SID 18: Organ Transplant

1⃣ Interplay Between Host Immune System & Immunosuppression

The core problem in transplant patients

Your immune system’s job is to detect foreign material and destroy it.

Unfortunately, a transplanted organ looks foreign to the immune system.

So the immune system tries to attack it → allograft rejection.

Transplant medicine therefore has to balance two competing risks:

⚖ Too little immunosuppression → organ rejection
⚖ Too much immunosuppression → infections & malignancy

This balance is shown conceptually in the lecture as a scale between:

• Opportunistic infections and

• Graft rejection.

Quick immune system refresher

Two arms of immunity matter here.

Innate immunity (fast)

• Neutrophils

• Macrophages

• NK cells

• Complement

Adaptive immunity (targeted)

• T cells

• B cells

Adaptive immunity is the main driver of transplant rejection.

Key functions:

Why immunosuppressants target T-cells

Transplant rejection is largely T-cell mediated.

T cells recognize donor antigens → activate cytokines → destroy graft tissue.

Therefore most transplant drugs aim to:

🛑 Block T-cell activation
🛑 Block T-cell proliferation
🛑 Reduce antibody formation

2⃣ Timing of Opportunistic Infections After Transplant

The type of infection strongly depends on how long after transplant the patient is.

Your exam will absolutely test this.

⏱ Infection timeline

Early period (<4 weeks)

Cause:

• surgery

• hospital exposure

• donor infections

Common infections:

• surgical wound infections

• catheter infections

• nosocomial pneumonia

• UTIs

Usually bacterial.

Intermediate period (1–12 months)

This is when immunosuppression is highest.

Classic opportunistic infections appear:

🦠 Viruses

• CMV

• EBV

• BK virus

• HSV

🍄 Fungi

• Candida

• Aspergillus

• Pneumocystis jirovecii

🦠 Bacteria

• Listeria

• Nocardia

• Mycobacteria

Late period (>12 months)

Immunosuppression is lower.

Infections resemble general population infections:

• community respiratory viruses

• pneumonia

• UTIs

Unless:

• patient is over-immunosuppressed

• graft rejection treatment increases immunosuppression

3⃣ Immunosuppressive Agents

Maintenance therapy usually uses 3 drugs together.

Why?

Different mechanisms → lower doses → fewer toxicities.

Typical regimen:

💊 Calcineurin inhibitor
💊 Antimetabolite
💊 Corticosteroid

3A️⃣ Calcineurin Inhibitors (CNIs)

Drugs:

• Tacrolimus

• Cyclosporine

These are the backbone of transplant therapy.

Mechanism

They block calcineurin, which prevents IL-2 transcription.

IL-2 is required for T-cell activation and proliferation.

Result:

🚫 ↓ T-cell activation
🚫 ↓ immune response
🚫 ↓ rejection

Differences

Tacrolimus is usually preferred because it has:

✔ lower rejection rates
✔ better graft survival

3B️⃣ mTOR Inhibitor

Drug:

• Sirolimus

Mechanism

Blocks mTOR, which stops cell cycle progression.

Result:

🛑 (STOPS) T-cell proliferation
🛑 (STOPS) B-cell proliferation

Important exam point

❗ NOT used immediately after transplant.

Why?

It causes:

• impaired wound healing

• thrombosis risk

• delayed graft function

Therefore it's used when:

• CNI toxicity occurs

• malignancy develops

• persistent rejection

3C️⃣ Antimetabolites

Drugs:

• Mycophenolate

• Azathioprine

These block DNA synthesis in immune cells.

Mycophenolate

Mechanism:

Blocks inosine monophosphate dehydrogenase (IMPDH) → prevents guanosine synthesis.

Result:

🚫 T-cell proliferation
🚫 B-cell proliferation

Common ADRs:

• diarrhea

• leukopenia

• hepatotoxicity

Preferred agent because it causes less bone marrow toxicity than azathioprine.

Azathioprine

Prodrug → converted to 6-mercaptopurine.

Mechanism:

🧬 blocks purine synthesis → impaired DNA replication.

Main toxicity:

💀 bone marrow suppression

3D️⃣ Corticosteroids

Drug:

• Prednisone

These have broad immunosuppressive effects.

They:

• decrease lymphocyte activity

• reduce antibody production

• reduce inflammatory cytokines

Major steroid adverse effects

Common ones your prof might test:

• hyperglycemia

• osteoporosis

• hypertension

• weight gain

• mood changes

• infections

4⃣ Drug-Drug Interactions (Very High Yield)

Most immunosuppressants are metabolized by:

⚠ CYP3A4

So many interactions occur.

Drugs that DECREASE tacrolimus/cyclosporine levels

(CYP3A4 inducers)

Examples:

• phenytoin

• carbamazepine

• phenobarbital

• rifampin

Effect:

⬇ tacrolimus levels
⬇ immunosuppression
⚠ rejection risk

Management:

• increase dose

• monitor levels

Drugs that INCREASE tacrolimus levels

(CYP3A4 inhibitors)

Examples:

• azole antifungals

• macrolides

• diltiazem

• verapamil

• amiodarone

• ritonavir (Paxlovid)

Effect:

⬆ tacrolimus levels
⚠ toxicity (nephrotoxicity, neurotoxicity)

Management:

• reduce dose

• monitor troughs

5⃣ Opportunistic Infection Prophylaxis

Your exam will probably ask which prophylaxis to use.

CMV prophylaxis

Drug:

💊 Valganciclovir

MOA:

Nucleoside analogue → inhibits viral DNA polymerase.

Risk depends on donor/recipient status

High risk → prophylaxis 3–12 months.

HSV prophylaxis

Most severe reactivation occurs first month post-transplant.

Prophylaxis used when:

• patient not receiving CMV prophylaxis

Drug:

💊 Valacyclovir

Duration:

~3 months

PJP prophylaxis

Most important opportunistic infection prophylaxis.

Preferred drug:

💊 TMP-SMX

Options:

Duration:

• 12 months after transplant

• lifelong in lung transplant

Alternatives if sulfa allergy:

• dapsone

• pentamidine

• atovaquone

⭐ High-Yield Exam Summary

If I were writing your exam questions, these are the 10 things I would test.

1⃣ Immunosuppression = balance between rejection vs infection

2⃣ T-cells drive transplant rejection

3⃣ Infection timing

• <4 weeks → surgical/hospital

• 1–12 months → opportunistic

4⃣ Maintenance regimen

• CNI + antimetabolite + steroid

5⃣ Tacrolimus preferred over cyclosporine

6⃣ Calcineurin inhibitors block IL-2 transcription

7⃣ Mycophenolate blocks IMPDH

8⃣ Sirolimus blocks mTOR

9⃣ CYP3A4 interactions are critical

10⃣ Prophylaxis

• CMV → valganciclovir

• HSV → valacyclovir

• PJP → TMP-SMX