Thymic hormones circulating levels

High levels of stress combined with lack of sleep or distorted wake/sleep cycles (e.g., shift work) leads to elevated levels of circulating cortisol. Cortisol depresses the synthesis and release of thymic hormones resulting in compromised development of T lymphocytes and a depressed immune response. Light inhibits the production of melatonin so its level falls when individuals have inadequate sleep. This reduces the melatonin-dependent inhibition of CRH release which amplifies the increase in circulating cortisol. The stress induced immunosuppression is therefore enhanced and prolonged. 

There are a number of other diseases that have been associated with aberrations of serum thymic hormone bioactivity, and these are listed in Table 1. It is noteworthy that serum thymic hormone bioactivity has been found to be low in 25% to 50% of patients with systemic lupus erythematosus (Bach et al., 1975 Twomey et al., 1979 Iwata et al., 1981 Lewis et al., 1981), Hodgkin s disease (Schulof et al., 1981), and acute lymphoblastic leukemia (Twomey et al., 1980). In all of these studies it has not been possible to correlate abnormalities of serum thymic hormone bioactivity with specific defects of T cell immunity. Thus, it remains to be established whether low serum thymic hormone levels in autoimmune or neoplastic disorders reflect an etiologic role for thymus dysfunction in these disease processes or merely a secondary manifestation of the diseases themselves. In patients with acute lymphoblastic leukemia it was demonstrated that the low bioactivity detected in the Twomey assay was related to a circulating inhibitor of thymopoietinlike bioactivity (Twomey et al., 1980). Thus, it is possible that other secondary immunodeficiencies that are associated with depressed serum thymic-hormonelike bioactivity may also reflect the presence of circulating inhibitors to thymic hormones rather than an absolute deficiency in their production. 

Serum thymosin Uj levels detected by RIA are approximately 10 times higher than those of circulating thymulin levels as determined by RIA (see Section 7.2.3). In addition, there are several differences between serum Tuj levels and thymulin levels in association with aging. First, the 3-fold decline of serum Tuj levels with age was not as dramatic as the 30-fold decline of serum thymic hormone activity determined in the various bioassays or in the thymulin RIA. In addition, serum Toj levels tend to drop abruptly in childhood and remain constant after age 20 and well past the sixth decade of life. 

Since the various thymic hormones have only recently entered clinical trials, there is little information available on circulating levels following parenteral administration in man. In their initial description of the rosette-azathioprine bioassay, Dardenne and Bach (1973) reported that after the intravenous injection of a crude thymosin fraction to adult thymectomized mice, transient serum thymic hormone bioactivity was demonstrable and peaked at 2 hours postinjection and disappeared after 48 hours. More recent studies using the rosette-azathioprine bioassay have indicated that FTS itself disappears rapidly from blood after intravenous administration, with a half-life of 15 minutes (Bach et al., 1978). The half-life of FTS could be prolonged by preincubation with serum from thymectomized mice or by binding to carboxymethyl cellulose. 

The ultimate significance of the thymic hormones is their potential clinical application for both the diagnosis and treatment of various immunodeficiency states. It had been hoped that the utilization of assays to detect low circulating thymic hormone levels would provide diagnostic tests for immunodeficiency diseases or more specifically for immunodeficiency diseases that would be responsive to thymic hormone administration. Unfortunately, since many different immunodeficiency states are characterized by abnormal circulating thymic hormone levels, neither high nor low levels are diagnostic of any specific disease entity. Furthermore, some diseases, sueh as SCID, may be associated with low serum thymic hormone aetivity but are not improved by parenteral thymic hormone administration. 

The cause of the T-cell depletion in peripheral blood is not certain. In preliminary unpublished studies Chandra and we (Keusch, Urrutia, Goldstein) have found that thymic hormones will induce the sheep erythrocyte rosette marker in vitro in PEM children with severely depressed T-cell numbers. There is also a suggestion of decreases in the level of circulating thymic hormone. However, the relevance of these findings to the process of T-cell maturation in PEM is uncertain, since the critical events undoubtedly take place within the thymic micro-environment itself and not in the periphery. However, Beatty and Dowdle (1978) have recently demonstrated that mitogenic responses of normal peripheral lymphocytes are suppressed in serum from Kwashiorkor patients compared to normal AB serum.. 

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