian Ca)
• Non-oncofetal: CA-125 (ovarian), CA 19-9 (various carcinoma), PSA (prostate), β2-microglobulin (multiple myeloma)
• Used as tumor markers (diagnosis/monitoring), NOT curative-response targets

Immune Response vs Tumor

Both humoral + cell-mediated; CELL-MEDIATED (CTL + NK) does most work.

CTL: recognizes tumor Ag via MHC-I. LIMITATION: many tumors ↓MHC-I to escape. NK: NOT MHC-restricted. ↓MHC-I on tumor → REMOVES inhibitory signal → tumor becomes MORE vulnerable to NK (tumor’s T cell evasion backfires against NK). Also ADCC (Fc receptor + Ab-coated tumor cell).

Evidence: beige mouse + human Chediak-Higashi syndrome — NK defect → ↑cancer risk.

Cancer Immunotherapy — 3 types

1. Cell-based (cancer vaccines): harvest immune cells (NK/CTL/dendritic) from blood/tumor → activate/expand ex vivo → reinfuse. ONLY approved: Dendritic cell therapy (Provenge/sipuleucel-T) — prostate cancer.

2. Monoclonal antibody (MOST SUCCESSFUL category):

• Alemtuzumab (anti-CD52) — CLL
• Bevacizumab (anti-VEGF) — colorectal/lung/renal
• Cetuximab (anti-EGFR) — colorectal/head-neck
• Ipilimumab (anti-CTLA4) — metastatic melanoma
• Rituximab, Tositumomab (anti-CD20) — CLL, non-Hodgkin lymphoma
• Trastuzumab (anti-ErbB2) — breast cancer

3. Cytokine therapy:

• Interferon-α — hairy cell leukemia, AIDS-Kaposi sarcoma, follicular lymphoma, CML, malignant melanoma
• IL-2 — malignant melanoma, renal cell carcinoma

Cancer vaccines:

• Preventive: HPV vaccine, Hepatitis B vaccine (prevent virus that causes cervical/liver Ca)
• Therapeutic: treat existing cancer, mostly still in development; oncogenic-virus-targeted vaccines proven effective

Two Opposite Immunological Problems

Transplantation and cancer sit at opposite poles of the same underlying question — how the immune system treats cells that aren’t ordinary self. In transplantation, the immune response against a graft is the barrier to success, so suppressing immunity is the goal. In cancer, a suppressed immune system is exactly what lets many tumours arise in the first place, so enhancing anti-tumour immunity is the therapeutic goal.

Transplant Immunology

Transplantation moves a graft (cells, tissue, or organ) from a donor to a recipient. Grafts are classified several ways: by organ/tissue (kidney, heart, skin); by anatomical site (orthotopic — transplanted to its normal anatomical site, e.g. skin graft; heterotopic — placed at an abnormal site, e.g. thyroid tissue in a subcutaneous pocket); by whether the tissue is alive and functioning (vital grafts — kidney, heart, expected to function physiologically; static grafts — bone, artery, merely providing a scaffold); and, most importantly, by the genetic relationship between donor and recipient — autograft (self to self, e.g. skin to a burn site), isograft/syngeneic graft (between genetically identical individuals, e.g. monozygotic twins), allograft (between genetically non-identical members of the same species, e.g. kidney/heart transplant — the most common clinical graft type), and xenograft (between different species).

Histocompatibility

Whether a graft is accepted or rejected depends on histocompatibility — antigenic similarity between graft and recipient. Autografts and isografts are histocompatible and accepted; allografts and xenografts are typically histoincompatible and rejected unless matched and immunosuppressed.

Transplantation antigens are what the recipient’s immune system actually reacts against: MHC molecules are the most important; ABO and Rh blood group antigens matter too; and minor histocompatibility antigens (MHA) — peptides from normal donor cellular proteins — provoke a weaker response and cause rejection less often, with one notable exception: male-donor-to-female-recipient grafts carry Y-chromosome-encoded H-Y minor antigens absent in the female recipient, causing more frequent rejection than the reverse direction — the Eichwald–Silmser effect.

Types of Graft Rejection

Hyperacute rejection is caused by circulating antibody already present before transplant (from prior blood transfusion, pregnancy, or transplantation) that reacts with graft endothelial antigens, activating complement and causing rapid intravascular thrombosis and vessel-wall necrosis. It is now uncommon clinically because it is avoidable — recipients are cross-matched for anti-ABO antibody and HLA-typed before transplant.

