Thymalin

Peptide drug Thymalin, isolated from the calve thymus, is successfully used for the treatment of various immunopathologies, including those in older age groups. The molecular mechanism of the Thymalin immunoprotective action is due to the effects of the short peptides KE, EW, EDP in its composition. These short peptides can specifically bind to double-stranded DNA and/or histone proteins and regulate gene expression, synthesis of immune system proteins, activity of gerontogenes, and stimulate stem cell differentiation. Regulation of immunogenesis is a key factor preventing the development of the “cytokine storm” that develops in severe COVID-19. The purpose of this work is to study the effectiveness of Thymalin in severe COVID-19 in older patients. Patients administered with Thymalin against the background of a standard therapy (n = 36) manifested a more rapid clinical improvement, higher proportions of recovery from lymphopenia, faster normalization of the concentration of C-reactive protein, D-dimer, the number of lymphocytes and NK-cells in the blood, compared to patients who received a standard therapy only (n = 44). Thymalin halved hospital mortality in older patients with severe COVID-19. The results obtained showed the effectiveness of Thymalin administration in the complex therapy of patients with severe COVID-19.

Thymalin (registration number LS-000267 dated February 26, 2010, Ministry of Health of the Russian Federation) is a medicinal drug based on a polypeptide complex isolated from the calve thymus. Thymalin is effective in case of various infectious diseases (hepatitis A and B, erysipelas, meningococcal infection, typhoid fever), acute respiratory diseases, pneumonia of various origins, cavernous pulmonary tuberculosis [2, 14, 15]. Administration of Thymalin reduced the incidence of acute respiratory infections in senior patients 2.0–2.4-fold [32].

Thymalin reduced mortality in senior patients over a 6-year observation period [12]. Thymalin is accumulated in epithelial cells of the human respiratory tract during early embryogenesis [20]. Thymalin prevents the “cytokine storm,” which develops during COVID-19, reducing the concentration of pro-inflammatory cytokines IL-lα, IL-6, IL-8, TNF-α in the blood [18]. Thymalin reduces the intensity of intravascular blood coagulation in the development of hypercoagulability syndrome [14, 15], which is known as a common cause of complications in patients with severe COVID-19.

A case of a successful Thymalin administration in an older patient with a severe form of COVID-19, developed on the background of chronic diseases (type II diabetes mellitus, stage III hypertension, ischemic heart disease), was reported [18]. Combination of Thymalin and comprehensive treatment allowed to arrest the “cytokine storm”, increase the concentration of blood lymphocytes 2-fold, eosinophils—7-fold, reduce the concentration of C-reactive protein, IL-6, D-dimer by 8, 2.5 and 7.2 times, respectively. It is noteworthy that initially the patient received only standard therapy, in the course of which his condition worsened.

In a study on human hematopoietic blood stem cells (HSC), Thymalin decreased the expression of CD44 on HSC 2.8-fold [19]. CD44 is a ligand for E- and L-selectin, which maintains the HSC subpopulation. CD44 is involved in the activation of proliferation, HSC survivability enhancement and modulation of cytokine action [8, 26]. Thymalin reduced the expression of CD117 on HSC 2.2-fold [19]. CD117 is a receptor for stem cell growth factor; it stimulates their proliferation and early stages of differentiation [27]. CD117 expression decreases during differentiation of immune cells [8]. Thymalin reduced the expression of CD28 on HSC 6.9-fold [19]. CD28 is expressed on CD4⁺, CD8⁺ lymphocytes and is involved in the activation of mature T cells. CD28 expression increases in antigen-presenting cells upon activation of toll-like receptors and plays an essential part in the activation of immunity in viral diseases. Patients with mild forms of COVID-19 manifest an increase in the number of CD4⁺, CD8⁺, CD28⁺ lymphocytes, which indicates the activation of the immune system functions. In severe cases of coronavirus infection, the number of T‑helpers and cytotoxic lymphocytes decreases alongside a simultaneous decline in the expression of CD28 on their surface [36]. Thus, Thymalin action on the differentiation of human HSCs, including the increase in the number of CD28⁺ cells in the blood, may be one of the mechanisms, activating the immune response in patients with COVID-19.

According to the molecular mechanism of action, Thymalin belongs to the group of drugs that epigenetically regulate gene expression and synthesis of immunogenesis proteins. Thymalin normalizes differentiation, proliferation and reduces apoptosis of lymphoid cells. Immunoprotective and geroprotective properties of Thymalin are due to the effects of short peptides EW, KE, EDP in its composition [3, 13, 17, 35]. Peptides EW, KE, EDP, which comprise the medicinal drug Thymalin, are able to penetrate into cell nucleus and nucleolus and complementary bind to certain DNA sequences and/or histone proteins [6, 7, 16, 21]. This binding results in a change in gene expression and synthesis of heat shock proteins, cytokines, fibrinolysis system, gerontogenes and proteins, involved in the differentiation, proliferation and apoptosis of immune cells. Normalization of the synthesis of proteins, which activate the immune and antioxidant systems’ functions, regeneration processes and hemostasis, manifests itself in the restoration of the functions of the body’s regulatory systems and explains the high efficiency of Thymalin in the treatment of a number of diseases.

Thus, Thymalin, an epigenetic regulator of gene expression and immunogenesis protein synthesis, can be considered a potentially effective agent for the complex therapy in patients with severe COVID-19. The purpose of this work is to study the effectiveness of Thymalin in severe COVID-19 in older patients.