Thymic factor

Fok, K.-F., Ohga, K., Incefy, G.S., and Erickson, B.W. (1982) Antigenic specificity of two antibodies directed against the thymic hormone serum thymic factor (FTS). Mol. Immunol. 19, 1667-1673. 

Thymic factors are naturally occurring substances that promote T-lymphocyte differentiation and differentiation of early stem cells into prothymocytes. Each of the available preparations (e.g., thymic humoral factor, thymosin fraction 5, and thymodulin) are mixtures of several polypeptides isolated from a calf thymus extract. 

By promoting the formation of T lymphocytes, thymic factors are used to enhance T-lymphocytic functions. Thymic factors have been used with some success in clinical trials in patients with severe combined immunodeficiency, DiGeorge s or Nezelof s syndrome, and viral disorders. Studies with thymodulin show promise in treating symptoms in asthmatics and patients with allergic rhinitis. The primary consideration in the use of thymic factors for immunodeficiency states is the presence of T-lymphocyte precursors. 

Zinc deficiency may also be of importance in Down s syndrome (Fll). Thus, oral supplementation of DS patients increased their serum thymic factor (TF) levels, decreased the levels of inactive zinc-free TF, and significantly increased the number of circulating T-lymphocytes. In addition, these individuals had fewer infections. 

It is a thymic factor thought to play a crucial role in the later stages of T-lymphocyte maturation. It is claimed to have IMMUNOMODUIATOR and antiviral properties, and to protect against some radiation damage. It is active as a Zn-complex. 

Indeed, levamisole is now thought to be cleaved in vivo to yield dl-2-0X0-3-(2-mercaptoethyl)-5-phenylimidazoline (60J, which was reported to be more potent than the parent compound in enhancing carbon clearance in mice . Recent evidence concurs to indicate that both levamisole and thymic factors (Trainin s thymic humoral factor and G. Goldstein s thymopoietin) have similar effects on cAMP and cGMP in lymphomyeloid target cells increase of cAMP in precursor populations, increase of cGMP in mature effector cells. In view of the apparent similarities of the in vivo... 

With the development of more sophisticated immunologic assays, many changes in immunologic competence were demonstrable in animals soon after adult thymectomy. These included a decrease in proliferative responses of lymphocytes to T cell mitogens (Johnston and Wilson, 1970) and in mixed leukocyte response (MLR) (Robson and Schwarz, 1971). One major postthymic T cell subset that remains under the control of the thymus in the adult is the T suppressor cell. Within 2 to 4 weeks after adult thymeetomy there is a decrease in suppressor T cell activity, which can be restored by administration of various thymic factors (Zatz and Goldstein, 1972 Simpson... 

In this section we will review the biochemical and biologic properties of the well-characterized thymic preparations. It should be stressed that although many different thymic factors have been described that can induce T cell differentiation in vitro and/or in vivo in various experimental systems, very few have satisfied all of the requirements for categorization as true thymic hormones. Indeed, detailed thymectomy and thymus reimplantation studies to establish the absolute thymus dependency of circulating bioactivity have only been performed for thymulin (Bach et al., 1972 Bach and Dardenne, 1973). Although thymosin otj, thymosin P4, and thymopoietin are all detectable in serum, strict thymus dependency has not, at this time, been completely established. 

There is no apparent relationship between the amino acid composition of THF and other purified thymic factors. At the present time the primary amino acid sequence of THF has not been established, nor have the cells of origin of THF been identified. 

The concept that thymic hormones exist is now well accepted. However, many controversies still persist because of the multiplicity of different thymic products that have been isolated from thymus tissue over the past several decades. Many of the peptides appear to fulfill at least some of the accepted criteria for categorization as true thymic hormones. However, it is still unclear whether the various thymic polypeptides are components of a single thymic hormone (prohormone) that is capable of exhibiting the complete gamut of biologic properties ascribed to all of the different thymic peptides or whether each peptide alone or in certain combinations with other factors, at both intrathymic and extrathymic locations, regulates specific steps of T cell maturation. In this section we will review the biologic properties attributable to thymic factors in both animals and man. 

The nude mouse is the best experimental model for primary T cell immunodeficiency. This mutant strain has a congenital thymic aplasia resulting in absence of functional T cells and severely impaired immunity (De Sousa et al., 1969). Attempts to fully reconstitute such animals with thymic factors have been mostly unsuccessful, with the exception of one report (Ikehara et al., 1975). It is likely that lull immunologic reconstitution requires an intact thymus and development of progenitor T cells in the thymic microenvironment. 

Nevertheless, the influence of thymic factors on components of the immune response has still been analyzed by using this model. Thus, it has been shown that TP3 and Tp can induce expression of TdT in bone marrow and spleen cells from nude mice (Pazmino et al., 1978a,b) and that Toj can... 

A broad spectrum of T cell functions is modulated by thymic factors in various animal models and in some systems identical effects of several different factors have been observed (cf. Kruisbeek, 1975). Many of the functional assays employed are susceptible to extrinsic perturbations, thus making it difficult at times to establish a true inductive effect of the thymic factor as opposed to the nonspecific alteration of the optimal assay condition. Such pleiotropic effects of thymic factors with a variety of influences on the functions of both immature as well as mature T cells has created more controversy than clarity with regard to the precise role the thymus plays in the... 

Fig. 10. T-cell Differentiation in man. This figure summarizes the data presented in Sections 4.3.3 and 10.2 regarding the influence of well-defined thymic factors on T cell differentiation. The hypothesized sites of action of several thymic polypeptides are shown at the right.

A select group of studies has helped to shed light on the possible physiological mechanisms by which thymic factors control the expression of functional aspects of immunity. Probably the most consistent effect of thymic factors is their ability to induce suppressor T cell activity in various animal models. For example, TF5 has been shown to induce suppressor cell activity in spleen cells of nude mice for both antibody and cytotoxic T cell responses (Marshall et al., 1981 Ahmed et ah, 1978, 1979). Similar effects have been observed with several purified thymic peptides including Ta (Ahmed, 1978, 1979) and thymulin (summarized in Bach, 1983). Other thymic peptides, such as Taj, appear to be more associated with the generation of functional helper T cells. Similar helper inductive effects have also been observed with thymulin in both normal thymocytes and nude mouse spleen cells, which may result from its ability to enhance the production of T cell growth factor (interleukin-2, IL-2) (Palacios et ah, 1982 Palacios 1983). 

Thus, the bulk of evidence available to date would suggest at least in mice that the spleen contains a population of thymic hormone-responsive lymphoid cells that functions mainly in the suppression of immune responses, perhaps masking concomitant helper effects. In the thymus, the predominant effects of thymic peptides appear to be the induction of functional helper cells, possibly by the enhancement of lymphokine production. The effects of thymulin, thymosin, or other thymic factors on IL-2 production may indeed represent a major function of the endocrine thymus, since IL-2 has been shown to be a potent physiological promoter of T cell maturation (Ruscetti and Gallo, 1981). 

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