Pharmacology Module 4 - Transplantation

Hypersensitivity and Autoimmunity, Immunocompromised Host, and Transplantation

Four types of graft-recipient combinations

Autograft: transfer of tissue within the same individual

Isograft: transfer between genetically identical individuals (monozygotic twins)

Allograft: transfer between genetically different individuals of the same species

Xenograft: transfer between different species

Features of an autograft

• No foreign antigens

• No immune response

• No rejection

Features of an isograft

• Identical MHC molecules

• No rejection

Features of an allograft

• Different MHC molecules

• Immune rejection occurs

• Most common type of transplant

Features of a xenograft

• Very different antigens/MHCs

• Strong rejection response

• Mostly experimental

Four clinical outcomes of transplant rejection

1. Hyper-acute rejection

2. Acute rejection

3. Chronic rejection

4. Graft-versus-host disease (GVHD)

When does hyper-acute rejection occur and what is the cause

Occurs immediately after transplantation (within minutes to hours)

Caused by recipient already possessing pre-formed antibodies against donor antigens

Mechanism of hyper-acute rejection

Recipient antibodies bind donor vascular antigens.

This activates:

• Complement system

• Inflammation

• Clotting

This is a Type II hypersensitivity reaction.

Pathological features of hyper-acute rejection

• Capillary destruction

• Thrombosis

• Vascular blockage

• Ischaemia

• Rapid graft failure

When does acute rejection occur and what is the cause

Occurs usually after the first week (days to months after transplantation)

Caused by recipient immune system encounters donor antigens for the first time.

Contributing factors:

• Poor tissue matching

• Inadequate immunosuppression

Mechanism of acute rejection

Mainly T-cell mediated.

T cells:

• Recognise donor MHC molecules

• Become activated

• Recruit macrophages and inflammatory cells

Antibodies may also contribute.

Pathological features of acute rejection

• Lymphocyte infiltration

• Macrophage infiltration

• Inflammation

• Tissue destruction

• Vascular injury

Outcome of acute rejection

Damage to:

• Blood vessels

• Organ tissue (parenchyma)

Leads to:

• Loss of blood supply

• Organ dysfunction

• Graft failure

When does chronic rejection occur and what is the mechanism

Occurs months to years later

Mechanism is repeated low-grade immune injury causes:

• Cycles of tissue injury

• Regeneration

• Remodelling

Mainly T-cell mediated.

Features of chronic rejection (3, FVP)

Fibrosis: Excess collagen deposition causes scarring.

Vascular Changes: Blood vessel narrowing reduces blood flow.

Progressive Organ Dysfunction: Gradual loss of organ function over time.

Example of chronic rejection

Lung Transplantation

Chronic immune injury causes:

• Loss of airway epithelium

• Thickening of airways

• Airflow obstruction

Eventually:

• Respiratory dysfunction develops

Average transplanted lung survival:

• Approximately 5 years.

When does graft-versus-host disease (GVHD) occur and give common examples

Occurs when transplanted tissue contains many immune cells.

Common examples/tissues:

• Bone marrow transplant

• Liver transplant

• Skin

• Liver

• GI tract

Mechanism of graft-versus-host disease (GVHD)

Donor T cells recognise recipient tissues as foreign.

Donor T cells:

1. Become activated

2. Undergo clonal expansion

3. Attack recipient tissues

Clinical effects of graft-versus-host disease (GVHD)

Can cause:

• Severe inflammation

• Tissue destruction

• Organ dysfunction

GVHD can be life-threatening.

Risks of immunosuppression as prevention of graft rejection

Major risks include:

• Increased infections

• Opportunistic infections

• Cancer risk

• Drug toxicities

Main goals of drug therapy in transplantation

• Prevent T-cell activation

• Reduce inflammation

• Suppress immune proliferation

Four main types of drugs used in transplantation drug therapy

1. Corticosteroids

2. Calcineurin Inhibitors

3. Anti-proliferative Agents

   1. Mycophenolate Mofetil

   2. Azathioprine

4. Monoclonal Antibodies

   1. Anti-CD3 Antibodies

   2. Anti-IL-2 Receptor Antibodies

Mechanism of action of corticosteroids

• Reduce peripheral lymphocytes

• Redistribute lymphocytes to spleen/bone marrow

• Inhibit T-cell proliferation

• Reduce B-cell maturation

They also suppress cytokines:

• IL-1

• IL-2

• IL-6

• IFN-γ

• TNF-α

Major toxicities of corticosteroids

• Diabetes (diabetogenic)

• Weight gain

• Osteoporosis

• Hypertension

• Infection risk

Importance of corticosteroids and example

These drugs made modern transplantation possible in the 1960s.

E.g. Prednisolone

Mechanism of action of calcineurin inhibitors

They inhibit calcineurin signalling, preventing:

1. T-cell receptor activation

2. IL-2 production

3. T-cell proliferation

Major toxicities of calcineurin inhibitors

Cyclosporine

• Renal dysfunction

• Hypertension

Tacrolimus

• Nephrotoxicity

• Neurotoxicity

• Diabetes

Mechanism of action of mycophenolate mofetil (anti-proliferative agent)

Converted to mycophenolic acid.

Blocks:

• Guanine nucleotide synthesis

Lymphocytes depend heavily on this pathway.

Result:

• Inhibits T and B cell proliferation.

Mechanism of action of azathioprine (anti-proliferative agent)

Inhibits:

• Purine synthesis

• DNA synthesis

Suppresses:

• Rapidly dividing T and B cells.

Mechanism of action of anti-CD3 antibodies (monoclonal antibodies) and an example

Targets CD3 on T cells:

• Prevents antigen recognition

• Reduces IL-2 production

E.g. Muromonab-CD3

Mechanism of action of anti-IL-2 antibodies (monoclonal antibodies) and examples

Mechanism of action of anti-CD3 antibodies (monoclonal antibodies) and an example

E.g. Basiliximab and Daclizumab