transplant

PART 1: INTRODUCTION TO TRANSPLANTATION

Section 1: Why Transplantation? (Page 1)

Transplantation is the treatment of choice for end-stage organ failure of:

• Kidney

• Liver

• Heart

• Lung

• Cornea

• Pancreas

It is also a curative treatment for haematological malignancies (e.g., leukaemia) via bone marrow transplantation.

Section 2: Tissue and Organ Transplantation (Page 2)

Today, many different organs and tissues can be transplanted.

Section 3: Types of Transplant (Page 3)

PART 2: SPECIFIC TRANSPLANT TYPES

Section 4: Blood Transfusion – The Most Common Transplant (Page 4)

• Most common form of transplantation.

• Requires ABO blood group matching to prevent immediate rejection.

Section 5: Bone Marrow Transplantation (Page 5)

Indications:

• Leukaemia

• Anaemia

• Immunodeficiency, especially Severe Combined Immunodeficiency (SCID)

Procedure:

• Approximately 10⁹ cells per kilogram of host body weight are injected intravenously into the recipient.

• Recipient is immunologically suppressed before grafting.

• Example: Leukaemia patients are often treated with cyclophosphamide and total body irradiation to kill all cancerous cells.

Special Consideration – Graft Versus Host Disease (GVHD):

• Because donor bone marrow contains immunocompetent cells, the graft may reject the host.

• This is called Graft Versus Host Disease (GVHD) .

PART 3: THE IMMUNOLOGICAL OBSTACLE – MHC

Section 6: Allogenic MHC Molecules (Page 6)

• Allogenic: Being genetically different although belonging to or obtained from the same species.

• Key Fact: Up to 1% of T cells recognise intact allogenic MHC molecules – this is a very high frequency compared to responses to conventional antigens (<0.01%).

• Consequence: Normally, organ transplants are rejected by the immune system, unless they are from an identical twin (isograft).

• In isografts, the donor organ is perceived as "self" by the immune system.

Section 7: The MHC Complex (HLA) (Page 7)

• MHC (Major Histocompatibility Complex) – in humans, called HLA (Human Leukocyte Antigen) .

• Function: Presents antigens being processed by the cell on the cell surface.

• Transplant Relevance: Because all nucleated cells express MHC Class I, the host T cell receptor can recognise non-self MHCs – this is called allorecognition.

Section 8: Direct Allorecognition (Pages 7-9)

8.1. Mechanism (Page 7):

• All nucleated cells express MHC Class I.

• The host T cell receptor (recipient) can recognise non-self MHCs (donor).

• Involves both CD8⁺ and CD4⁺ T cells.

8.2. Process (Page 8):

1. Donor APCs migrate to regional lymph nodes.

2. They are recognised by the recipient's T helper cells (TH) .

3. Alloreactive TH cells induce generation of donor-specific cytotoxic T lymphocytes (CTLs) .

4. These CTLs then migrate into the graft and cause graft rejection.

Section 9: Two Phases of Allograft Rejection (Pages 9-10)

Section 10: Role of Cytokines in Graft Rejection (Page 11)

• These cytokines promote graft rejection by inducing expression of MHC molecules on graft cells, making them more visible to the immune system.

Section 11: Importance of MHC (HLA) Matching (Page 12)

• MHC matching leads to improved graft survival.

• Improvements in MHC typing techniques allow more precise matching of unrelated individuals.

• Crucial in bone marrow transplantation, where even minor mismatches can cause severe GVHD.

Section 12: Indirect Allorecognition (Pages 13-14)

12.1. Mechanism (Page 13):

• Host Antigen Presenting Cells (APCs) present graft antigens (processed by the host's own APCs) to T cells.

• <0.01% of T cells are specific for any foreign antigen recognised in the context of self-MHC molecules.

12.2. Diagram (Page 14):

• Shows host APC taking up donor antigens, processing them, and presenting them to host T cells in the context of self-MHC.

• This is a slower, less robust response than direct allorecognition.

PART 4: EFFECTOR MECHANISMS OF ALLOGRAFT REJECTION

Section 13: Three Types of Rejection (Page 15)

Section 14: Hyperacute Rejection (Page 16)

• Characterised by: Thrombotic occlusion of the graft (blood clots block vessels).

• Onset: Begins within minutes or hours after anastomosis (surgical connection of vessels).

• Mechanism:

  • Pre-existing antibodies in the host circulation bind to donor endothelial antigens.

  • This activates the complement cascade.

  • Leads to rapid destruction of the graft.

• Common Cause: ABO blood group incompatibility or pre-sensitisation to HLA antigens (e.g., from previous transplant, pregnancy, or blood transfusion).

• Xenograft Response: Hyperacute rejection is the typical response to xenografts.

Section 15: Acute Rejection (Page 17)

• Characterised by: Vascular and parenchymal injury mediated by T cells and antibodies.

• Onset: Usually begins after the first week of transplantation if there is no immunosuppressant therapy.

