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Overview
Thymosin Alpha-1 (Tα1) is a peptide with significant immune regulatory functions. It was first isolated from thymus tissue and consists of 28 amino acids, with N-terminal acetylation. Tα1 plays a crucial role in maintaining immune balance and responding to disease states in the body. As an immune enhancer, it shows great potential for application in the treatment and prevention of various diseases.
Figure 1 Thymosin alpha 1 has a wide range of biological activities. IL: Interleukin; IFN: Interferon; TLR: Toll-like receptors.
Under physiological conditions, Tα1 participates in the normal development and functional maintenance of the immune system, exerting significant influence on the differentiation, maturation, and activation of immune cells. Under pathological conditions, such as viral infections, tumorigenesis, and immune deficiencies, Tα1 can help the body combat diseases by regulating immune responses.
In the field of viral infectious diseases, Tα1 is commonly used to treat hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. It can regulate immune function, assist the body in clearing viruses, and improve patients' conditions.
Immunomodulatory Mechanisms
(1) Interaction with Toll-like receptors (TLRs)
One important pathway through which Tα1 exerts its immune regulatory effects is by interacting with Toll-like receptors (TLRs). TLRs are a class of pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), thereby activating immune cells and initiating immune responses.
Tα1 can bind to multiple TLRs, such as TLR3, TLR4, and TLR9. Upon binding to these receptors, Tα1 activates downstream signaling pathways, including the interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling pathways. Taking TLR3 as an example, after Tα1 binds to TLR3, it promotes the phosphorylation of IRF3, which then translocates to the cell nucleus, inducing the expression of antiviral and immune-regulatory genes such as type I interferon (IFN-I). IFN-I has broad antiviral and immune-regulatory functions, enhancing the body's resistance to viral infections.
For TLR4, the binding of Tα1 similarly activates the NF-κB signaling pathway, upregulating the expression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). These cytokines play a crucial role in the early stages of the immune response, recruiting immune cells to the site of infection and enhancing the body's immune defense capabilities.
Additionally, TLR2 and TLR7 are also associated with Tα1. Tα1 can activate the TLR2/NF-κB, TLR2/p38 mitogen-activated protein kinase (p38MAPK), or TLR7/myeloid differentiation factor 88 (MyD88) signaling pathways, promoting the production of various cytokines such as IL-1 and IL-12, thereby further enhancing innate and adaptive immune responses.
(2) Regulatory effects on immune cells
T cells
Tα1 influences the development, differentiation, and activation of T cells. In the thymus, Tα1 accelerates the replenishment and maturation of thymocytes. Studies have shown that after inhibiting T cell-mediated antibody production in mice using 5-fluorouracil (5-FU), chemically synthesized Tα1 can restore this antibody production capacity, and exhibits activity even at a low dose of 30 μg/kg.
Flow cytometry analysis revealed that this dose of Tα1 accelerates the replenishment and maturation of thymocytes; however, it does not affect the expression of Smoothened (Smo), a key negative regulator of the Hedgehog (Hh) signaling pathway in CD4⁻CD8⁻ thymocytes. This suggests that Tα1 may promote T cell maturation through specific signaling pathways that bypass or are independent of Smo-regulated pathways.
In terms of mature T cells, Tα1 can regulate the balance of T cell subsets. In the tumor microenvironment, Tα1 can alter the ratio of CD8⁺ T cells and regulatory T cells (Tregs) by regulating dendritic cell (DC) differentiation and chemokine expression profiles, thereby enhancing the body's antitumor immune response.
Figure 2 Thymosin α1 (Tα1) prevents epithelial damage in DSS plus anti–CTLA-4–induced colitis.
B cells
Although direct studies on the effects of Tα1 on B cells are relatively scarce, existing research suggests it may indirectly influence B cell function by regulating T cells. Since T cells play a key auxiliary role in B cell activation, antibody class switching, and affinity maturation, Tα1's regulation of T cell function can indirectly influence B cell antibody production, thereby enhancing the body's humoral immune response.
Macrophages
Tα1 also has important regulatory effects on macrophage function. Using the MTT assay, it was found that Tα1 exhibits cytotoxic effects on RAW 264.7 macrophages, with a half-maximal inhibitory concentration (IC50) of 368.105 μg/ml. As Tα1 concentration increases, the cytotoxic effects on RAW 264.7 cells intensify, leading to a decrease in cell density.
