Overview of Cytokine Genes
Cytokine genes are a class of genes encoding cytokines. Cytokines are a class of low-molecular-weight proteins or glycoproteins that can transmit signals between cells and regulate the function of the immune system. Cytokines include chemokines, interferons, interleukins, tumor necrosis factors, colony-stimulating factors, and other types, and they act by binding to specific receptors. Cytokines can be produced by a variety of immune cells, such as macrophages, B lymphocytes, T lymphocytes, and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells, and can affect different cell types. Therefore, cytokines are characterized by diversity, redundancy, and pleiotropy. Cytokines play a crucial role in human health and disease, especially in the immune response against pathogens, the inflammatory response to tissue damage, and the immune regulation in tumorigenesis. However, the expression and activity of cytokines can also be abnormal, leading to various pathological conditions, such as autoimmune diseases and inflammation-induced carcinogenesis. Therefore, an in-depth understanding of the different mechanisms of action of cytokines and the design of novel selective drugs to regulate the activity of cytokines are of great significance for the prevention and treatment of related diseases.
Application of Cytokine Genes in Autoimmune Diseases
Autoimmune diseases are a class of inflammatory diseases caused by the immune system attacking its own tissues or organs, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, systemic Lupus erythematosus (SLE), and other types. The occurrence and development of these diseases involve abnormal expression and activation of various immune cells and cytokines, resulting in tissue damage and dysfunction. Therefore, targeted therapy against cytokines is an effective strategy for the treatment of autoimmune diseases.
At present, a variety of monoclonal antibodies against cytokines or their receptors have been used to treat autoimmune diseases, such as anti-TNF antibodies (such as infliximab, etanercept), anti-IL-6R antibodies, IL-12/IL-23 p40 inhibitors (such as ustekinumab), and IL-23 p19 inhibitors (such as gemuxumab). These drugs neutralize or block the corresponding cytokines or their receptors, thereby inhibiting the pro-inflammatory and pro-immune responses mediated by them, and improving the clinical manifestations and quality of life of patients. For example, in RA patients, anti-TNF antibodies can significantly reduce joint swelling, morning stiffness, erythrocyte sedimentation rate, C-reactive protein, and other indicators, reduce joint erosion and deformity, and improve joint function and quality of life. In IBD patients, IL-12/IL-23 p40 inhibitors can effectively alleviate the clinical manifestations of ulcerative colitis and Crohn's disease in the active and maintenance phases, reducing the need for bowel surgery. In psoriasis patients, IL-23 p19 inhibitors can significantly improve the size and severity of skin lesions and increase the rate of skin clearance and complete clearance.
Although targeted therapy targeting cytokines has achieved certain progress and effectiveness in the treatment of autoimmune diseases, there are still some challenges and problems that need to be further resolved and improved. For example, cytokines can play different roles in different cells, tissues, and organs, and can also cooperate or antagonize each other. Therefore, targeted therapy targeting a certain cytokine or its receptor may affect the balance and function of other cytokines, leading to adverse reactions or treatment failure. For example, in RA patients, anti-TNF antibodies, although effective in alleviating arthritis, may also increase the risk of infection, malignancy, and cardiovascular events. In SLE patients, although anti-IL-6R antibodies can improve skin lesions and arthritis, they may also lead to complications such as thrombocytopenia, abnormal liver function, and infection. In order to improve the specificity and efficacy of cytokines or their derivatives in autoimmune diseases and reduce their toxicity and tolerance, it is necessary to use molecular biology techniques to improve the structure and function of cytokines or their derivatives. For example, the half-life, affinity, and side effects of a cytokine can be extended, its affinity increased, and its side effects reduced by changing the binding site of the cytokine or its receptor, increasing or decreasing glycine-linked fragments, adding polyethylene glycol or other molecules.
Application of Cytokine Genes in Tumor Immunotherapy
Tumor immunotherapy is a treatment method that uses the immune system to identify and eliminate tumor cells, including immune checkpoint inhibitors, chimeric antigen receptor T cell (CAR-T) therapy, cancer vaccines, and other types. Cytokines play an important regulatory role in tumor immunotherapy, both enhancing tumor-specific immune responses and inhibiting tumor-induced immune tolerance. Therefore, utilizing cytokines or their derivatives to improve the efficacy and safety of tumor immunotherapy is a promising strategy.
