Vectors of Antitumor Immunotherapy
Modern medicine is actively developing and implementing methods to stimulate or targetedly modify immune responses to destroy malignant neoplasms. In clinical practice, as well as during development stages, several key therapeutic approaches are distinguished.
First, this is cytokine therapy—the use of specialized molecules that regulate intercellular immune interactions. Second, drugs based on monoclonal antibodies are widely used. Based on these, immunotoxins are constructed—complex agents capable of delivering a damaging payload specifically to target tumor cells. In addition, the physicians' arsenal includes immunocytotherapy (therapy using cellular elements) and therapeutic cancer vaccines, which are administered to the patient to specifically train the antigen recognition system.
Immunological barriers: from tumors to transplants
The study of how the body's defense systems respond to tissue incompatibility goes far beyond classical oncology and touches upon so-called allogeneic systems. This complex problem has two global vectors of study:
- Practical aspect. Directly related to the development of transplantation: how to successfully transplant a vital organ and prevent its destruction by an attack of lymphocytes.
- Fundamental aspect. Lies in the very nature of mammals. Studying the mechanisms of carrying a fetus, which is genetically half-foreign to the mother's body, provides a unique key to understanding natural immunological tolerance.
Main problem when working with tissue incompatibility is finding a delicate balance. Physicians and biologists need to learn how to manage the system to deliberately shift the scales between an aggressive immune response (which leads to transplant rejection) and anergy (lack of response, life-saving tolerance).
Evidence of the immune nature of rejection
The understanding that foreign tissue rejection is not merely a surgical failure, but a powerful and specific biological reaction, was formed in the 1940s.
An outstanding researcher P. Medawar (P. Medawar) made a fundamental breakthrough, convincingly demonstrating the central role of lymphocytes in the destruction of transplanted structures. Moreover, he proved that this process possesses immunological memory and is capable of proceeding according to the scenario of a secondary immune response. This means that upon re-exposure to the same antigen, the reaction develops much more rapidly.
These data were supported by the elegant experiments of E.N. Mitchison (E.N. Mitchison). He provided additional irrefutable evidence specifically for the cellular immunological nature of the rejection reaction. The scientist transferred lymphocytes that were already in a sensitized state (tuned against a specific transplant) to a syngeneic (genetically absolutely identical) recipient. As a result, the recipient immediately initiated a rejection reaction of the corresponding tissues.
Genetic laws of allotransplantation
The patterns by which transplanted tissues engraft or perish depend on how genetically homogeneous the donor and recipient are. These rules were studied in detail using inbred mouse strains (e.g., H-2b, H-2h strains) and their first-generation hybrids (F1).
Conditions under which the transplant engrafts:
- Transplantation between individuals of the same genetically homogeneous, syngeneic strain.
- Transfer of tissues from a pure parental strain to their first-generation hybrid (donor: pure strain $\rightarrow$ recipient: F1 hybrid). The hybrid recognizes the parent's antigens as its own.
- Transplantation between identical hybrids (donor: F1 hybrid $\rightarrow$ recipient: F1 hybrid).
Conditions under which the transplant is rejected:
- Allogeneic transplantation — transfer of tissues between mice of different inbred strains.
- Tissue transplantation from a first-generation hybrid back to individuals of the parental strains (donor: F1 hybrid $\rightarrow$ recipient: pure parental strain). The reason lies in the fact that the hybrid carries antigens of both parental strains on its cells. Consequently, for any of the pure strains, exactly half of the antigens of such a hybrid will appear unfamiliar, which will inevitably provoke immune aggression.
Briefly: answers to topical questions
What drugs are used in cytokine therapy and immunocytotherapy of tumors?
In tumor cytokine therapy, recombinant cytokines, muteins, and leukocyte extracts are used, whereas specific drugs for immunocytotherapy are not described in the sources.
- Interferon-alpha (IFNα / recombinant IFNα2) — used in combination with baseline therapy.
- Interleukin-2 (IL-2) — use is suspended due to the risk of regulatory T cell induction.
- Interleukin-15 (IL-15) — tested as a substitute for IL-2.
- Tumor necrosis factor alpha (TNFα) — used for local treatment and in the form of muteins.
- Leukinferon — human leukocyte interferon.
- Superlymph — a topical preparation based on cytokines and defensins.
Also, GM-CSF, G-CSF, and IL-1β are used.
What inbred mouse models were used in studying the laws of allotransplantation?
In studying the genetic laws of allotransplantation, inbred mouse strains and their first-generation hybrids were used.
- Inbred strains — genetically homogeneous individuals, for example, H-2b and H-2h strains. Tissue transplantation between them leads to rejection, whereas within the strain, it leads to engraftment.
- First-generation hybrids (F1) are the progeny of crosses between pure parental lines. Grafts from a pure parental line to an F1 hybrid engraft successfully, as the hybrid possesses the antigens of both lines. Transplantation from an F1 hybrid to individuals of the parental lines causes rejection.
What are the molecular mechanisms of anergy formation in tissue incompatibility?
The main molecular mechanism of anergy induction is the absence of one of the components of the costimulatory system at the moment of antigen recognition. This occurs in the absence of B7 costimulatory molecules on antigen-presenting cells or CD28 receptors on maturing thymocytes. The weakening of the intracellular signal leads to the following changes:
- Impairment of transcription factor AP-1 formation (c-Fos/c-Jun dimer).
- Decreased expression of the interleukin-2 (IL-2) gene, which is critically important for T cell activation.
- Involvement of the Cbl-b factor, acting as an activation inhibitor.
The usual outcome of such a state is accelerated cell death via apoptosis.
What are the specific embryonic antigens during fetal development?
The sources do not provide a complete list of specific embryonic antigens, but mention individual antigenic structures expressed by the fetus and trophoblast.
- Rhesus antigens (especially D) — fetal erythrocytic alloantigens possessing high immunogenicity and capable of causing hemolytic disease.
- Paternal antigens — alloantigens to which immunological tolerance is induced in the mother.
- Non-classical molecules (HLA-G and HLA-E) — expressed by trophoblast cells to block the activity of NK cells.
- Stress molecules (MICA and MICB) — expressed on fetal cells in the absence of classical MHC-I.
The expression of embryonic proteins to which physiological tolerance exists is also mentioned.
The F1 hybrid rule: "The child (hybrid) will accept tissue from the parent, but the parent from the child will not, since half of the child's genes come from another, foreign parent."
Class and exam questions
What is the difference between the practical and fundamental aspects of studying tissue incompatibility?
The practical aspect focuses on the development of clinical organ transplantation, whereas the fundamental aspect studies natural phenomena, primarily the mechanisms protecting the fetus from the mother's immune system during pregnancy.
Who proved that the rejection reaction has immune memory?
This discovery was made by P. Medawar. He proved that allograft rejection is capable of developing as a secondary immune response.
Why are F1 hybrid tissues always rejected by the parental line?
The hybrid inherits antigens from both parental lines. When its tissues are transplanted to one of the parents, the recipient's immune system recognizes half of the antigens as foreign and triggers a rejection reaction.
What else to study on this topic
- Detailed mechanisms of action and classification of monoclonal antibodies in oncology.
- Principles of creation and clinical application of therapeutic cancer vaccines.
- Cellular and humoral regulation of the secondary immune response.
- Physiological mechanisms of the formation of immunological tolerance during pregnancy.
- Role and types of cytokines used in modern antitumor therapy.
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