Tα1 also exhibits anti-inflammatory effects, which were assessed by analyzing nitric oxide (NO) production in RAW 264.7 cells. The results showed that within the concentration range of 7.813–31.25 μg/ml, NO production in the Tα1-treated group decreased in a dose-dependent manner compared to the control group, indicating that Tα1 may exert its anti-inflammatory effects by inhibiting NO production in macrophages, thereby regulating immune responses.
Natural killer cells (NK cells)
Tα1 promotes NK cell proliferation and activation, enhancing their cytotoxic activity. NK cells are an important component of the innate immune system, capable of non-specifically killing virus-infected cells and tumor cells. Tα1 enhances their ability to recognize and kill target cells by upregulating the expression of activation receptors on the surface of NK cells, thereby playing a crucial role in antiviral infection and antitumor immunity.
(3) Regulation of the cytokine network
Tα1 exerts its immunoregulatory functions by regulating the cytokine network. Cytokines are a class of small molecular proteins secreted by immune cells and certain non-immune cells, which transmit information between cells and regulate the function of immune cells as well as the intensity and type of immune responses.
Tα1 can promote the production of various cytokines, such as interleukin-2 (IL-2), interleukin-3 (IL-3), and interferon-γ (IFN-γ). IL-2 is an important T cell growth factor that promotes T cell proliferation and activation, enhances the activity of NK cells and cytotoxic T lymphocytes (CTLs), thereby improving the body's immune defense capabilities. IL-3 promotes the proliferation and differentiation of various hematopoietic stem cells and progenitor cells, helping to maintain the cellular composition and function of the immune system. IFN-γ has multiple functions, including antiviral, antitumor, and immune regulatory effects, enhancing the phagocytic and cytotoxic capabilities of macrophages, promoting the differentiation of Th1 cells, and regulating the immune response toward a cellular immune direction.
Additionally, Tα1 can regulate the balance between pro-inflammatory and anti-inflammatory cytokines. During inflammatory responses, Tα1 can suppress the overproduction of pro-inflammatory cytokines such as TNF-α and IL-1, while promoting the production of anti-inflammatory cytokines like interleukin-10 (IL-10), thereby reducing the damage caused by inflammatory responses to the body and maintaining immune balance.
Immune-enhancing effects
(1) Antiviral infection
Hepatitis B and Hepatitis C
Tα1 plays a significant role in the treatment of hepatitis B and hepatitis C. For chronic hepatitis B virus (HBV) infection, Tα1 can regulate the body's immune function and enhance its ability to clear HBV. Tα1 activates immune cells such as T cells and NK cells, enabling them to better recognize and eliminate HBV-infected liver cells. Tα1 can regulate the cytokine network, promoting the production of antiviral cytokines such as IFN-γ and inhibiting HBV replication.
In the treatment of hepatitis C virus (HCV) infection, Tα1 also demonstrates positive effects. It can enhance the body's immune response, aid in clearing HCV, and exhibit synergistic effects when used in combination with other antiviral drugs, thereby improving treatment success rates.
Other viral infections
In addition to HBV and HCV, Tα1 may also play a role in other viral infectious diseases. Tα1 may help improve the prognosis of severely ill patients with COVID-19. By repairing damage caused by lymphocyte immune overactivation and preventing excessive T-cell activation, Tα1 may alleviate patient symptoms and improve survival rates.
(2) Immune Regulation and Anti-Inflammation
Regulating Immune Balance
Tα1 plays a crucial role in maintaining immune balance in the body. In immune-deficient states, Tα1 can promote the proliferation and differentiation of immune cells, restoring the body's immune function. For example, in some congenital immune deficiency diseases or immune-suppressed states caused by chemotherapy or radiation therapy, Tα1 can help the body reestablish immune balance by regulating the development and function of immune cells.
In autoimmune diseases, Tα1 may suppress excessive immune responses and reduce autoimmune damage by regulating the activity of immune cells and the cytokine network.
Anti-inflammatory Effects
Tα1 possesses anti-inflammatory effects. During inflammatory responses, Tα1 can regulate the expression of inflammation-related cytokines and inhibit excessive inflammatory reactions. As mentioned earlier, Tα1 can inhibit NO production in macrophages, reduce the expression of pro-inflammatory cytokines such as TNF-α and IL-1, and simultaneously promote the production of anti-inflammatory cytokines such as IL-10.
