Genevieve S. Incefy

Circulating thymic hormone levels in zinc deficiency

Abstract The effect of zinc deficiency (Zn − ) on the circulating thymic hormone (FTS) levels in A/J mice was studied. After 3 weeks of feeding the mice a Zn − diet, FTS levels were markedly reduced and after 17 weeks, FTS was undetectable. By contrast, the zinc-supplemented (Zn + ) group seemed to maintain FTS levels better than the normal diet group with aging. On the other hand, spleen spontaneous rosette-forming cells (sRFC) were studied for their azathioprine (AZ) sensitivity in A/J mice on different diets. The Zn − mice had fewer sRFC than did the normally fed or Zn + mice. The role of zinc in controlling levels of FTS and thus thymic function is discussed.

Circulating thymic hormone activity in patients with primary and secondary immunodeficiency diseases

Abstract Levels of circulating thymic hormone, facteur thymique serique (FTS), were quantitated in the serum of normal subjects ranging in age from three days to 85 years and in a wide variety of patients with primary and secondary immunodeficiency diseases. FTS levels were low in the serum of a high proportion of patients with common variable immunodeficiency and selective absence or deficiency of IgA. Patients with DiGeorge syndrome always had low levels. In infants with severe combined immunodeficiency (SCID) FTS levels were low in 21 of 23 instances and normal in only two. In patients classified as having primary T-cell deficiency FTS levels were regularly lower than normal as in those with osteopetrosis and ataxia telangiectasia. In patients with Wiskott-Aldrich syndrome and chronic mucocutaneous candidiasis FTS levels were frequently lower than normal. In patients with systemic lupus erythematosus (SLE) FTS levels were below the normal range in the majority of instances, whereas FTS levels within the normal range were characteristic of patients with the X-linked infantile form of agammaglobulinemia (Brutons disease) and patients with progeria. Serums from seven patients were shown to inhibit FTS activity. Of these, serum from six patients with common variable immunodeficiency was studied for its capacity to inhibit synthetic FTS and FTS activity in normal serum. In two of these, FTS activity was inhibited in normal serum, and in five synthetic FTS activity was inhibited. Another patient with immunodeficiency, who had increased IgM levels and neutropenia, also had a serum inhibitor that was active against FTS. Search for an inhibitor of FTS in the serum of individual patients with SCID, chronic mucocutaneous candidiasis and a thymectomized infant revealed no such inhibition. Twenty-seven patients with common variable immunodeficiency were studied for both FTS activity and lymphocytic proliferative responses to phytomitogens and antigens. In 10 of these patients, FTS levels were low and in three of these 10 the responses to both mitogens and antigens were deficient; in four, responses were normal for both, and in three, the responses to antigen were low but the responses to mitogen were normal. In four of 27 patients with low FTS titers, however, an inhibitor against FTS activity was present in their serum, but their proliferative response to mitogens was normal and in two responses to antigens were reduced as well. This finding may explain the frequent dissociation of FTS activity and lymphocyte functions.

Multivariate analysis of T-cell functional defects and circulating serum factors in Hodgkin's disease.

A comprehensive immunologic and serologic analysis was performed on 31 untreated patients with Hodgkins disease. Immune evaluations stressed T‐cell functional activity and included traditional parameters (PHA responsiveness and delayed hypersensitivity skin reactivity), as well as newer functional assays (T‐cell colony formation, chemotaxis, spontaneous and antibody‐dependent cytotoxicity, and concanavalin A‐induced suppressor cell activity (CISA)). Serum factors included ferritin, prostaglandins, zinc, copper, immune complexes, and thymic hormone activity. Every patient exhibited at least one T‐cell or serum abnormality. The greatest percentage of patients exhibited T‐cell defects in chemotaxis (85%), colony formation (81%), and PHA reactivity (64%). Immune defects were more common with advanced disease but were not related to absolute T‐cell or monocyte count, skin test anergy, or abnormalities of Tμ/Tγ cell proportions. Linear relationships were identified among abnormalities in the three assays employing mononuclear cells (PHA, colony formation, CISA) which may have reflected the inhibitory influence of monocytes present in the mononuclear cell preparations. Low serum zinc correlated with marked impairment of T‐cell chemotaxis. Elevated prostaglandins were associated with high PHA reactivity and with depressed colony formation. Our results indicate that many complex factors, including intrinsic T‐cell defects, contribute to the impaired immunity associated with Hodgkins disease.

