Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Author: Dr. Prashant Kumar
MBBS, MD (Pulmonary Medicine), FAPSR, Sr. Consultant, Dept. of Respiratory, Sleep and Critical Care Medicine, IQ City Medical College and Hospital Durgapur, West Bengal
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Abstract
Thymosin alpha-1 is a peptide found naturally in the thymus that has long been known to alter, improve, and restore immune function. Thymosin alpha-1 has been used to treat immunocompromised states and cancers, as well as to boost vaccination response and reduce morbidity and mortality in sepsis and a variety of diseases. Thymosin alpha-1 could help improve the result in seriously ill COVID-19 patients by healing damage caused by over activation of lymphocytic immunity and preventing excessive activation of T cells, according to studies. We examined key literature on background knowledge and current clinical usage of thymosin alpha-1 in this review. We believe that thymosin alpha-1 merits further investigation into its antiviral properties and possible repurposing as a treatment against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), based on known biochemical properties such as antibacterial and antiviral properties, time-honored applications, and new promising findings regarding the use of thymosin.
Keywords: Thymosin alpha-1, COVID 19, Immunomodulation, T lymphocytes, Infectious diseases, Immune deficiency, Cancer, Hepatitis, Immunological function.
Introduction
With the commencement of the worldwide SARS-CoV-2 pandemic in 2020, there has been an increase in research activity surrounding specific disease-modifying medications that are used to treat inflammatory disorders for the treatment of coronavirus symptoms. Immunomodulatory medications may be protective in decreasing specific aspects of SARS-CoV-2 and enhancing recovery, according to new research. In patients who are at high risk of requiring intensive care to prevent uncontrolled inflammation and death, immunomodulatory medications are more likely to play a role in cytokine storm and macrophage activation [1]. Thymosin alpha-1 is an immunomodulatory drug that suppresses viral replication, activates stem cells, and aids in the formation of new immune cells.
Thymosin alpha-1 therapy dramatically reduced death in COVID-19 patients with severe disease. Thymosin alpha-1 was more beneficial to COVID-19 patients with CD8+ T cell counts in circulation less than 400/L or CD4+ T cell counts in circulation less than 650/L, respectively. During SARS-CoV-2 infection, thymosin alpha-1 promoted thymus production, which reversed T-cell fatigue and restored immunological reconstitution [2].
Biological Activities/Health Benefits of Thymosin alpha-1
Thymosin alpha-1 contains a diverse spectrum of biological functions, from anticancer to immune-modulating capabilities (Figure 1). Thymosin alpha-1 is responsible for the immunological response by increasing the activity of T cell maturation into CD4+/CD8+ T cells. It operates by directly activating natural killer cells and CD8+ T cells, which then kill virus-infected cells. Thymosin alpha-1 inhibits IL-1 and tumor necrosis factor, resulting in a reduced inflammatory response, which is useful in diseases such as chronic hepatitis and severe pancreatitis [3]. Thymosin alpha-1 has a diverse spectrum of targets for its immune-enhancing function, according to Naylor and colleagues [4].
Thymosin alpha-1 has been shown to inhibit tumor growth, making it useful in the treatment of a variety of malignancies. It contains anti-proliferative characteristics that have been seen in tumor metastases in the lungs and liver. According to Moody et al [4], thymosin alpha-1 anti-tumor action was most effective when tumors were small. Overall, thymosin alpha-1 functions in one of two ways: either by boosting the immune system or by inhibiting tumor cell proliferation. Armutcu et al [5] investigated the beneficial impact of thymosin alpha-1 against oxidative damage as a result of its impact on liver superoxide dismutase and glutathione peroxidase.
Thymosin alpha-1 is a polypeptide found naturally in the thymus and is involved in the regulation of inflammation, immunity, and tolerance. Thymosin alpha-1 modulates the immune system via interacting with toll-like receptors. Thymosin alpha-1 is employed as a therapeutic treatment for disorders with obvious immunological dysfunction because of its effects on other cell types [6].
