Thymic peptides as immunoregulators or biological response modifiers

As mentioned above, only thymulin can today be described as a classical hormone. Nevertheless, further investigations are required regarding the physiological relevance of the numerous data showing immunological effects of thymic peptides. 1) Between 400 and 800 pg/ml Tal (or ProTa, this fact remains to be elucidated), 300-500 ng/ml thymopoietin and 0.5-3 pg/ml thymulin are present in human plasma. THF has also been detected. Except for thymulin, these levels are not reduced by thymic involution, but Tal levels are decreased or augmented in some groups of sick patients or monkeys. 2) Thymic peptides, except for THF, were secreted specifically by some epithelial cells in the thymic stroma. 3) They bind to different receptors on T cells and other cells and tissues. So while some investigators believe that thymic peptides are a result of cellular damage or death, others have postulated that certain nucleoproteins may be targeted by proteases during cellular activation to produce 'nucleokines' that in turn migrate to the cytoplasm and may be secreted.

Although the discovery and the first studies on thymic peptides (TPs) are historically linked with their role in the developmental events of T lymphocytes within the thymus, more recent investigations have focused upon the effects of TPs on mature effector cells (Figure 1). TPs have been extensively explored as potential regulators of T cell deficits which would allow specific immunotherapeutical approaches of clinical utility. Thus, whereas the involvement of TPs in the induction of markers of T cell differentiation is of minor significance compared with the role of cytokines, TPs appear to play a potentially important role in stimulating various T cell functions in normal and in partly T cell deficient rats, mice and humans. In general, TPs tend to normalize the immune balance, either by enhancing suppressed systems or by stimulating suppressor mechanisms in hyperrespons-ive states. Thus, TPs may act, outside of the thymus, as fine physiological immunoregulators contributing to the maintenance of T cell subset homeostasis.

In vitro effects

Thymulin restores basal NK activity in spleen cell cultures obtained from old, but not young mice. It increases the release of interferon y (IFNy), IL-2 and IL-la by mitogen-stimulated cells of normal individuals, whereas it inhibits the release of these cytokines and also of IL-6 in systemic lupus erythematosus (SLE) patients. Inhibition of tumor necrosis factor a (TNFa) production was found in both groups. Thus, thymulin may function as an immunomodulator by exerting control over cytokine production.

Peripheral blood mononuclear cells obtained from patients with chronic hepatitis B virus infection have an increased production of IL-2 and TNFa in response to THFy2, suggesting an antiviral role for this peptide in vivo. An effect on hematopoietic progenitor cell proliferation was recently documented in which THFy2 increased the number of myeloid colonies of bone marrow cells from normal mice. Human erythroid and myeloid hematopoietic progenitor cells are also stimulated to growth by THFy2.

Thymopentin (TP5), the synthetic pentapeptide corresponding to the active structure of thymopoietin, has shown impressive immunoregulatory activity. TP5 modulates TH1 and TH2 cytokine response; it enhances IFNy, TNFa and IL-2 release and reduces the levels of IL-4 in different models. In addition, bone marrow T lymphocyte precursors treated with TP5 show increased thymus colonization.

Tal and ProTa increase the number of high-affin-ity IL-2 receptors, IL-2 production and IL-2/IL-2R internalization in stimulated lymphocytes. They enhance T lymphocyte proliferative responses and improve NK- and LAK-cell activity of normal and cancer patients. Moreover, ProTa enhances MHC class II expression and mRNA accumulation in human monocytes, murine splenocytes and tumor cell lines.

In vivo effects

Thymulin and thymopentin restore antibody avidity in aged or thymectomized animals, enhance antibody production in aging mice, stimulate the male-to-female skin graft rejection, the prolongation of skin graft survival and the abrogation of delayed-type hypersensitivity. There are positive correlations between zinc levels, active thymulin and peripheral immunological parameters in young cancer patients. Additionally, thymulin reduces induced hyperalgesia in rats and mice.

TP5 reduces the susceptibility of aged mice to cutaneous leishmaniasis and modulates cytokine production by splenocytes from aged mice.

THFy2 injections in neonatally thymectomized mice restore myeloid colony formation. THFy2 reduces the metastatic load and restores immuno-competence in 3LL tumor-bearing mice receiving anticancer chemotherapy, raises the T cell activities in immunodeficient aging mice, and enhances the responsivenes of both CD4+ and CD8+ T cells to murine cytomegalovirus infection.

Tal and ProTa protect mice against opportunistic infection by Candida albicans, increase NK- and LAK-cell activity in tumor-bearing mice and stimu late the responsiveness to IL-2 in immunosuppressed mice. Tal enhances the fertilizing capacity of human sperm. It can be used in combination with an antiviral drug in controlling influenza virus. ProTa increases the production and release of migration inhibitory factor by mononuclear cells.

Clinical research

TPs have been used clinically as antiviral agents and in the immunotherapy of cancer. TP5 is a highly effective drug as an antiviral therapy in recurrent herpes simplex, herpes zoster and human papilloma virus infection, reducing the relapse rate. It has also been shown to be a safe and effective adjunct to therapy in patients with severe atopic dermatitis, in which it decreases the release of polymorphonuclear leukocyte-derived inflammatory mediators. TP5 is able to produce consistent clinical and immunological effects in melanoma patients with cutaneous metastases, and is a potentially useful agent in the treatment of a subgroup of patients with Sezarv syndrome.

Combination therapies with Tal are used in infections and tumors, for example, AZT, Ta 1 and IFNa in HIV patients. Tal is being used in clinical trials of head and neck cancer, advanced non-small-cell lung cancer and metastatic melanoma. Tal is being used in hepatitis B and C trials worldwide. Other thymic preparations such as thymostimulin (TP1) are used in combination therapies, for example in metastatic colon cancer.

See also: Aging and the immune system; Immune response; Immunopotentiation; Immunotherapy of tumors; Neuroendocrine regulation of immunity; Thymus; T lymphocyte differentiation; T lymphocytes; Zinc and the immune system.

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