Cytokine therapy

Main areas of application of cytokine drugs

Historically, interferons were the first to enter clinical practice due to their ability to suppress viral activity. Today, the spectrum of indications includes the following areas:

• Antiviral therapy: IFN-alpha and IFN-beta preparations are actively used to treat viral hepatitis B and C.
• Neurology: IFN-beta is an important component in the maintenance therapy of multiple sclerosis.
• Hematology: Colony-stimulating factors (GM-CSF, G-CSF) stimulate granulopoiesis following severe suppression by chemotherapy or radiation. In addition, G-CSF mobilizes stem cells into the bloodstream for subsequent harvesting and transplantation in patients with hemoblastosis.
• Oncology: The only firmly established drug is recombinant IFN-alpha2, which is used as an adjunct to chemotherapy in renal cell carcinoma, melanoma, and lymphomas. It works by increasing the expression of MHC-I molecules, suppressing cellular proliferation, and stimulating the differentiation of Th1 lymphocytes.

Limitations: why are cytokines difficult to use as drugs?

The introduction of immunobiotherapy has encountered serious physiological obstacles determined by the very nature of these molecules:

1. Too rapid degradation in the blood. Most mediators are strictly local-action factors. Their half-life is a matter of minutes. This forces physicians to use continuous intravenous drip administration via micropumps.
2. Polyfunctionality. The same molecule exhibits a dozen different effects, making targeted action virtually impossible without concurrent adverse reactions.
3. Domino effect (cytokine network).u00a0 The administration of one substance inevitably stimulates the production of other components of the network. The resulting clinical picture is often driven not by the drug itself, but by a massive secondary release of endogenous substances.

For these reasons, the direct administration of many molecules has been deemed unjustified. For example, the treatment of solid tumors with interleukin-2 (IL-2) has been suspended, and the use of IFN-gamma and IL-12 has been found to be of low efficacy and capable of causing inappropriate macrophage hyperactivation.

Specific complications of systemic therapy

Systemic administration of cytokines is associated with high risks. There are four main types of severe reactions:

• Flu-like syndrome: A classic reaction to the systemic release of pro-inflammatory mediators. The patient experiences muscle aches, nausea, vomiting, and joint pain similar to the onset of an infectious disease.
• Septicemic shock: A severe condition occurring without a bacterial infection in the blood. It is accompanied by a sharp drop in blood pressure and intravascular coagulation (DIC syndrome). As a rule, it is triggered by a secondary excess of TNF-alpha.
• Capillary leak syndrome: A poorly understood complication in which blood vessels become excessively permeable. The fluid part of the blood massively leaves the vascular bed. The condition starts with a runny nose and diarrhea, but rapidly progresses to pulmonary edema with a high probability of a fatal outcome.
• Drug dependence syndrome: A specific side effect that often develops against the background of long-term course administration of interferons.

Anticytokine therapy: blockade instead of stimulation

Instead of stimulating immunity from the outside, modern clinical immunology often blocks its own excessive mediators in autoimmune inflammatory diseases.

• Physicians have receptor antagonists in their arsenal (e.g., soluble TNF-alpha receptors — TNFRII, or the raIL-1 receptor antagonist).
• Humanized monoclonal antibodies such as infliximab (anti-TNF-alpha) are widely used. These drugs have proven exceptionally high clinical efficacy in rheumatoid arthritis, Crohn's disease, severe psoriasis, and spondyloarthritis.
• In allergies and asthma, anticytokine monoclonal antibodies (against IL-4, IL-5, IL-13) currently show moderate or minor effect: they improve laboratory parameters by reducing eosinophilia, but clinically help only at extremely high doses.

The use of monoclonal antibodies in oncology (treatment of leukemias): Antibodies (e.g., rituximab against the B-lymphocyte marker CD20 or CAMPATH against CD52) act as specific "tags." By binding to the tumor cell membrane, an IgG class antibody dooms it to destruction via phagocytosis, antibody-dependent cellular cytotoxicity, or lysis through complement system activation.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of elimination of leukemic cells using humanized monoclonal antibodies.
• Development of immunotoxins (conjugation of an antibody with ricin) for targeted therapy of solid tumors.
• Preparations based on leukocyte extracts: Leukinferon and Superlymph.
• Cytokine muteins: principles for creating modified molecules with reduced toxicity.
• Specific features of G-CSF use for stem cell mobilization before bone marrow transplantation.

Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"

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