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The role of the thymus in the modulation of T-cell function and in the release of various hormonelike factors (thymic hormones) has been the subject of major studies in a number of laboratories (Bach, 1983; Goldstein, 1993; Goldstein et al., 1982; Goldstein and White, 1971; Miller, 1961; Oates and Goldstein, 1991; Schulof et al., 1986,1988; Stutman, 1983; Trainin et al., 1979). It is well known that the thymus undergoes a gradual age-dependent involution during which the thymic parenchymal tissue is infiltrated with fat and adipose cells (Hammar, 1971). The thymus reaches its maximum size just before puberty and then gradually decreases in size and weight. The loss of hormone-producing epithelial cells begins early in life and by the second decade in humans, there is a substantial decrease in the number of hormone-containing medullary thymic epithelial cells. The number of hormone-containing thymic cortical epithelial cells also gradually decreases, although these cells can still be observed in the fifth decade of life (Hirokawa et al., 1982). The age-associated decrease in thymic hormone-like activity correlates with the decrease in hormone-containing thymic epithelial cells in both humans (Bach and Dardenne, 1972; Iwata et al., 1981; Lewis et al., 1978; Twomey et al., 1979; Wara and Amman, 1976) and animals (Dardenne et al., 1974; Hammar, 1971; Savino et al., 1983).

The secondary immunodeficiency present in advanced tumors justifies the use of biological response modifiers, like thymic hormones and/or Interferon (IFN)1.

The normal function of the immune system involves a myriad of synergistic interactions among cytokines of many types (e.g. lymphokines, monokines and thymic hormones). It seems then eminently logical that efforts to modify immune function with exogenous cytokines should involve the employment of combinations. It will be the intent of this chapter to summarize our recent efforts to employ combination therapy to restore and direct the thymus-dependent T cell system.

Although there is general agreement on the central role of immune anti-tumoral defences and on the possibility of using immunopotentiating substances in tumor therapy, the clinical use of these substances has not produced the expected results. Thus an amount of skepticism has arisen about the therapeutical potentiality of the immunostimulating substances and about the importance of the immune system itself towards neoplasia 1,2,3

The involution of the thymus gland and subsequent decline of thymic hormone serum levels is involved, to a considerable extent, in the development of age-associated immune deficiency (Weksler and Siskind, 1984). Thymus grafting or substitutive therapy with thymic hormones was reported to improve and/or restore age-associated immune defects in experimental animals (Doria et al., 1986).

As a series of methods were available for determination of serum thymic hormone-like activity (Bach and Dardenne, 1973; Astaldi et al., 1976; Lewis et al., 1981), studies were carried out by several researchers in order to determine modifications of thymic activity in different clinical and experimental conditions. This area of investigation has been considered of primary interest in the recent years for the following reasons: a) understanding the pathogenesis of several diseases; b) possibility of substitute therapy with thymic hormones; c) contribution to a better knowledge of the pathophysiology of the thymus.

T-cell differentiation proceeds under the command of several signals, among which thymic hormones (TH) play a central role. A number of T-cell abnormalities have been described in rheumatoid arthritis (RA), both by marker and functional studies. One may raise the question of thymic hormone production in RA and in related immunologic diseases such as systemic lupus erythematosus (SLE). Additionally, since thymic hormones can modulate T-cell functions, one may attempt to improve the clinical status of RA patients by using pharmacological doses of the hormones independently of a preexisting abnormality of thymic hormone production.

Prostaglandins have been implicated as possible mediators of the biological activity of thymic factors. Our recent studies reported that thymic hormones [i.e., thymosin fraction 5(TF5) and thymosin α1] restore lowered thymic functions, such as serum thymic-like activity (STA) and azathioprine (AZ) sensitivity of spontaneous rosette-forming cells (sRFC), when administered to adult thymectomized (ATx) mice (Garaci et al., 1981; Rinaldi-Garaci et al., 1982, 1983a). This effect was completely abolished by indomethacin administration, which is a potent inhibitor of prostaglandin biosynthesis. These data suggested that the action of thymic hormones would require prostaglandin biosynthesis.

Thymosin α1 is a peptide (MW 3108) originally isolated from calf thymosin fraction 5, a partially purified preparation of bovine thymus (Low and Goldstein, 1979). It is believed to be one of the thymic hormones secreted by the thymic epithelium (Kater et al., 1979; Dalakas et al., 1981; Hirokawa et al., 1982; Haynes et al., 1983) and has known biological properties in inducing differentiation and maturation of T lymphocytes in experimental animal models as well as in man (Zatz et al., 1982).

A number of laboratories have now isolated and purified thymic hormone-like factors from animal tissues and blood. These thymic hormones may have the potential to mature precursor lymphocytes to adult functioning cells. This effect could be advantageous for cancer patients to reverse the immunosuppressive effects of chemotherapy, radiotherapy, surgery, and of the tumor itself (W. Wara et al., 1975).

Several years ago, I (K.F.) listened to a lecture by Allan Goldstein on the thymic hormones, and he inspired me to initiate research in this field. I am pleased to thank and acknowledge Allan for his inspiration and leadership in the complicated research on the thymus and the immune system. After my initiation of efforts to isolate thymic hormones, I was also significantly influenced by the research of Nathan Trainin and his group in this field.

The mechanisms by which the thymus affects immune processes are still not defined. The role played by putative hormones produced by the thymus is one of the outstanding questions, and the evidence for the existence of such hormones is the main theme of this chapter; different aspects of the same topic have already been discussed in Chapters 18 and 19.

It is established that thymus-derived lymphocytes play a role in cell-mediated immunity and that hormones determine the development and expression of the immune response (1–3). The question in how far the postulated thymic hormones are involved in the formation of the T-cells and in expressing their capacities is far from clear. Also virtually nothing is known on the relation of the supposed thymic humoral factors and other endocrine glands. Since the development of the immune responsiveness and certain endocrine glands is interdependent» such a study is of importance.