Figure 1: Thymosin alpha-1 has a wide range of biological activities. [IL: Interleukin; IFN: Interferon; TLR: Toll-like receptors]
Clinical and Commercial Applications of Thymosin alpha-1
Thymosin alpha-1 has been thoroughly investigated, and its synthetic version is frequently utilized in clinical practice. The following are some of its applications.
Cancer:
Patients with cancer frequently have substantial cellular immunity deficits. Furthermore, typical cancer treatments commonly cause a significant reduction in immunological response. Thymosin alpha-1 has been shown to inhibit tumor cell proliferation in vitro and in vivo, and offers therapeutic potential in a variety of cancers. Thymosin alpha-1 coupled with chemotherapy could protect patients from chemotherapy-induced neurotoxicity in advanced lung or advanced breast cancer [7]. Different dose levels of thymosin alpha-1 in combination with Dacarbazine (DTIC) chemotherapy were given to patients with stage IV melanoma in a Phase II multi-center, randomized open-label research. In comparison to patients treated with DTIC plus IFN, the combination therapy tripled overall response rate and extended overall life by nearly 3 months, according to published studies. Trans Arterial Chemoembolization (TACE) combination with thymosin alpha-1 resulted in numerically greater rates of survival and tumor response, including transplant eligibility, with fewer bacterial infections in patients with unrespectable Hepatocellular carcinoma (HCC) than TACE alone [8].
When thymosin alpha-1 was coupled with other treatment methods, significant tumor growth suppression and survival rate increases were shown in many human tumor models. Combinatorial therapies, in which thymosin alpha-1 is one of the essential mediators, are an effective therapeutic method against tumors and will be the primary emphasis for thymosin alpha-1 use in cancer treatment in the future.
Hepatitis C:
Thymosin alpha-1 appears to be ineffective as a single therapy for hepatitis C infection. In hepatitis C patients, however, a combination of thymosin alpha-1 and PEGylated interferon alpha 2a could successfully suppress viral replication. Patients with chronic hepatitis C have also been treated with thymosin alpha-1 in combination with interferon-alpha 1. Furthermore, thymosin alpha-1 is well tolerated, with no serious side effects reported. Sherman did a meta-analysis that included numerous trials that showed that the combination of thymosin alpha-1 and interferon alpha 1 was superior to interferon alpha monotherapy [9]. It's worth noting that, like Hepatitis B, the use of thymosin alpha-1 in the treatment of Hepatitis C has been phased out in favor of direct antiviral medicines.
Hepatitis B:
Chronic HBV infection is a severe clinical concern due to its global dissemination and probable side effects such as cirrhosis and hepatocellular cancer [10]. Thymosin alpha-1 has been licensed in several countries across the world for the treatment of hepatitis B, with a considerably increasing virological response over time [11]. Thymosin alpha-1 has been studied for its efficacy in the treatment of chronic hepatitis B in both HBeAg-positive and HBeAg-negative patients. For example, giving thymosin alpha-1 at doses of 0.8 mg or 1.6 mg to 316 Japanese patients with HBeAg-positive chronic hepatitis B resulted in HBeAg seroconversion in 18.8% and 21.5%, respectively, 48 weeks after therapy ended [12]. Similarly, giving thymosin alpha-1 1.6 mg twice weekly to Chinese patients with HBeAg-negative chronic hepatitis B resulted in a full response, defined as normalization of alanine transaminase (ALT) and undetectable HBV DNA by PCR testing, in 11 of 26 patients (42.3%) at 6 months [13]. Zhang et al. used meta-analysis to seek materials from various databases and assess eight studies. In terms of ALT normalization rate, virological response rate, and HBeAg seroconversion rate, they discovered that lamivudine and thymosin alpha-1 combination treatment outperformed lamivudine monotherapy [14].
Sepsis:
The use of thymosin alpha-1 in sepsis patients has been found to reduce mortality owing to multiple organ failure, which is the leading cause of death [15].
