U01.02.037 Immunosuppression targets

Immunosuppressive drugs are commonly used to manage autoimmune diseases, prevent organ transplant rejection, and treat inflammatory conditions. Understanding the mechanisms of these drugs, especially their effects on DNA replication, cell proliferation, and cytokine production, is crucial for the USMLE Step 1.

Key Targets and Mechanisms of Immunosuppression

1. DNA Replication Inhibition

Mechanism: Some immunosuppressive agents inhibit DNA replication by targeting key enzymes involved in nucleotide synthesis.
Drugs: 6-mercaptopurine (6-MP) and other purine analogs.

2. Calcineurin Inhibition

Mechanism: Calcineurin is a calcium-dependent phosphatase that activates NF-κB, leading to T-cell activation. Inhibition of calcineurin prevents the transcription of pro-inflammatory cytokine genes.
Drugs: Cyclosporine, Tacrolimus.

3. Proliferation Inhibition

Mechanism: Many immunosuppressive agents prevent the proliferation of lymphocytes by interfering with cell cycle progression.
Drugs: Methotrexate, Azathioprine.

4. Cytokine Gene Suppression

Mechanism: Immunosuppressants target the signaling pathways involved in the transcription of inflammatory cytokine genes, such as IL-2, TNF-α, and IFN-γ.
Pathways: NF-κB, JAK-STAT.

Drugs and Their Targets

Drug	Target	Mechanism of Action
Cyclosporine	Calcineurin	Inhibits T-cell activation by blocking calcineurin.
Tacrolimus	Calcineurin	Inhibits T-cell activation by blocking calcineurin.
Methotrexate	Dihydrofolate reductase	Inhibits DNA synthesis by blocking purine and pyrimidine synthesis.
Azathioprine	Purine synthesis (6-MP metabolite)	Inhibits DNA replication by blocking purine nucleotides.
6-MP (6-mercaptopurine)	Purine nucleotides	Inhibits purine metabolism and DNA replication.

Key Points to Remember

Calcineurin inhibitors (Cyclosporine, Tacrolimus) block T-cell activation by inhibiting calcineurin, preventing the transcription of inflammatory cytokine genes.
Purine synthesis inhibitors (Azathioprine, 6-MP) target the de novo synthesis of purine nucleotides, disrupting DNA replication.
Methotrexate inhibits DNA replication by blocking the synthesis of purine and pyrimidine nucleotides.
NF-κB plays a crucial role in the transcription of inflammatory cytokine genes (e.g., IL-2, TNF-α), which are key targets of immunosuppressive drugs.

Learning Objective

Students should be able to identify the major immunosuppressive drugs, their mechanisms of action, and their targets in the context of DNA replication, calcineurin signaling, and inflammatory cytokine gene transcription.

USMLE Step 1 Review Series

Curriculum