Acute rejection stems from an active immune response to graft alloantigens: cytotoxic T cells directly kill graft cells (or TH-cell cytokines drive destructive inflammation), while antibodies contribute mainly to vascular injury via classical complement activation. Current immunosuppressive therapy targets this stage specifically, by blocking alloreactive T cell activation.

Chronic rejection is an indolent process over months to years — graft fibrosis and progressive narrowing of graft vessels (graft arteriosclerosis) from cytokine-driven fibroblast and vascular smooth-muscle proliferation, essentially a specialized chronic DTH reaction, plus a contribution from alloantibody. It resists most available therapy and is now the leading cause of long-term graft failure.

Factors Influencing Rejection Rate

Rejection speed depends on the tissue involved (skin rejects faster than kidney or heart), the genetic distance between donor and recipient (greater distance, faster rejection — autografts/isografts are well tolerated), and immunological memory (a second graft from the same donor is rejected faster than the first, since memory cells from the first graft differentiate rapidly into effector cells). This produces three distinct patterns when a skin graft is placed as (1) an autograft, (2) a first-time allograft, and (3) a repeat allograft from the same donor:

• Autograft — revascularizes days 3–7, heals by days 7–10, resolves and is accepted by days 12–14.
• First-set rejection — revascularizes days 3–7, but the developing immune reaction infiltrates the graft with lymphocytes/monocytes/neutrophils, vascularization then decreases by days 7–10, necrosis appears by day 10, and rejection is complete by days 12–14.
• Second-set rejection — accelerated: vascularization starts but is quickly interrupted by inflammation, necrosis sets in early, and the graft sloughs off by day 6.

Mechanism of Rejection

Rejection is principally a T cell response against alloantigens (chiefly MHC molecules) on the graft, unfolding in a sensitization phase and an effector phase.

The sensitization phase presents donor alloantigen to recipient T cells by two routes: the direct pathway — donor APCs (dendritic cells, macrophages) carried along with the graft present donor MHC directly to recipient TH cells, responsible for most cytotoxic-T-cell-mediated acute rejection; and the indirect pathway — recipient APCs ingest graft material and present processed donor alloantigen via their own MHC to recipient TH cells, responsible for most chronic-DTH-mediated rejection.

The effector phase deploys three mechanisms: delayed-type hypersensitivity (activated TH cells become TDTH cells, whose IFN-γ activates macrophages that destroy graft cells via lytic enzymes); cytotoxic T cells (CD8+ TC cells recognizing allogeneic MHC-I directly kill graft cells); and antibody-mediated mechanisms (complement-mediated lysis, and ADCC via NK cells/macrophages) — antibodies dominate hyperacute rejection but play only a minor role in acute and chronic rejection.

Prevention of Rejection

Pre-transplant workup includes ABO compatibility testing/cross-matching and HLA typing — historically by phenotypic methods (serologic microcytotoxicity, mixed lymphocyte reaction), now superseded by genotypic PCR-based methods (PCR-SSOP, PCR-SSP, PCR-DNA sequencing), which give the highest-resolution matching currently available.

Immunosuppressive therapy is stage-specific: hyperacute rejection is managed by immediate graft removal (it cannot be reversed pharmacologically); chronic rejection is largely irreversible, with retransplant the main option; acute rejection is the stage immunosuppressive drugs actually target, using corticosteroids (prednisolone, hydrocortisone), calcineurin inhibitors (cyclosporine, tacrolimus), mitotic inhibitors (azathioprine, cyclophosphamide, methotrexate), antiproliferatives (mycophenolic acid) and mTOR inhibitors (sirolimus, everolimus), and monoclonal-antibody-based agents (anti-CD2/CD3/CD4, anti-IL-2Rα — basiliximab, daclizumab; anti-CD20 — rituximab; anti-TNFα — infliximab; antithymocyte/antilymphocyte globulin).

Graft-versus-Host (GVH) Reaction

GVH reverses the usual direction of attack: the graft mounts an immune response against the host, rather than the host rejecting the graft. It requires three conditions: the graft contains immunocompetent T cells (as in bone marrow, stem cell, or thymus transplants), the recipient carries transplantation antigens the graft lacks, and the recipient is immunosuppressed enough that they cannot mount a counter-response against the graft.

