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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.
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.
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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.
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.
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.
The contact sensitivity response to DNFB is decreased after adult thymectomy (ATX). This response decreases to 50% of the control response of normal age-matched mice as soon as 3 weeks after ATX and is not further depressed 9 to 16 weeks after ATX. These results suggest that two T cell subsets of different lifespan are involved in the anti-DNFB response. A circulating thymic factor (FTS) is able to restore the contact sensitivity response to DNFB when injected 3 to 9 weeks after ATX but not 16 weeks later. By contrast, FTS has a depressive effect on the contact sensitivity response to DNFB of normal mice through a cyclophosphamide-sensitive T cell subset. These results suggest that FTS regulates DNFB contact sensitivity by acting on a cyclophosphamide-sensitive T cell subset, still present 9 weeks after ATX but absent after 16 weeks. Thus although the T cell defect, causing a depression of the contact sensitivity reaction to DNFB is quantitatively similar 3 and 16 weeks after ATX, its nature is probably different.
Thymic function was evaluated by quantitation of circulating thymic factor in patients with several forms of severe infantile immunodeficiency diseases. Direct quantitation of thymic factor in serum of patients with severe combined immunodeficiency revealed heterogeneity of this syndrome by this parameter, as was also shown by study of susceptibility of the marrow cells to differentiation in vitro. Thymic factor was not detectable in one patient with severe combined immunodeficiency, but was present in normal or near-normal concentrations in three others. Circulating levels of this hormonal activity were also not detectable in a patient with DiGeorge athymic syndrome. Following marrow or fetal liver transplantation, which corrected the severe combined immunodeficiency thymic factor levels either increased slightly or did not change appreciably. Fetal thymic transplantation, which together with fetal liver transplantation corrected the immunodeficiency in one patient with severe combined immunodeficiency, was associated with increase of thymic factor to normal levels. Fetal thymus transplantation alone, which was employed to correct the immunodeficiency of DiGeorge athymic syndrome, caused an increase in thymic factor activity to normal or near normal levels in this patient.
Adult thymectomy, as well as ageing, depressed splenic lymphocyte-mediated cytotoxicity (LMC) in the mouse. Ageing depressed significantly LMC as early as 19 weeks of age, independently of the number of cells used for immunization. Thymectomy affected LMC only when supoptimal numbers of immunizing allogeneic cells were used. This effect peaked at 6 to 12 weeks after thymectomy. No difference between thymectomized and normal mice was observed when LMC was tested 16 to 20 weeks after thymectomy, at an age when normal control mice themselves already showed a lowered LMC due to ageing. The effect of in vivo treatment with a circulating thymic factor (TF), which was shown to disappear with ageing as well as after adult thymectomy, has been tested in adult thymectomized mice and normal young and ageing mice. TF treatment prevented LMC depression in adult thymectomized mice, whereas it depressed paradoxically splenic LMC in normal young and old mice. The possible mechanisms of the effects of adult thymectomy, ageing, and thymic factor on the different T cell subsets involved in allogeneic killer cell generation are discussed.
A small percentage of normal mouse thymus and spleen lymphocytes form rosettes with autologous erythrocytes. The number of these autologous rosettes increases 15- to 20-fold after adult thymectomy and to a lesser degree with aging. Autologous rosette level is also abnormally high in nude (congenitally athymic) mice. The high level of autologous rosette-forming cells found after adult thymectomy is normalized by injecting ng amounts of purified circulating thymic factor. Autologous rosette-forming cells adhere to nylon, belong to the less dense spleen cells, are in majority steroid-resistant in the thymus. All these properties suggest that autologous rosette-forming cells might belong to immature T-cell (thymic-dependent cell) precursors.
We have studied the effects of a circulating thymic factor (TF), cyclic AMP (cAMP) and prostaglandins on T-lymphocyte differentiation in the mouse using three parameters: 1) 0-bearing cell percentage evaluated by a cytotoxicity test with anti-0 serum (A0S) plus complement; 2) 0-antigen presence on rosette forming cells (RFC) assessed by the inhibition of rosette formation with A0S; 3) lymphocyte mediated cytotoxicity (LMC) against allogeneic target cells after in vivo sensitization, using a chromium release assay.
6 weeks after adult thymectomy (ATx) in the Mouse, the contact sensitivity reaction to dinitrofluorobenzene (DNFB) is enhanced. 4 to 7 months after ATx, this reaction is deeply, but incompletely depressed, whereas the concomitant antibody response is not affected. These results suggest that both a suppressor, and an amplifier, T lymphocytes, the life span of which is different after ATx, are involved in the regulation of contact sensitivity. The effect of circulating thymic factor on this reaction suggests that this factor acts exclusively, at least in short treatments, on the suppressor function.
