Pathophysiological rationale: why suppress immunity?
The immune system has a dual nature. On the one hand, it is a reliable defense mechanism; on the other hand, these very forces can cause severe pathology requiring pharmacological suppression.
- Autoimmune diseases: when internal regulation is disrupted, autoaggression occurs, where the immunity begins to destroy the body's own healthy tissues.
- Transplantation: organ transplantation is impossible without suppression. Despite all the successes of modern surgical technique, the graft rejection reaction remains the main limiting factor. Pharmacological prevention of rejection is of critical importance here.
- Allergies: inadequate, excessive hypersensitivity reactions also require the use of immunosuppressants.
Molecular mechanism of T-lymphocyte activation
To understand how drugs work, it is necessary to examine the intracellular cascade that triggers the immune response. A key role in this process is played by the nuclear factor of activated T-cells (NFAT — Nuclear Factor of Activated T-Cells).
- Inside the cell, the enzyme calcineurin binds to the NFAT factor and dephosphorylates it.
- Dephosphorylated NFAT undergoes translocation—it moves into the nucleus of the T-lymphocyte, where it binds to DNA.
- This triggers the transcription of the interleukin-2 (IL-2) gene.
The synthesized IL-2 begins to act on its own receptors. It transitions T-lymphocytes from the resting phase ($G_1$) to the DNA synthesis phase ($S$-phase), causing their rapid proliferation (multiplication) and differentiation.
Further development of the immune response proceeds via two pathways:
- Cellular immunity pathway: Type 1 T-helper cells produce interferon-gamma (IFN$\gamma$), which activates macrophages and T-killers.
- Humoral immunity pathway: Type 2 T-helper cells produce interleukin-4 (IL-4), causing B-lymphocyte proliferation.
Classification of immunosuppressants
Drugs are classified according to 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 antibody (mAb) preparations and polyclonal sera
- Against tumor necrosis factor (TNF-$\alpha$): etanercept, infliximab.
- Against IL-2 receptor: daclizumab, basiliximab.
- Miscellaneous: antithymocyte globulin, muromonab-CD3, alemtuzumab.
Features of cytotoxic drug administration
Cytotoxic drugs are agents that suppress cell growth and differentiation. Their primary field of application is oncology, where they act as antineoplastic agents. However, they are highly demanded in immunology due to their ability to inhibit lymphocyte division, providing potent immunosuppression.
The main problem with cytotoxic drugs is their safety profile. The action of these drugs is not strictly selective. They suppress the division of any rapidly proliferating cells in the body. Hematopoietic tissue is primarily affected, leading to severe adverse effects: suppression of hematopoiesis with the development of leukopenia, thrombocytopenia, and anemia.
Briefly: answers to topical questions
What is the mechanism of action of glucocorticoids as immunosuppressants?
The mechanism of action of glucocorticoids involves binding to specific intracellular receptors followed by the regulation of DNA transcription. Upon penetrating the cell membrane, the drug binds to a cytosolic receptor, after which the complex translocates into the cell nucleus and interacts with gene promoters.
Implementation of the immunosuppressive effect includes:
- Inhibition of gene transcription — suppression of major histocompatibility complex (MHC) protein synthesis.
- Suppression of synthesis — inhibition of pro-inflammatory cytokine production.
- Inhibition of proliferation — arrest of T-lymphocyte multiplication.
What is the mechanism of action of mTOR inhibitors (sirolimus)?
The mechanism of action of mTOR inhibitors involves the blockade of the intracellular kinase pathway regulating the cell cycle. Sirolimus binds to the intracellular protein FKBP-12, and the resulting complex inhibits the mTOR protein (mammalian target of rapamycin).
As a result:
- Proliferation arrest — the transition of T-lymphocytes from the resting phase ($G_1$) to the DNA synthesis phase ($S$) is blocked.
- Reduced sensitivity to IL-2 — the drug does not decrease interleukin-2 production, but blocks the perception of the signal from it.
- Inactivation of protein kinases — the activation of the IL-2 receptor $\alpha$-chain gene (CD25) is impaired.
What are the contraindications to the use of cytotoxic drugs as immunosuppressants?
Contraindications to the use of cytotoxic drugs depend on the specific agent and include conditions associated with bone marrow suppression and organ failure.
Main contraindications:
- Azathioprine — contraindicated during pregnancy and lactation.
- Cyclophosphamide — contraindicated in severe leukopenia and thrombocytopenia, severe hepatic and renal failure, and pregnancy.
In addition, planned immunosuppressive therapy with cyclophosphamide must be interrupted in the setting of COVID-19 infection.
How does the mechanism of action of cyclosporine differ from that of sirolimus?
The main difference lies in the intracellular targets and the effect on interleukin-2 (IL-2). Cyclosporine suppresses IL-2 synthesis, whereas sirolimus blocks the cellular response to it.
| Characteristic | Cyclosporine | Sirolimus |
|---|---|---|
| Binding | To cyclophilin | To FKBP-12 protein |
| Target | Calcineurin | mTOR protein |
| Effect on IL-2 | Suppresses IL-2 synthesis | Does not decrease IL-2 production, reduces sensitivity to it |
| Effect on the cell | Impairs dephosphorylation of the NF-AT factor | Blocks the transition of T-lymphocytes from the $G_1$ phase to the $S$ phase |
To avoid confusing the pathways of the immune response, remember: T-helper type 1 cells are responsible for cell-mediated immunity (activation of macrophages and cytotoxic T cells via IFN$\gamma$), while T-helper type 2 cells are responsible for humoral immunity (B-lymphocyte proliferation under the action of IL-4).
Class and exam questions
What is the role of calcineurin in the immune response?
This enzyme binds to the nuclear factor NFAT and dephosphorylates it. This allows the factor to enter the T-lymphocyte nucleus and trigger the synthesis of interleukin-2.
Why do cytotoxic drugs cause leukopenia and anemia?
Their action is not strictly selective. They suppress the division of any rapidly proliferating cells, which is why hematopoietic tissue suffers first (hematopoiesis is suppressed).
Why are immunosuppressants necessary in organ transplantation?
Transplant rejection is the main barrier in surgery. Without pharmacological prevention of rejection, the patient's immune system will destroy the transplanted donor organ.
How does interleukin-2 affect T lymphocytes?
It acts on the cells' own receptors, shifting T-lymphocytes from the resting phase to the DNA synthesis phase. This causes their active multiplication and differentiation.
What else to study on this topic
- Mechanism of action of calcineurin inhibitors (cyclosporine and tacrolimus).
- Differences between mTOR inhibitors (sirolimus) and other immunosuppressant groups.
- Pharmacodynamics of monoclonal antibodies against TNF-$\alpha$ and IL-2 receptors.
- Features of the application of antimetabolites and alkylating agents in immunology.
- The role of glucocorticoids in combination immunosuppressive therapy.
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