HIV Infection:
Combination therapy with thymosin alpha-1, interferon alpha 1, and zidovudine has been well tolerated in HIV patients. Thymosin alpha-1 improves function and raises CD4+ T cell numbers while also lowering viral load. Thymosin alpha-1 affects the production of thymic T-cells. Thymosin alpha-1 has been shown to be safe and effective in boosting immunological reconstitution when used in conjunction with highly active antiretroviral therapy [6]. Thymosin alpha-1 has been demonstrated to be well tolerated and has the potential to significantly raise the levels of signal joint T cell receptor excision circles (sjTREC) in patients with advanced HIV illness. The administration of high-dose thymosin alpha-1 for a longer period of time is more effective [16].
Pseudomonas - Bone Marrow Transplant Patients:
Thymosin alpha-1 is also used to treat infections such as Pseudomonas infections after bone marrow transplantation [17].
Mold Toxicity:
This thymic peptide has the capacity to activate dendritic cells as well as boost Th1 and Treg cells, resulting in a balanced inflammatory response and an antifungal response. Th1 response stimulates phagocytic activity by activating the production of Th2 cytokines (IFN, IL-2, IL-12, IL-18). As a result, cytotoxic CD4+, CD8+, and T lymphocytes, as well as opsonizing antibodies, will be generated, providing protection against fungal infections [18].
Immune Deficiency:
Thymosin alpha-1 stimulates the expression of IL-2 receptors and the internalization of IL-2. It also restores lymphokine-activated killer cell activity in patients with immunodeficiency and decreased lymphokine-activated killer cell activity [19]. Thymosin alpha-1 activates signaling pathways and promotes the production of immune-related cytokines by acting on Toll-like receptors in both myeloid and plasmacytoid dendritic cells. As a result, it is expected that Thymosin alpha-1 will have promising effects in the treatment of immunocompromised patients. Overall, it boosts immunological function without creating side effects [20].
Psoriatic Arthritis:
Thymosin alpha-1 is a powerful immune and inflammatory modulator. Evidence is mounting that disorders defined by immune system dysregulation and inflammation, such as psoriatic arthritis, are linked to blood levels of thymosin alpha-1 that are much lower than in healthy people. The findings support thymosin alpha-1 involvement as a regulator of immunity, tolerance, and inflammation in psoriatic arthritis patients [6].
Vaccine Adjuvant:
The use of thymosin alpha-1 as an influenza vaccine adjuvant has shown encouraging results, particularly in elderly and immunocompromised patients [21]. Thymosin alpha-1 has also been demonstrated to boost influenza vaccine immunogenicity [22].
Oxidative Damage, Pancreatic Lesions and Diabetes:
Thymosin alpha-1 has been established in numerous investigations to protect against oxidative damage. Thymosin alpha-1 lowers the generation of reactive oxygen species and prevents oxidative damage to hepatic tissue by significantly increasing the activities of catalase, superoxide dismutase, and glutathione peroxidase. Thymosin alpha-1 has been shown to have anti-proliferative characteristics in a variety of human cancers, and this is due to its ability to reduce oxidative stress [6]. It also reduces the generation of malondialdehyde and improves the activity of superoxide dismutase and catalase, which helps to alleviate pancreatic damage and diabetes. Thymosin alpha-1's antioxidant capabilities are thought to be beneficial in the treatment of pancreatic lesions [23].
Evidence from Previous Human Clinical Studies
Thymosin alpha-1 has been used in a variety of situations to improve cell-mediated immunity and treat a variety of disorders (Table 1).