So far, a variety of cytokines or their derivatives have been used in tumor immunotherapy, such as IL-2, IFN-γ, IL-12, IL-15, IL-18, IL-21, and so on. These drugs enhance tumor-specific T-cell responses by directly stimulating immune effector cells (such as NK cells and CTL cells) and indirectly activating antigen-presenting cells (such as DC cells), thereby inducing tumor cell apoptosis or necrosis. For example, in patients with metastatic melanoma, high-dose IL-2 was able to induce complete or partial remission in about 10% of patients. In patients with metastatic RCC, IFN-γ can significantly improve survival and remission rates. In patients with various solid tumors, IL-12 can enhance the activity and number of NK cells and CTL cells, and inhibit angiogenesis and metastasis.
However, the use of cytokines or their derivatives for tumor immunotherapy also has some limitations and challenges, such as drug stability, half-life, side effects, selectivity, tolerance, etc. Therefore, there is a need to further improve the structure and function of cytokines or their derivatives in order to increase their specificity and efficacy and reduce their toxicity and tolerance. At present, some novel cytokines or their derivatives are in clinical trials, such as IL-2 variants (such as NKTR-214), IL-15 supercomplexes (such as ALT-803), IL-18 binding proteins (such as Tadekinig alfa), and IL-21 fusion proteins (such as RG7840). These drugs prolong their half-life, increase their affinity, and reduce their toxic side effects by changing the structure of cytokines or fusing them with other molecules.
Fig.1 Potential combinations of cytokine-based drugs with other modalities of cancer immunotherapy. (Berraondo, 2019)
In conclusion, the use of cytokines or their derivatives for tumor immunotherapy is an effective and promising method, but further optimization of drug design and clinical programs is still required to improve its safety and efficacy, and to combine it with other immunotherapeutic methods, to achieve a broader and longer-lasting antitumor effect.
Structural Characterization and Functional Optimization of Cytokine Genes
Cytokines are a class of proteins or glycoproteins with various biological activities and signaling functions, and they exert their effects by binding to specific receptors. The structural features of cytokines determine their affinity, selectivity, and potency for receptors, and also affect their distribution, half-life, and stability in vivo. Therefore, analyzing and modifying the structural characteristics of cytokines is a method to improve the safety and efficacy of cytokines or their derivatives in the treatment of autoimmune diseases.
To date, various technologies and methods have been developed to optimize the structural characteristics and functions of cytokines:
- Cytokine variants. Cytokine variants are molecules that increase or decrease affinity, selectivity, or potency for a cytokine or its receptor by altering amino acid residues in its receptor binding site. For example, the IL-2 variant NKTR-214 is enhanced by adding polyethylene glycol (PEG) molecules to IL-2 to increase its affinity with the IL-2Rβ chain, thereby enhancing its stimulatory effect on NK cells and CD8+ T cells, reducing its stimulating effect on Treg cells. This variant can improve the efficacy and safety of IL-2 in tumor immunotherapy.
- Cytokine fusion proteins. Cytokine fusion proteins refer to molecules that prolong their half-life and increase their targeting or stability by fusing cytokines or their receptors with other molecules (such as antibodies, ligands, and carriers). For example, the IL-15 super complex ALT-803 increases its stimulatory effect on NK cells and CD8+ T cells by fusing IL-15 with its receptor α chain and IL-15Rβ/γc complex, prolonging their half-life in blood. This fusion protein can improve the efficacy and safety of IL-15 in tumor immunotherapy.
- Cytokine vectors and delivery systems. Cytokine carriers and delivery systems refer to encapsulating or linking cytokines or their derivatives to molecules such as nanoparticles, antibodies, and ligands to enhance their affinity, penetration, and protection for specific cells or tissues. molecular. For example, IL-12 nanoparticles can increase their targeting effect on DC cells and T cells in the tumor microenvironment by encapsulating IL-12 on polyethyleneimine (PEI) nanoparticles while reducing their effect on normal cells. Tissue toxicity. Such nanoparticles can improve the efficacy and safety of IL-12 in tumor immunotherapy.
In conclusion, optimizing the structural characteristics and functions of cytokines is a way to improve the safety and efficacy of cytokines or their derivatives in the treatment of autoimmune diseases, but further exploration of more effective and innovative technologies and techniques is still needed. Approach to achieve broader and longer-lasting modulation of autoimmune responses.
Reference
- Berraondo P, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019 Jan;120(1):6-15.