Figure 3 Nitric oxide release after treatment with LPS and different concentrations of Tα-1 in RAW 264.7 cells.
In an inflammatory pain model, Tα1 alleviates mechanical allodynia and hyperalgesia induced by complete Freund's adjuvant (CFA), and reduces the upregulation of inflammatory mediators such as IFN-γ, TNF-α, and brain-derived neurotrophic factor (BDNF) induced by CFA. Additionally, Tα1 can regulate the Wnt3a/β-catenin signaling pathway in the spinal cord, which is activated during the inflammatory pain process, and Tα1 can reverse its activated state, thereby alleviating inflammatory pain.
Clinical Applications
(1) Treatment of Viral Hepatitis
In the clinical treatment of viral hepatitis, Tα1 has been widely applied. For patients with chronic hepatitis B, multiple clinical studies have shown that Tα1 combined with nucleoside (acid) analogues or interferon therapy achieves higher rates of HBV DNA seroconversion, HBeAg seroconversion, and ALT normalization compared to monotherapy. In some clinical trials, the combination of Tα1 and entecavir for the treatment of chronic hepatitis B patients resulted in a significantly higher rate of HBV DNA seroconversion after 48 weeks of treatment compared to the group treated with entecavir alone, and the rate of HBeAg seroconversion also improved.
In the treatment of hepatitis C, Tα1 combined with direct-acting antiviral agents (DAAs) can enhance antiviral efficacy, particularly for some treatment-resistant hepatitis C patients, potentially improving treatment success rates.
(2) Treatment of Immunodeficiency Disorders
For certain primary immunodeficiency diseases, such as congenital thymic hypoplasia, Tα1 can be used as part of alternative therapy. Although Tα1 cannot completely cure these diseases, it can regulate immune function, enhance patients' immunity, reduce the frequency and severity of infections, and improve patients' quality of life.
In acquired immune deficiency diseases, such as HIV/AIDS, Tα1 combined with antiretroviral therapy (ART) can enhance immune reconstitution, increase CD4⁺ T cell counts, improve immune function, and reduce the incidence of opportunistic infections.
(3) Other Applications
Adjuvant Therapy for Infectious Diseases
In the treatment of severe infections such as sepsis, Tα1 can be used as an adjuvant therapy. Sepsis patients often have immune dysfunction. Tα1 regulates immune cell function and cytokine networks, helping to restore immune balance, reduce inflammatory responses, and improve patient survival rates.
In the treatment of chronic infectious diseases such as tuberculosis, Tα1 combined with antituberculosis drugs may enhance the body's immune clearance capacity against Mycobacterium tuberculosis and improve treatment efficacy.
Inflammation-related diseases
In the treatment of inflammatory-related diseases such as rheumatoid arthritis and inflammatory bowel disease, Tα1's anti-inflammatory and immune-modulating effects may have potential application value. Although clinical application is currently limited, some basic research and small-scale clinical trials have indicated that Tα1 may reduce inflammatory responses and improve patient conditions by regulating immune cells and cytokines.
Conclusion
Thymosin α1 (Tα1), as a peptide with immune-enhancing properties, has demonstrated extensive and profound effects in the field of immune regulation. From its mechanism of action, Tα1 interacts with Toll-like receptors to activate multiple downstream signaling pathways, thereby regulating the function of immune cells and cytokine networks, and achieving precise control of the body's immune response.
In terms of immune-enhancing effects, Tα1 plays a significant role in antiviral infection, antitumor activity, immune balance regulation, and anti-inflammatory effects. In the antiviral field, Tα1 shows broad application prospects, whether for common viral infections such as hepatitis B and C, or for emerging viral infections like COVID-19. The role of Tα1 in immune deficiency diseases and inflammation-related diseases indicates that it can help restore immune balance and reduce inflammatory damage. Overall, Tα1 plays a significant role as an immune enhancer.
Sources
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[4] Renga G, Bellet M M, Pariano M, et al. Thymosin α1 protects from CTLA-4 intestinal immunopathology[J]. Life Science Alliance, 2020,3(10).DOI:10.26508/lsa.202000662.
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