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How does Thymosin Alpha 1 improve anti-viral immune responses?

“product By Nemo 2 months ago

Antigen, Antibody, and Lymphocytic White Blood Cell Recruitment.

“Importantly, Ta1 acts without overstimulation of cytokine production and is generally well tolerated; it has an excellent safety profile and does not appear to induce the side effects and toxicities commonly associated with agents in this class such as interferon alpha and interleukin-2.” (1)

“Clinical trials using Ta1 in the treatment of patients with immunodeficiency or cancer indicate that this agent is nontoxic, enhances immune responsiveness and augments specific lymphocyte functions, including lymphoproliferative responses to mitogens, maturation of T-cells, antibody production, and T-cell-mediated cytotoxicity” (5)

• Increased Natural Killer (NK) activity

• A shift of T helper (Th or CD4) cells to the Th1 cell subset

• Increased expression of Th1 type cytokines such as Interleukin (IL) 2, and Interferon (IFN)-alpha

• Increased levels of Cytotoxic T (Tc1 or CD8) cells

“Sequential expression of selected antigens during T cell development. Depicted is the pathway of T cell differentiation from the bone marrow stem cell to thymocyte maturation in the thymus, leading to the diversion of the CD4+ helper and CD8 cytotoxic suppressor cell sublineages, each of which undergoes further differentiation in peripheral lymphoid tissues.” (3)

The maturation of the T cell from the bone marrow to the thymus to the peripheral blood, lymph nodes, spleen, and skin:

The maturation of the T cell from the bone marrow to the thymus to the peripheral blood, lymph nodes, spleen, and skin.

“Ta1 can reduce apoptosis of immune cells, as shown in mouse and human thymocytes, and increase stem cell expansion in immunosuppressed mice. Additionally, Ta1 leads to increased expression of the thymopoetic cytokines IFN-alpha, IL-7, and IL-15.” (1)

“These immunological effects can explain Ta1’s effectiveness in indications where a stimulated or enhanced immune response is desirable for health outcome, including viral, bacterial, and fungal infections and cancers, as well as vaccination of immunocompromised subjects (e.g., the elderly or those with renal failure). NK cells, and CD4 helper Th1 and CD8 cytotoxic Tc1 cells acting in concert, lead to killing of virally-infected cells and tumors. Activated DCs [Dendritic Cells] also provide anti-viral and anti-tumor responses, as well as killing of bacterial and fungal infections. Activated DCs also lead to more efficient antigen presentation for increased production of antibodies, an effect of Ta1 which is especially important for the elderly who do not respond well to vaccination due to being immunosuppressed.” (1)

Antigens are molecules capable of stimulating an immune response. Each antigen has distinct surface features, or epitopes, resulting in specific responses. Antibodies (immunoglobins) are Y-shaped proteins produced by B cells of the immune system in response to exposure to antigens.” (6)

Figure 2:

“By inducing IDO1 and promoting Treg cells, Ta1 successfully ameliorated respiratory allergy and intestinal inflammation in different experimental models. Thus, maintaining diplomatic relations between mammals and microbial communities could be added to the therapeutic and immunomodulatory properties of Ta1.” (8)

“Stimulation of IDO leads to an increase in FoxP3 IL-10 producing regulatory T cells, and this increase leads to feedback inhibition of cytokine production, hence dampening immune response to prevent a pro-inflammatory cytokine storm and possibly autoimmune phenomena (Figure 3).” (6)

Figure 3:

FoxP3 IL-10 producing regulatory T cells

“Heterocomplexes and collaborative interactions between endogenous and/or exogenous TLR agonists and Ta1 may lead to novel reciprocal trends of immune surveillance and effector mechanisms aiding safe disposal of pathogens and/or pathogenic insults whereby excessive inflammatory responses and tissue injury may effectively be prevented.” (8)

Enhancing Immunosurveillance.

Thymosin Alpha 1 boosts MHC production, thereby disabling immune system-cloaking techniques of viruses:

“Not only activating immune-effector cells or modulating cytokines expression, T1 also directly exerted its effects on target cells. It could increase the expression of MHC I and tumor antigens, directly depress viral replication, and increase expression of viral antigens on the surface of target-infected cells, making them more visible to the immune system and less prone to escape from immunosurveillance.”

“Ta1 has also been shown to increase expression of proteins on the surface of virally-infected or tumor cells, including those that mediate antigen presentation such as Major Histocompatibility (MHC) Class I, MHC Class II, and beta-2 microglobulin, as well as tumorspecific antigens. Immune escape by virally-infected and tumor cells has been correlated with down-regulation of antigen-presenting molecules.” (1)

Partially restored mucociliary clearance (cilia cells clearing mucus).

"Multi-DDM detects partially restored ciliary beating following treatment with CFTR-modulating drugs and Thymosin-α1” (7)

“We treated HAECs obtained from three different subjects homozygous for the F508del/F508del mutation in CFTR with 100ng/mL Tα1 over a period of 48 hrs and compared this with the same cells treated with a vehicle-only control. The range of average CBFs for subjects is 4.5 – 5.8 Hz at 48 hours following Tα1 treatment, compared to 4.1 – 4.4 Hz for the vehicle-only control. The markedly decreased coordination length scale observed in response to all three drug treatments is indicative of partial restoration of normal ciliary beating dynamics, which is consistent with the previously reported roles of these drugs in modulating CFTR functionality in CF cells.” (7)

Evidence of ACE inhibition combating viral pneumonia by boosting ACE2.