Acute (fulminant) GVH disease occurs within the first 100 days post-transplant — a major complication specifically of bone marrow transplantation — causing hepatomegaly, skin rash, mucosal damage, and diarrhoea via the graft’s immunocompetent T cells (the experimental animal model is called Runt disease). Chronic GVH disease occurs after day 100, is less severe, attacks the same organs, and additionally damages connective tissue and exocrine glands. Intravenous glucocorticoids are the standard treatment for both forms.

Cancer (Tumour) Immunology

Tumour immunology studies the antigens tumour cells display and the immune response mounted against them.

Tumour Antigens

Tumour-specific transplantation antigens (TSTA) exist only on tumour cells, never on normal cells — typically arising from mutated cellular proteins whose novel peptides, presented via MHC-I, drive a tumour-specific cytotoxic T cell response. Chemically/physically-induced TSTAs (e.g. from methylcholanthrene or UV light) are unique to each individual tumour, even when induced by the same carcinogen; virus-induced TSTAs are virus-specific, meaning every tumour caused by the same virus shares the same antigen (e.g. EBV-associated nasopharyngeal carcinoma and lymphomas).

Tumour-associated transplantation antigens (TATA) are not unique to tumours — normal cells express them too, just at far lower levels, with tumour cells expressing them at dramatically elevated levels. Oncofetal antigens (alpha-fetoprotein, carcinoembryonic antigen) are normally expressed only during fetal development, with tumour cells reactivating the same embryonic genes. Non-oncofetal TATAs include carbohydrate antigens (CA-125 for ovarian cancer, CA 19-9 for various carcinomas), prostate-specific antigen, and β2-microglobulin (multiple myeloma) — these serve clinically as tumour markers for diagnosis and monitoring, not as targets for a curative immune response.

Immune Response Against Tumours

Both humoral and cell-mediated responses target tumour antigens, with cell-mediated immunity — particularly cytotoxic T cells and NK cells — doing most of the actual work. Tumour-specific TC cells recognize tumour antigen presented via MHC-I, but many tumours downregulate MHC-I precisely to escape this recognition. NK cells compensate for exactly this evasion strategy: since NK activity isn’t MHC-restricted, and reduced MHC-I actually removes the inhibitory signal that normally restrains NK cells, low-MHC-I tumour cells become more vulnerable to NK killing, not less — a case where the tumour’s own immune-evasion tactic against T cells backfires against NK cells. NK cells also participate via ADCC (Fc receptors binding antibody-coated tumour cells). The clinical importance of NK cells in tumour surveillance is underscored by the beige mouse mutant and human Chediak–Higashi syndrome, where a genetic NK-cell defect is associated with increased cancer risk.

Cancer Immunotherapy

Three broad approaches use the immune system therapeutically against cancer, all exploiting tumour antigens as targets:

• Cell-based therapies (cancer vaccines) — immune cells (NK cells, cytotoxic T cells, dendritic cells) are harvested from the patient’s blood or tumour, activated and expanded against tumour antigen ex vivo, and reinfused to provoke an anti-tumour response. Dendritic-cell therapy (sipuleucel-T/Provenge) for prostate cancer is currently the only approved cell-based therapy.
• Monoclonal antibody therapy — currently the most successful immunotherapy category, with agents approved across a wide range of cancers: alemtuzumab (anti-CD52, CLL), bevacizumab (anti-VEGF, colorectal/lung/renal), cetuximab (anti-EGFR, colorectal/head-and-neck), ipilimumab (anti-CTLA4, metastatic melanoma), rituximab and tositumomab (anti-CD20, CLL and non-Hodgkin lymphoma), and trastuzumab (anti-ErbB2, breast cancer).
• Cytokine therapy — administered cytokines regulate/coordinate immune behaviour against tumours: interferon-α (hairy-cell leukaemia, AIDS-related Kaposi sarcoma, follicular lymphoma, CML, malignant melanoma) and interleukin-2 (malignant melanoma, renal cell carcinoma).

Cancer vaccines split by purpose: preventive vaccines (HPV vaccine, hepatitis B vaccine) prevent the viral infections that themselves cause cervical and liver cancer respectively; therapeutic vaccines treat existing cancer and remain largely under active development, though vaccines targeting oncogenic viruses specifically have proven genuinely effective.

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