Table 1: Summarizing studies for application of Thymosin alpha-1
|
Reference |
Year |
Application of Thymosin alpha-1 |
|
Eckert et al [9] |
1994 |
Combination therapy of thymosin alpha-1 and PEGylated interferon alpha 2a preferred over interferon monotherapy for the treatment of chronic hepatitis C. |
|
Sugahara et al [24] |
2002 |
Patients with chronic hepatitis B who were treated with thymosin alpha-1 showed an overall improvement in serum ALT levels. ALT levels were reduced to normal in 42.9%. A total disappearance of serum HBV DNA was noted in 28.6% of patients. |
|
Romani et al [25] |
2007 |
A single-blind randomized control trial was conducted in six tertiary hospitals in China to study the beneficial effects of thymosin alpha-1 on patients with sepsis. The results showed 9% lower mortality in the treatment group compared to the control group. |
|
Qin et al [23] |
2009 |
Thymosin alpha-1 can reduce oxidative damage to the pancreas and mitigate the risk of resulting diabetes. |
|
Li et al [3] |
2010 |
Thymosin alpha-1 can be safely used as an adjuvant to antiretroviral therapy in HIV patients. It helps increase CD4+ count, stimulates the function of CD4+ cells, and helps decrease viral load. By amplifying the activity of catalase, superoxide dismutase, and glutathione peroxidase, it decreases oxidative damage to tissues. Thymosin alpha-1 reduces tumor cell proliferation in human malignancies by decreasing oxidative stress. |
|
Sherman et al [19] |
2010 |
Thymosin alpha-1 was tested as monotherapy and in combination with interferon-alpha for the treatment of chronic hepatitis B. It was also shown to stimulate IL-2 receptor expression and IL-2 internalization and to enhance immune response in patients with immunodeficiency. |
|
Panatto et al [21] |
2011 |
Thymosin alpha-1 has shown promising results as an adjuvant to the influenza vaccine. |
|
Antachopoulos et al [18] |
2012 |
Thymosin alpha-1 might be effective against mold toxicity. |
|
Carraro et al [22] |
2012 |
Thymosin alpha-1 improves immunogenicity of the influenza vaccine. |
|
Camerini et al [17] |
2015 |
Thymosin alpha-1 can be used in Pseudomonas infections or infections following bone marrow transplant. |
|
Guo et al [26] |
2015 |
The anti-tumor effect of thymosin alpha-1 was studied on human cancer cell lines. The study concluded that thymosin alpha-1 can decrease proliferation and induce apoptosis in human leukemia, non-small cell lung cancer, melanoma, and other cancers. The study concluded that thymosin alpha-1 could be an approach to breast cancer treatment. |
|
Li et al [15] |
2015 |
Significant decrease in mortality due to multiple organ failure in patients with sepsis. |
|
King et al [20] |
2016 |
Thymosin alpha-1 increases cytokine production and is expected to be beneficial in immunocompromised patients. |
|
Matteucci et al [16] |
2017 |
Thymosin alpha-1 significantly increases levels of sjTREC in patients with advanced HIV disease. |
|
Pica et al [6] |
2018 |
It has been postulated that thymosin alpha-1 can help regulate immunity and reduce inflammation in patients with psoriatic arthritis. |
|
Costantini et al [26] |
2019 |
Thymosin alpha-1 has shown promising results in patients with malignancies, such as metastatic melanoma, head and neck carcinoma, lung cancer, breast cancer, and hepatocellular carcinoma. |
|
ALT: Glutamic-pyruvic transaminase; DNA: Deoxyribonucleic acid; HBV: Hepatitis B virus; HIV: Human immune deficiency virus; IL: Interleukin; sjTREC: Signal joint T cell receptor excision circles. |
||
Conclusion
Thymosin alpha-1 is a thymus peptide that has been shown to have immunomodulatory and biochemical characteristics. Thymosin alpha-1 therapy may be used to counteract the immunosuppressive effects of the SARS-CoV-2 viral envelope in producing cytokine storm. In more severe circumstances, this might be especially useful in preventing catastrophic events like cytokine storm. Thymosin alpha-1 has a well-known safety profile and is well tolerated, with just mild side effects. Clinical investigations have indicated that thymosin alpha-1 plays an important role in immunological and inflammatory responses, and substantial research has established its efficacy in a variety of disorders, from hepatitis and HIV to immunological deficiencies and malignancies, as well as its use as a vaccine adjuvant. It has been demonstrated to lower mortality in people with severe COVID-19 infection and aid in the restoration of some immunological function by enhancing thymic activity. Further research is needed to see if thymosin alpha-1 can be used as a therapeutic agent or in combination with other treatments to slow the disease progression and severity.
References
