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Neonatal thymus grafts. I. Studies on the regulation of the level of circulating thymic factor (FTS).

The level of circulating thymic factor (FTS) tested by its action on spleen rosette-forming cells from adult thymectomized mice, has been shown to be stable in young animals. This stability suggests a regulatory mechanism. An approach of this regulation has been attempted by disrupting the FTS level either by neonatal thymus grafting in adult normal and thymectomized animals, or by injections of synthetic thymic factor into normal, thymectomized mice, grafted or ungrafted. In all cases, after an initial increase over the normal value, FTS levels returned close to the previous range, indicating the existence of some homeostatic mechanism of FTS secretion.

Animals

Structural study of circulating thymic factor: a peptide isolated from pig serum. II. Amino acid sequence.

The amino acid sequence of a circulating thymic factor (FTS, facteur thymique sérique) isolated from pig serum has been established as less than Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn-OH. This sequence was obtained by Edman analysis both on the intact peptide and after tryptic digestion. The COOH-terminal residue was identified by carboxypeptidase A digestion. A synthetic peptide was prepared which showed the same biological activities as native pig circulating thymic factor, thus confirming the proposed primary structure.

Amino Acid Sequence

Thymic function in NZB mice. II. Regulatory influence of a circulating thymic factor on antibody production against polyvinylpyrrolidone in NZB mice.

Administration of a circulating thymic factor isolated from normal pig blood prevented the development of the exaggerated production of anti-polyvinyl pyrrolidone (PVP) antibody in young NZB mice. However, treatment was ineffective if initiated after the 4th week of life at a time when endogenous serum thymic factor (TF) normally disappears in these mice. These data suggest that circulating TF is necessary for the survival of short-lived suppressor T cells normally implicated in the regulation of the production of antibodies against PVP, a thymus-independent antigen. In older NZB mice, TF treatment increased paradoxically anti-PVP antibody production, which suggests that "amplifier" T cell activity could also be under TF influence.

Age Factors

Structural study of circulating thymic factor: a peptide isolated from pig serum. I. Isolation and purification.

A circulating thymic factor (FTS) has been characterized by a bioassay based on its ability to render theta-negative rosette-forming cells theta-positive and azathioprine-sensitive. FTS was sequentially purified and finally isolated from 1000 liters of pig serum by ultrafiltration, gel filtration, and ion exchange chromatography. Its amino acid composition and apparent molecular weight estimated by Sephadex G-25 chromatography, indicate that FTS is a nonapeptide of composition lysine, aspartic acid (or asparagine), serine 2, glutamic acid (or glutamine) 2, glycine 2, and alanine.

Amino Acids

Effects of antithymic reticuloepithelial cells serum on the levels of circulating thymic factor and on the sensitivity to azathioprine of spleen spontaneous rosette-forming cells.

Swiss mice treated with an antithymic reticuloepithelial cells serum (ATRES) showed a drastic and prolonged depression of the serum thymic factor. A similar but less pronounced effect was also observed following the administration of the antithymocyte (ATS) and the antilymphocyte (ALS) sera. Conversely, the azathioprine sensitivity of spleen spontaneous rosette-forming cells was highly modified by the ATRES but not by the ATS or the ALS. The probable mechanisms of such effects are discussed.

Animals

[Biochemical characterization of a circulating thymic factor].

A serum thymic factor has been isolated from pig serum. Its amino-acid sequence has been determined by Edman technique, modified by Gray: Gln-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn. A nonapeptide, synthesized on the basis of this sequence is active in the rosette assay used for the isolation of the biological product, both in vitro (10(-15) M) and in vivo (0.1 ng per Mouse).

Amino Acid Sequence

Ontogeny of thymus factor secretion.

The circulating thymic factor (TF) detected by 0-conversion assay has been followed up in ontogeny. Serum TF evaluation in pregnant thymectomized mice and in new born mice indicates that TF secretion starts on day 12-13 of foetal life and has reached the adult's level at birth.

Animals

[A chronological study of thymic crystalline inclusions and autoimmune disorders in Swan and NZB mice (author's transl)].

Swan and NZB mice represent good animal model for human systemic erythematosus with autoimmune phenomena (antinuclear antibodies, deposits of immunoglobulins in kidney and skin). The level of circulating thymic factor, responsible for T lymphocyte differenciation, falls during the first month of life in NZB mice, during the third month in Swan mice, during the sixth month in control mice (Swiss). In Swan mice, cytoplasmic crystalline inclusions have been found within the epithelial cells which are said to have a thymosine-like activity. The time-sequence of the appearance of the crystalline inclusions has been studied in relation to the development of autoimmune disorders (antinuclear antibodies, immunoglobulins in tissues). In each group of mice, the drop in circulating thymic factor appears before the appearance of crystalline inclusions and of autoimmunisation. Therefore, these crystals appear to represent a store of circulating thymosine-like factor or of a precursor in an ageing thymus.

Animals

[The production of immunomodulating polypeptides by the thymus during its acute (accidental) involution in children].

The content of the thymalin polypeptides in the thymus is studied in the course of the 1st to 4th stages of the acute thymus involution in children dying from noninfectious and infectious disease. The results obtained were compared to the level of the circulating thymic factor and the number of T- and 'O' lymphocytes in the circulating blood of children with identical diseases and control group of the same age. It is concluded that the acute involution of the thymus in children with non-infectious and acute infectious diseases results in the progressive decrease of the production by the thymus of the immunomodulating polypeptides (thymic hormones) which is restored in the period of recovery.

Acute Disease

Respective influence of extrinsic and intrinsic factors on the age-related decrease of thymic secretion.

The serum level of a circulating thymic factor (FTS) described in our laboratory diminishes in mice after adult thymectomy and with age. However, thymuses from old mice, when grafted into young adult thymectomized recipients lacking circulating FTS, can still partially restore the circulating FTS level of the recipients, whereas newborn thymuses are less efficient in restoring the serum level of FTS in old recipients than in young adult thymectomized recipients. Taken together, our results suggests that in addition to an intrinsic deficiency of the thymic secretion, "environmental" factors play a role in the disappearance of circulating FTS with age, the more so since we observed in old mouse sera factors inhibiting the in vitro biologic activity of FTS, factors that are absent from young mouse sera.

Aging

Thyroid function modulates thymic endocrine activity.

The thymus produces humoral factors that induce proliferation and differentiation of T-cells, which are responsible for cell-mediated immunity. Recent data in animals suggest that such thymic hormone activity is modulated by the neuroendocrine network and, in particular, by thyroid hormones, but no information is presently available in humans. To study this question, we measured the circulating thymic factor called thymulin (Zn-FTS) in hyperthyroid and hypothyroid patients. Thymulin levels were higher in hyperthyroid patients than in normal subjects, whereas hypothyroid patients had lower thymulin levels than normal subjects. A significant correlation was found between circulating thymulin and serum T4 and T3 levels. Thymulin changes could be reversed by appropriate treatment in both groups of patients. Recent data indicate that zinc is required to confer biological activity on thymic hormone molecules. This raised the question of whether the influence of thyroid status on thymulin activity could be mediated by changes in serum zinc concentrations. No support for such an explanation was obtained by thymulin measurements by a modified bioassay using an optimal zinc concentration in the assay system. In conclusion, thyroid status modulates thymic endocrine function in humans. Whether and to what extent such modulation is relevant to the function of the immune system remain to be established.

Adolescent