• Incidence: High (30%) for the first 90 days post-transplant, even with immunosuppression.

• Pathology (Page 18):

  • T-cell, macrophage, and antibody-mediated damage.

  • Myocyte and endothelial damage.

  • Inflammation.

Section 16: Chronic Rejection (Pages 19-20)

• Occurs in most solid organ transplants: Heart, kidney, lung, liver.

• Characterised by:

  • Fibrosis (scarring) and vascular abnormalities.

  • Loss of graft function over a prolonged period (months to years).

• Mechanism (Page 20):

  • Macrophage and T cell mediated.

  • Concentric medial hyperplasia (thickening of the vessel walls, leading to narrowing and ischaemia).

  • Chronic donor TH reaction.

PART 5: PREVENTION OF REJECTION – IMMUNOSUPPRESSION

Section 17: Principles of Immunosuppression (Page 21)

• Transplant rejection can be prevented by the use of systemic immunosuppression.

• By suppressing immunity, organ transplants can "take" without rejection.

• Immunosuppression is usually fairly harsh at first, but can be eased up over time, suggesting that a certain degree of tolerance is reached.

• Why? The donor organ probably becomes less immunogenic over time. Some of the most immunogenic cells (passenger leukocytes) move out of the graft or die off, leaving less immunogenic tissues behind.

Section 18: Immunosuppressive Drugs (Pages 22-23)

18.1. Three Main Classes (Page 22):

18.2. Steroids – Mechanism (Page 23):

• Anti-inflammatory and immunosuppressive.

• Inhibition of lymphocyte clonal expansion (blockade of IL-1 and IL-2 production).

• Reduced CD4 counts.

• Mobilisation of neutrophils (may increase neutrophil count).

• Decrease in monocytes.

Section 19: Sites of Action of Immunosuppressive Agents (Page 24)

• A cocktail of immunosuppressive agents is often used, tailored according to the level of immunological risk.

• Different drugs act at different stages of T-cell activation and proliferation.

Section 20: Specific Immunosuppressants by Transplant Type (Page 25)

Section 21: Side Effects of Systemic Immunosuppression (Page 26)

21.1. Related to Immunosuppression:

• Increased incidence of opportunistic infections (e.g., CMV, Pneumocystis jirovecii, fungal infections).

• Increased incidence of malignancy (especially skin cancers and lymphoproliferative disorders).

21.2. Drug-Specific Adverse Effects:

• Hypertension

• Hyperlipidaemia

• Diabetes mellitus (especially with calcineurin inhibitors and steroids)

• The goal is to achieve immunological tolerance, thereby allowing prolonged, drug-free transplant survival.

PART 6: STRATEGIES FOR INDUCING IMMUNOLOGICAL TOLERANCE

Section 22: How Do We Circumvent Allorecognition Without Immunosuppression? (Page 28)

• This is the "holy grail" of transplantation – achieving donor-specific tolerance without the need for lifelong immunosuppression.

Section 23: Strategies for Induction of Tolerance (Page 29)

23.1. How Do We Make Tolerant T Cells?

• T cell activation requires two signals:

  1. Signal 1: Antigen recognition (MHC + peptide).

  2. Signal 2: Co-stimulation (e.g., CD28-CD80/86).

• Peripheral tolerance can be induced by providing only ONE signal (antigen without co-stimulation), leading to T cell anergy or deletion.

23.2. Co-stimulatory Blockade:

• Blocking co-stimulatory molecules (e.g., CTLA-4-Ig, belatacept) can prevent full T cell activation and promote tolerance.

23.3. Anti-CD3 Antibody:

• Partial T cell activation without full effector function.

23.4. Pre-treatment with Non-Immunogenic Donor Antigen:

• Before transplant, give the recipient:

  • Donor white blood cells, OR

  • Small doses of donor antigen.

Section 24: Case Study – Combined Bone Marrow and Kidney Transplant (Page 30)

• Procedure: Renal transplant, preceded by bone marrow transplant from the same donor.

• Key Finding: Transplants were not from HLA-matched donors and therefore fairly immunogenic.

• Outcome: After a while, all the donor bone marrow had gone, but tolerance to the kidney remained.

• Mechanism: The procedure had created regulatory T cells (Tregs) that maintained tolerance to the donor organ.

PART 7: SUMMARY

Section 25: Summary (Page 31)

• Allograft rejection is driven by allorecognition of donor MHC molecules.

• Direct allorecognition (high frequency of T cells) and indirect allorecognition both contribute.

• Hyperacute rejection is antibody-mediated and occurs immediately.

• Acute rejection is T cell-mediated and occurs within weeks.

• Chronic rejection is a slow process of fibrosis and vascular damage.

• Immunosuppressive drugs (calcineurin inhibitors, antimetabolites, steroids) prevent rejection but have significant side effects.

• The goal is immunological tolerance – strategies include co-stimulatory blockade, regulatory T cells, and mixed chimerism (e.g., combined bone marrow and organ transplant).

SUMMARY TABLE: TYPES OF REJECTION