Thymosin Alpha-1.

Introduction.

Thymosin Alpha-1 is a biologically active peptide derived from prothymosin-alpha. Current hypotheses consider Thymosin Alpha-1 to be the main constituent of Thymosin Fraction-5, and as such it is considered to be the active component that restores the immune function in both athymic animals and animals with dysfunctional thymus glands. Thymosin Alpha-1 was among the first peptide isolates of Thymosin Fraction-5 to be sequenced and thereafter synthetically synthesized.

In humans, the PTMA gene encodes prothymosin-alpha, a 113 amino-acid polypeptide. Thymosin Alpha-1 is a 28 amino-acid fragment of prothymosin-alpha, and research has shown that this fragment derivative enhances the cell-mediated immune component of the human immune system. Its immune actions have enabled it to be used for treating viral infections such as Hepatitis B and Hepatitis C. It has also been incorporated into vaccines as an immune booster. Clinical studies have also shown that Thymosin Alpha-1 can be used to manage neoplasias since they upregulate cytotoxic T-cells which are involved in immune surveillance.

Thymosins.

Thymosins are proteins with diverse biological actions. They are found in numerous animal tissues. They were originally isolated from thymic tissues, hence their name Thymosins. The main functions of thymosins are modulation and modification of biological responses. They are also known to stimulate leucopoiesis in the bone marrow. Leucopoiesis refers to the process of production of white blood cells from their stem cell precursors; and as such, endogenous thymosins do improve the immunocompetence status of an individual. Studies done on isolated thymic extracts have shown that two types of thymosins: Thymosin alpha-1 and Thymosin Beta-4 could be synthetically produced and then used therapeutically for immunostimulation and immunomodulation.

Thymosins were discovered in the 1960s as researchers sought to identify, categorize and study the biologically active humoral factors released by the thymus. The studies showed that some isolates from the thymus gland did restore immune functions while other isolates did not. These isolates were collectively termed as Thymosin Fraction-5. Further analysis of Thymosin Fraction-5 showed that it was comprised of about 40 peptides which were collectively termed as thymosins. Electric field studies were used to categorize these thymosins into alpha, beta and gamma fractions. Further molecular studies on the thymosin fractions showed that these fractions are genetically and structurally unrelated. Recent studies on thymosins have shown that thymosin beta-1 is ubiquitin. The studies also showed than thymosins can be produced by cells located outside the thymus. Research also showed that Thymosin alpha-1 administration did promote the differentiation of T-cells in athymic mice (that is, mice lacking the thymus). Thymosin alpha-1 has also been shown to have immune-potentiating actions that do interact with a dysfunctional thymus to reconstitute and normalize the immune status in children suffering from immunodeficiency.

The studies reviewed below have provided conclusive findings that demonstrate that Thymosin alpha-1 can be used clinically to improve the immune status.  

Selected studies.

The three studies reviewed hereafter have provided adequate and conclusive findings that Thymosin alpha-1 can be used clinically to manage cellular immunodeficiency.

1.      Thymosin Alpha-1 and Cellular Immunity.

In 1975, Goldstein et al published a study entitled “Thymosin Activity in Patients with Cellular Immunodeficiency” in The New England Journal of Medicine. The aim of this study was to investigate whether Thymosin alpha-1 increases the number of T-cell rosettes.

The subjects of this study were two groups of patients. One group suffered from primary immunodeficiency while the other group was affected by a viral illness. Lymphocytes extracted from these patients were incubated in-vitro with calf thymus extracts and sheep erythrocytes. The results showed that the T-cells populations increased until they reached their normal population after which thymosin had no further effect on them.

Thereafter, a female patient with primary immunodeficiency secondary to thymic hypoplasia was chosen to receive thymosin-α₁ in-vivo. Results showed that her T-cells rosettes increased by 33%. She also showed remarkable clinical improvement. However, she later on developed delayed-type hypersensitivity reactions to thymosin-α₁ extracted from calves.

This study therefore showed that Thymosin alpha-1 increases the number of T-cell rosettes in patients who have thymic hypoplasia. It also showed that thymosin-α₁ could be used to partially reconstitute the cellular arm of the immune system.

2.      Thymosin Alpha-1 and expression of lymphocytic interleukin-2 receptors.

In 1990, Kimberly D. Leichtling, Marcelo B. Sztein and Susana A. Serrate published a study entitled “Thymosin alpha 1 modulates the expression of high affinity interleukin-2 receptors on normal human lymphocytes” in the International Journal of Immunopharmacology. The aim of this study was to investigate the effects of Thymosin alpha-1(abbreviated in this study as Tα1) on high affinity IL-2R (interleukin 2 receptors). Peripheral lymphocytes derived from normal healthy human beings were used in this study. The results showed that Tα1 increased the population of high affinity IL-2R expressed by the lymphocytes. Likewise, it also increased Interleukin-2 production. Peak responses to Tα1 occurred when the Tα1 concentrations was 10⁻¹²M and 10⁻⁸M. Flow cytometry studies also showed that Tα1 upregulated Tac antigen expression.  However, it had no effect on the affinity of IL-2R for its respective ligands. Also, Tα1 demonstrated no effect in lymphocytes not subjected to mitogenic stimulation.

Thus, it can be concluded from this study that thymosin alpha-1 modulates the immune function by increasing the expression of Interleukin 2 and its corresponding receptors (IL-2R). Interleukin-2 (IL-2) is a cytokine that promotes lymphopoiesis, and it can therefore be inferred that the up-regulation of both IL-2 and IL-2R expression causes an increase in the T-cell population.

3.      Thymosin Alpha-1 and Chronic Hepatitis C.

In 1995, Rasi et al published their study under the title “Combination thymosin alpha 1 and lymphoblastoid interferon treatment in chronic hepatitis C” in the British Medical Journal. The aim of this study was to assess the effect on combination therapy on chronic hepatitis C. The combination therapy used was a twice weekly dose of 1mg thymosin alpha-1 and a thrice weekly dose of the lymphoblastoid-interferon, 3MU. The total number of subjects in this study was 15 chronic hepatitis C patients whose serum was positive for Hepatitis C Virus Ribonucleic acid (HCV RNA). 4 patients had failed standard interferon monotherapy and the rest were treatment naïve. All the 15 patients were treated with the combination therapy for 12 months and then subsequently followed-up for the next 6 months.

The results showed that 7 patients were HCV RNA negative after 6 months of combination therapy; and at the end of the treatment, this number had increased to 11 patients including 2 patients who had failed standard interferon monotherapy. During the follow-up period, 6 of the 11 patients showed a sustained HCV RNA negative status. It can therefore be concluded that this study showed that combination therapy of thymosin alpha-1 and interferon does provide potential benefit in the management of Chronic Hepatitis C disease.

In conclusion, the above three studies have shown that Thymosin alpha-1 partially reconstitutes the cellular arm of the immune system by increasing the number of T-cell rosettes in patients with thymic hypoplasia. It has also shown that Thymosin alpha-1 modulates the immune function by up-regulating the expression of IL-2 and IL-2R; and that it can also be used in the management of Chronic Hepatitis C.