Home › Pharmacology › Immunosuppressants: Mechanisms, Classes and Clinical Use

Immunosuppressants

Immunosuppressiva

For medical students2 min readUpdated 2026-10-10

Immunosuppressants are a pharmacological group of drugs used to purposefully suppress unwanted immune responses. They are essential for preventing graft rejection in transplantology, as well as for treating severe allergies and autoimmune conditions where the body attacks its own tissues.

Main TargetT-lymphocytes and intracellular cascades triggering interleukin-2 synthesis.

Drug ClassesCytostatics, glucocorticoids, cytokine inhibitors, and monoclonal antibodies.

Side EffectsCytostatics act non-selectively, suppressing hematopoiesis (leukopenia, anemia).

Key FactorNuclear factor NFAT translocates into the nucleus and initiates immune response gene transcription.

Pathophysiological Rationale: Why Suppress Immunity?

The immune system has a dual nature. On one hand, it is a reliable defense mechanism; on the other, these same forces can cause severe pathology requiring pharmacological suppression.

Autoimmune diseases: When internal regulation fails, autoaggression occurs, where the immune system destroys the body's own healthy tissues.
Transplantation: Organ transplantation is impossible without immunosuppression. Despite advances in surgical techniques, graft rejection remains the primary limiting factor, making pharmacological rejection prophylaxis critical.
Allergies: Inadequate, excessive hypersensitivity reactions also require immunosuppressive therapy.

Molecular Mechanism of T-Lymphocyte Activation

To understand how these drugs work, one must examine the intracellular cascade that triggers the immune response. A key role is played by the nuclear factor of activated T-cells (NFAT).

Inside the cell, the enzyme calcineurin binds to NFAT and dephosphorylates it.
Dephosphorylated NFAT undergoes translocation into the T-lymphocyte nucleus, where it binds to DNA.
This initiates the transcription of the interleukin-2 (IL-2) gene.

Synthesized IL-2 acts on its own receptors, driving T-lymphocytes from the resting phase ($G_1$) into the DNA synthesis phase ($S$-phase), causing rapid proliferation and differentiation.

Subsequently, the immune response proceeds via two pathways:

Cell-mediated immunity pathway: Type 1 T-helper cells produce interferon-gamma (IFN$\gamma$), which activates macrophages and cytotoxic T-cells.
Humoral immunity pathway: Type 2 T-helper cells produce interleukin-4 (IL-4), triggering B-lymphocyte proliferation.

Classification of Immunosuppressants

Drugs are classified by their mechanism of action and chemical structure into several major groups:

1. Cytostatics

Antimetabolites: azathioprine, mycophenolate mofetil.
Alkylating agents: cyclophosphamide.

2. Glucocorticoids

Prednisolone, dexamethasone.

3. Selective Inhibitors of Cytokine Synthesis and Action

Calcineurin inhibitors: cyclosporine, tacrolimus.
mTOR inhibitors: sirolimus.

4. Monoclonal Antibodies (mAbs) and Polyclonal Sera

Anti-TNF-$\alpha$: etanercept, infliximab.
Anti-IL-2 receptor: daclizumab, basiliximab.
Other: antithymocyte globulin, muromonab-CD3, alemtuzumab.

Characteristics of Cytostatics

Cytostatics are agents that inhibit cell growth and differentiation. Their primary application is in oncology as antineoplastic drugs. However, they are vital in immunology for suppressing lymphocyte division, providing potent immunosuppression.

The main challenge with cytostatics is their safety profile. Their action is not strictly selective; they inhibit the division of any rapidly proliferating cells. Hematopoietic tissue is affected first, leading to severe adverse effects such as bone marrow suppression with leukopenia, thrombocytopenia, and anemia.

Mnemonic

To remember the immune pathways: Type 1 T-helpers govern cell-mediated immunity (activating macrophages and cytotoxic T-cells via IFN$\gamma$), while Type 2 T-helpers govern humoral immunity (B-cell proliferation driven by IL-4).

Frequently asked questions

What is the mechanism of action of glucocorticoids as immunosuppressants?

Glucocorticoids bind to specific intracellular receptors and subsequently regulate DNA transcription. After crossing the cell membrane, the drug binds to a cytosolic receptor, and the complex translocates to the cell nucleus to interact with gene promoters.

The immunosuppressive effect involves:

Inhibition of gene transcription — suppressing the synthesis of major histocompatibility complex (MHC) proteins.
Suppression of synthesis — inhibiting the production of pro-inflammatory cytokines.
Inhibition of proliferation — halting T-lymphocyte division.

What is the mechanism of action of mTOR inhibitors (sirolimus)?

mTOR inhibitors block the intracellular kinase pathway that regulates the cell cycle. Sirolimus binds to the intracellular protein FKBP-12, and the resulting complex inhibits mTOR (mammalian target of rapamycin).

This results in:

Cell cycle arrest — blocking the transition of T-lymphocytes from the $G_1$ phase to the $S$ phase.
Reduced sensitivity to IL-2 — the drug does not decrease interleukin-2 production, but blocks the cellular response to it.
Inactivation of protein kinases — disrupting the activation of the IL-2 receptor $\alpha$-chain gene (CD25).

What are the contraindications for using cytostatics as immunosuppressants?

Contraindications depend on the specific drug and generally involve bone marrow suppression and organ failure.

Key contraindications:

Azathioprine — contraindicated during pregnancy and lactation.
Cyclophosphamide — contraindicated in severe leukopenia, thrombocytopenia, severe hepatic and renal failure, and pregnancy.

Additionally, planned immunosuppressive therapy with cyclophosphamide must be interrupted during acute COVID-19 infection.

How does the mechanism of action of cyclosporine differ from sirolimus?

The main difference lies in their intracellular targets and their effect on interleukin-2 (IL-2). Cyclosporine suppresses IL-2 synthesis, whereas sirolimus blocks the cellular response to it.

Feature	Cyclosporine	Sirolimus
Binding protein	Cyclophilin	FKBP-12
Target	Calcineurin	mTOR protein
Effect on IL-2	Inhibits IL-2 synthesis	Does not decrease IL-2 production; reduces sensitivity to it
Cellular effect	Impairs NFAT dephosphorylation	Blocks T-cell transition from $G_1$ to $S$ phase

What is the role of calcineurin in the immune response?

This enzyme binds to the nuclear factor NFAT and dephosphorylates it, allowing the factor to enter the T-lymphocyte nucleus and trigger interleukin-2 synthesis.

Why do cytostatics cause leukopenia and anemia?

Their action is non-selective. They inhibit the division of all rapidly proliferating cells, primarily damaging hematopoietic tissue and suppressing hematopoiesis.

Why are immunosuppressants needed in organ transplantation?

Graft rejection is the primary barrier in transplant surgery. Without pharmacological rejection prophylaxis, the patient's immune system will destroy the donor organ.

How does interleukin-2 affect T-lymphocytes?

It binds to cellular receptors, driving T-lymphocytes from the resting phase into the DNA synthesis phase, causing active proliferation and differentiation.

Go deeper

Mechanism of action of calcineurin inhibitors (cyclosporine and tacrolimus).
Differences between mTOR inhibitors (sirolimus) and other immunosuppressant classes.
Pharmacodynamics of anti-TNF-$\alpha$ and IL-2 receptor monoclonal antibodies.
Specific uses of antimetabolites and alkylating agents in immunology.
Role of glucocorticoids in combination immunosuppressive therapy.