The in vivo effect of a calf thymus extract, thymostimulin, on the levels of circulating immune complexes (CIC) and serum lysozyme was evaluated in 32 patients with untreated Hodgkin's disease. Using the platelet aggregation test for detecting CICs, 12 patients (37%) had positive titers before thymostimulin treatment; 3 patients (10%) remained positive following therapy. Serum levels of Clq-binding immune complexes were evaluated (greater than 24.5 micrograms/ml) in 8 patients prior to thymostimulin therapy (mean value: 42.3 micrograms/ml); 3 patients continued to have elevated levels after treatment. Serum lysozyme levels for Hodgkin's patients was similar to control values (10.6 vs. 8.3 micrograms/ml); however, the Hodgkin's patients with initially elevated CICs had a lower serum lysozyme level than patients with initially normal CICs (12.9 vs. 7.3, p less than 0.02). Thymostimulin increased serum lysozyme levels in the Hodgkin's patients in whom the CICs were initially elevated (7.3 vs. 10.4 micrograms/ml, p less than 0.05). These data suggest that thymostimulin exerts an effect on the nonspecific immune system of Hodgkin's disease patients.
The activity of thymus-dependent serum factor SF was significantly lower in 18 children wit Down's syndrome (DS) than in 14 matched controls. The percentage of circulating T lymphocytes forming E-rosettes was also low in DS. Together with the previous finding of immature of T lymphocytes in peripheral blood, the present data suggest that the basic immune defect of DS is failure in differentiation of peripheral post-thymic precursors to fully immunocompetent T lymphocytes resulting from lack of thymic hormonal factors.
The level of thymus serum factor (TSF) was studied in the circulation of adrenalectomized rats and in the administration of corticosteroids. The effect of adrenocortical hormones on the receptor properties of thymocytes by the ability of mast cells to form mastolymphocytic rosettes (MLR) with thymocytes was also studied. The TSF content was shown to decrease to the level observed in thymectomized animals 40 h after administration of 125 mg/kg hydrocortisone. The MLR amount formed by thymocytes decreased significantly either. Adrenalectomy mas accompanied by an increase in the TSF content early after operation and at later time the MLR amount rose. Sham adrenalectomy resulted in a decrease in the TSF amount early after operation.
By means of direct measurement of intracellular cyclic AMP in thymocytes in vitro we demonstrated the existence in human serum of a thymus-dependent factor (SF). This activity of SF appeared to be due to a very low M.W. (less than 500) peptide distinct from other circulating thymic peptides. SF was found to act selectively on immunologically immature, hydrocortisone (HC)-sensitive peanut lectin-agglutinating thymocytes. In a period of 240 min SF sequentially induces in thymocyte synthesis of cyclic AMP, protein synthesis and synthesis of phosphorylated non-histone chromatin proteins of high molecular weight. Because SF does not induce a change in DNA synthesis, it seems likely that the events induced by SF are associated with a process requiring DNA translation, but not DNA replication. The biochemical events induced by SF are accompanied by the acquisition of immunological maturation by thymocytes. This has been shown by the acquisition of HC resistance, by the expression of FC receptors for IgM, by the decrease of terminal transferase activity and by the induction of the capacity to elicit a graft-versus-host reaction. We conclude that, most likely, SF acts on immature thymocytes inducing a part of them to acquire some properties of mature T cells.
Immunoglobulin levels (IgG, IgA, IgM), percentage and number of circulating B and T lymphocytes, mitogen responsiveness (PHA and Con A) and activity of thymus-dependent serum factor (SF) were estimated in 29 patients with Turner's syndrome (TS), ranging in age from 2.2/12 to 18.4/12 yr. IgG and IgM were decreased in 14 and 12, respectively, while IgA was very low in 1, and increased in 7. Peripheral blood B and T lymphocytes, in vitro responsiveness to PHA, and Con A, and SF activity were in the normal range. The present immunological study suggests that TS is often associated with low levels of serum IgG and IgM. The possible mechanism of these derangements, whether genetic or hormonal (low estrogen/androgen ratio), is discussed.
We measured serum levels of Facteur Thymique Sérique (FTS) in 56 young cancer patients compared to normal controls. All patients who received immunosuppressive therapy had low age-corrected titres of FTS. Low levels were also found at diagnosis and off therapy. Plasma from 22 patients contained factors capable of inhibiting biological activity of FTS in vitro. The nature of this inhibitor has not been elucidated. No zinc deficiency was found in the patients studied, suggesting that FTS is secreted in its active form. Our study points out the importance of monitoring FTS activity in young cancer patients for its implications on immunological surveillance. The practical applications of thymic hormone therapy in cancer patients are discussed.