“The inhibitory effect of Thα1 on angiotensin-converting enzyme (ACE) was determined. The kinetic parameters (Km and Vmax) and the inhibition pattern were examined. Based on the Lineweaver-Burk plot, Thα1 displayed a mixed inhibition pattern. The IC50 and Ki values of Thα1 were 0.8 µM and 3.33 µM, respectively. Molecular modeling suggested that Thα1 binds to ACE-domains with higher affinity binding to N-domain with the binding energy of −22.87 kcal/mol. Molecular docking indicated that Thα1 interacted with ACE enzyme (N- and C-domains) due to electrostatic, hydrophobic, and hydrogen forces.” (2)

“This study looked at patients (humans) with viral pneumonia and demonstrated an association with improved outcomes in patients with continued ACEi use during viral pneumonia… An animal study in Scientific Reports (mouse) demonstrated the importance of ACE2 in viral pneumonia from H7N9 influenza virus pneumonia. This study showed worse pathology and survival in ACE2 KO mice. Thus, showing the potential benefit of ACE2 in viral mediated lung injury presumably from the removal of Ang II and generation of Ang I-7.” (9)

Thymosin alpha 1 stimulates endothelial cell migration, angiogenesis, and wound healing.

“Talpha1, a 28 amino acid peptide initially isolated from the thymus, enhanced the morphologic differentiation of endothelial cells and was a potent chemoattractant for endothelial cells and monocytes in vitro. In vivo, Talpha1 stimulated angiogenesis in a subcutaneous model. When given either topically or i.p., it accelerated wound healing in a punch model, demonstrating that Talpha1 promotes angiogenesis and wound healing.” (10)

Synergy from Combining Thymosin Alpha 1.

“combination TA1 and IFN-α2b was compared with IFN-α2b alone. One trial found a normal serum ALT level at six months in 71% of patients receiving combination therapy, versus 35% of patients receiving IFN-α2b alone. Hepatitis C virus RNA clearance occurred in 65% of patients treated with combination therapy and 29% of patients treated with IFN-α2b alone.” (4)

Powerful Anti-Oxidation.

“Ta1 treatment also increases intracellular Glutathione (GSH), important for anti-viral effects, and importantly has been shown to directly inhibit the in vitro growth of virally infected and cancer cells.” (1) "The effect of Thα1 on eliminating superoxide radicals was higher (62.23%) than other antioxidant assays.” (2)

Sourcing Studies:

(1) Robert S. King, C.W.T. (2013). Thymosin Apha 1–A Peptide Immune Modulator with a Broad Range of Clinical Applications. Clinical & Experimental Pharmacology, [online] 03(04). Available at: https://www.longdom.org/open-access/thymosin-apha-...

(2) J, K.-K., A, A. and H, T. (2019). Antioxidant and Angiotensin-Converting Enzyme (ACE) Inhibitory Activity of Thymosin alpha-1 (Thα1) Peptide. [online] Bioorganic chemistry. Available at: https://pubmed.ncbi.nlm.nih.gov/30974297/

(3) www.sciencedirect.com. (n.d.). Thymosin α1 - an overview | ScienceDirect Topics. [online] Available at: https://www.sciencedirect.com/topics/immunology-an...

(4) Ancell, C.D., Phipps, J. and Young, L. (2001). Thymosin alpha-1. American Journal of Health-System Pharmacy, [online] 58(10), pp.879–885. Available at: https://academic.oup.com/ajhp/article-abstract/58/...

(5) You, J., Zhuang, L., Tang, B.-Z., Yang, W.-B., Ding, S.-Y., Li, W., Wu, R.-X., Zhang, H.-L., Zhang, Y.-M., Yan, S.-M. and Zhang, L. (2001). Randomized controlled clinical trial on the treatment of Thymosin-a1 vs interferon-α in patients with hepatitis B. World Journal of Gastroenterology, [online] 7(3), pp.411–414. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC46887...

(6) Technology Networks (2017). Antigen vs Antibody – What Are the Differences? [online] from Technology Networks. Available at: https://www.technologynetworks.com/immunology/arti...

(7) Chioccioli, M., Feriani, L., Kotar, J., Bratcher, P.E. and Cicuta, P. (2019). Phenotyping ciliary dynamics and coordination in response to CFTR-modulators in Cystic Fibrosis respiratory epithelial cells. Nature Communications, 10(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/30992452

(8) Moretti, S., Oikonomou, V., Garaci, E. and Romani, L. (2015). Thymosin α1: burying secrets in the thymus. Expert Opinion on Biological Therapy, 15(sup1), pp.51–58. Available at: https://www.tandfonline.com/doi/full/10.1517/14712...

(9) NephJC. (n.d.). The Coronavirus Conundrum: ACE2 and Hypertension Edition. [online] Available at: http://www.nephjc.com/news/covidace2

(10) Malinda, K.M., Sidhu, G.S., Banaudha, K.K., Gaddipati, J.P., Maheshwari, R.K., Goldstein, A.L. and Kleinman, H.K. (1998). Thymosin alpha 1 stimulates endothelial cell migration, angiogenesis, and wound healing. Journal of Immunology (Baltimore, Md.: 1950), [online] 160(2), pp.1001–1006. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9551940/

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