Thymalin boosts immune system while mitigating fever and excess cell death induced by cytokine storms.

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by Dr. Timothy J.

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Thymulin, free or bound to PBCA nanoparticles, protects mice against excessive cytokine response induced by chronic septic inflammation.

"Recent studies of sepsis, which is accompanied by multiple organ failure, have identified various stages of this severe pathology. The first stage constitutes a “cytokine storm”, during which, an uncontrolled cytokine response leads to fever and respiratory deficiency." (2)

"Currently available treatments for sepsis, such as antibacterial therapy using antibiotics, infusion therapy with donor fresh frozen plasma, and therapies that alleviate hypercytokinemia by decreasing levels of cytokines [particularly tumor necrosis factor (TNF)-α], are not successful in all cases. Over 40 clinical trials of treatments designed to decrease the proinflammatory response have been performed, none of which had promising results." (2)

"Treatment of these mice with thymulin alleviated fever, reduced apoptosis, increased splenic cell number, and decreased cytokine production, Hsp72, Hsp90, and TLR4 expression, and the activity of the signaling pathways examined." (2)

"Apoptosis, as a programmed cell death mechanism, maintains immune homeostasis by elimination of immune cells. In this process, the caspase family of cysteine proteases are instrumental in the cleavage of cellular proteins, and the transcription factor NF-κB activates transcription of pro-apoptotic and anti-apoptotic genes. Given that NF-κB mediates hyperinflammatory responses by stimulating cytokine production, it simultaneously induces, together with caspases, apoptosis of cells of the adaptive immune system. Many investigators have demonstrated increased apoptosis during the “cytokine storm” stage of sepsis both in animal models and in patients with severe sepsis, who exhibit significantly decreased T, B, and dendritic cell counts." (2)

"As proinflammatory cytokine expression is known to be regulated by the NF-κB and MAPK pathways, the increase in plasma levels of such cytokines (e.g., IL-6, IFN-γ, and TNF-α) after LPS treatment in the present study was expected. Plasma levels of the anti-inflammatory cytokine IL-10 were also elevated, but to a lesser extent. Thymulin treatment completely normalized proinflammatory cytokine levels, independently of the form used (free or nanoparticle-bound)." (2)

C = Control
IB = Inflammation Bearing
TM = Thymalin
TMN = Thymalin bound to nanoparticles

Thymulin, A Thymic Peptide, Prevents the Overproduction of Pro-Inflammatory Cytokines and Heat Shock Protein Hsp70 in Inflammation-Bearing Mice.

"Inflammation induced by LPS resulted in accumulation of several plasma pro-inflammatory cytokines, IL-1β, IL-2, IL-6, TNF-α, interferon-γ, and also IL-10, anti-inflammatory cytokine. Thymulin previously injected in dose of 15 μg/100 g body weight, prevented the accumulation of proinflammatory cytokines in plasma. Thymulin also prevented LPS-induced up-regulation of production of several cytokines by spleen lymphocytes and peritoneal macrophages. Added in vitro, thymulin decreased the peak of TNF-α production in macrophages cultivated with LPS. In addition, thymulin lowered the peak of Hsp70 production induced by LPS treatment." (1)

Immune Paralysis Following "cytokine storm" may be reversed by Thymalin.

"Uncontrolled development of the initial [cytokine storm] stage inevitably leads to immune imbalance, which increases the probability of secondary infections, such as pneumonia, and activation of latent herpes virus (including cytomegalovirus) infections." (2)

"Over the last decade, preclinical and clinical studies have definitively shown that sepsis leads not only to hyperinflammation, but also impaired immunity, including dysfunction of the adaptive immune system. Certain investigators and clinical practitioners believe that the main cause of the failure of sepsis therapy involves the development of severe immunodeficiency..." (2)

“Administration of Thymalin to old mice led to an increase of the titer of FTS in the blood, the restoration of disturbed circannual rhythm, the number of CD4+ cells in the bone marrow, and the concentration of corticosterone in the blood.” (4) “Both natural and synthetic pharmaceuticals activated T-cell differentiation, T-cell recognition of peptide-MHC complexes, induced the changes in intracellular composition of cyclic nucleotides and cytokine [interleukin (IL-2), interferon (IFN)] excretion of blood lymphocytes.” (3)

"Adequate zinc is essential for T-cell division, maturation, and differentiation. Zinc itself is a cofactor for thymulin, a best known zinc-dependent thymic hormone crucial for T-cell formation and maturation which exists in two forms, a zinc-bound active one, and a zinc-free inactive form. What’s more, zinc may also prevent the programmed death (apoptosis) of precursor T-cell populations and mature CD4+T cells through various enzymatic mechanisms and through chronic production of glucocorticoids. Thymulin and thymopentin restore antibody avidity in aged or thymectomized animals, enhance antibody production in aging mice... Additionally, thymulin reduces induced hyperalgesia in rats and mice.” (7)

Inflammatory cytokines hinder mucociliary clearance.

"A key parameter determining the rate of mucus clearance is ciliary beat frequency (CBF). The density (cilia per cell and number of ciliated cells) and length of cilia are greater in the trachea than in small airways, and this correlates with an increase in mucus transport and CBF toward the oropharynx." (10)

"Addition of IL-4 and IL-13 and IL-4 + IL-13 decreased the mean CBF by 17, 21, and 22%, respectively, compared with untreated controls. Addition of IL-5 and IL-9 lead to an increase in mean CBF (20 and 10%, respectively). Lower concentrations of IFN-γ (0.1 and 1 ng/ml) decreased mean CBF and higher concentrations (10 ng/ml) increased CBF by 6%. Addition of IFN-γ to IL-13 reversed the effect of IL-13 on the CBF of spheroids. Cytokines directly influence the ciliary function of respiratory epithelium and contribute to the impaired mucociliary clearance in asthmatic disease." (9)

Thymulin and Zinc reduce toxin-induced cytokine production and fibrosis in lung alveolar epithelium.

"Thymulin has a selective immunomodulatory effect, enhancing anti-inflammatory and inhibiting pro-inflammatory cytokines. It suppresses p38 (implicated in glucocorticoid-resistance) and inhibits NF-kappaB activation, which has an important pathogenic role in several lung diseases." (5)

"Alveolar epithelial cells treated with thymulin markedly showed a downregulation of the nuclear translocation of RelA (p65), the major transactivating member of the NF-kappaB family, in addition to NF-kappaB(1) (p50) and c-Rel (p75), an effect mildly substantiated with Zn(2+). Furthermore, thymulin/Zn(2+) reduced, in a dose-dependent manner, the DNA-binding activity of NF-kappaB (RelA/p65). These results indicate that the anti-inflammatory effect of thymulin, which is mediated by cAMP, is NF-kappaB-dependent and involves the downregulation of the release of proinflammatory cytokines, particularly IL-1beta, an effect synergistically amplified, at least in part, by Zn(2+).The molecular regulation of thymulin via a NF-kappaB-dependent pathway is critical to understanding the anti-inflammatory alleviating role of this nonapeptide..." (8)

“Furthermore, thymulin reduced bleomycin-induced cytokine and chemokine production and inhibited pulmonary fibrosis in mice... Haddad et al. demonstrated an immunomodulatory potential of thymulin in the lung perinatal epithelium." (6)