Zinc deficiency, depressed thymic hormones, and T lymphocyte dysfunction in patients with hypogammaglobulinemia

Abstract Zinc deficient humans and animals have depressed thymic mass and increased susceptibility to infection. In the present studies, we investigated the relationship between cellular immunity, thymic hormones, and serum zinc levels in 19 patients with common varied immunodeficiency. Five (26%) had serum zinc levels 2 SD below normal and 11 (58%) had abnormally low lymphocyte proliferation to at least one mitogen. A significant statistical correlation between zinc levels and lymphocyte proliferation to phytohemagglutinin and concanavalin A was identified. Forty-two percent had abnormally low levels of facteur thymique serique and 74% had low levels of thymopoietin, although no statistical relationship between the levels of these hormones, zinc levels, or lymphocyte proliferation could be identified. Three patients with the most profound zinc deficiency had substantial increases in thymic hormones after zinc repletion, and two had complete resolution of intractable diarrhea. A therapeutic potential of zinc for certain patients with hypogammaglobulinemia is suggested.

Effect of zinc deficiency on autologous rosette-forming cells.

Abstract Ability to form autologous rosettes (A-rosettes) is characteristic of a certain population of immature T cells, present in the thymus of various species including man. In mice, few A-rosettes are normally found in peripheral blood and spleen but their number increases markedly in spleen following thymectomy. In our studies, A-rosette formation could be demonstrated to be significantly enhanced in the spleen of C57B1/Ks mice after the animals had been maintained 3, 6, and 8 weeks on a zinc-deficient diet (Zn − ) and to increase progressively with duration of feeding the Zn − diet. These changes were quickly reversed by feeding a normal diet containing zinc but could not be eliminated by complete adrenalectomy, a finding that ruled out their dependence on pituitary-adrenal as is function attributable to stress. Pair-fed controls and mice fed a zinc-supplemented diet ad libitum showed few A-rosettes, as expected.

EFFECT OF THYMIC FACTORS ON THE DIFFERENTIATION OF HUMAN MARROW CELLS INTO T‐LYMPHOCYTES IN VITRO IN NORMALS AND PATIENTS WITH IMMUNODEFICIENCIES*

Immune functions can be restored by thymus grafting in neonatally thymectomized animals, nude mice, and in patients with DiGeorge syndrome.’-’ In these situations, unlike in stem-cell deficiencies, the newly developed T-lymphocytes usually bear markers of the recipient,5q6 thus suggesting that the reconstitution has not involved a proliferation of the donor’s thymocytes but rather the “induction” of differentiation into T-lymphocytes from the recipient’s precursor cells. That such an effect was in part under the dependence of diffusible humoral factors, has been suggested by the restoration of some immunological functions when the thymus graft was placed in a Millipore@ diffusion chamber or when injection of acellular extracts was performed instead of the organ graft.* Although some controversy still exists on that matter: the investigation of the in vivo and in vitro effects of thymic extracts or factors has been extensively carried out over the past years. Recent studies in the mouse have shown that a fraction of spleen or bone marrow cells can acquire T-lymphocyte characteristics in vitro after a short incubation with thymic extracts lo, l1 or with a serum factor of thymic origin.I? We have obtained similar results in man,I3 thus providing a means for the study of differentiation of human lymphocytes and for the analysis of various immunodeficiency diseases.”, l8

Radioimmunoassays for the thymic hormone serum thymic factor (FTS).

Four radioimmunoassays (RIA) are described for the quantitation of serum thymic factor (facteur thymique serique, FTS), a thymic peptide hormone. Each assay employs an antibody specific for FTS, synthetic FTS (Glp-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn) as the hormone standard, and a radioiodinated FTS analogue as the tracer. Since FTS lacks a tyrosine residue, 2 FTS analogues were synthesized by the solid-phase method with tyrosyl-alanyl or 3-(2,6-dichlorobenzyl)tyrosyl-alanyl in place of the amino-terminal pyroglutamyl residue (Glp). They showed full FTS immunoreactivity and their radioiodinated derivatives served as FTS tracers. Two assays used the antiserum from a rabbit immunized with an FTS-protein conjugate. Two other assays used a monoclonal antibody against FTS produced by a hybridoma derived from mouse myeloma cells and splenocytes from a BALB/c mouse immunized with an FTS-mouse IgG conjugate (Ohga et al., 1982). All 4 RIAs were specific for FTS. The more sensitive rabbit antiserum can detect as little as 1 pg of FTS in a 50 microliters sample, which may allow quantitation of the FTS circulating in human peripheral blood.

Circulating thymic factor, facteur thymique serique (FTS), in mycosis fungoides and Sezary syndrome.

Abstract Levels of Facteur Thymique Serique (FTS) were measured by rosette inhibition assay in the sera of patients with mycosis fungoides (MF) and Sezary syndrome (SS). Increased levels of FTS were detected in 15 of 23 patients with MF. Two patients with SS showed normal values. The biological activity quantitated in the serum was shown by specific immunoabsorption using anti-FTS antibodies to be due to FTS and not to allogeneic factors (AF).

Interaction between thymopoietin and facteur thymique serique in the rosette inhibition assay

Abstract In the rosette inhibition assay, thymopoietin was active and its activity was enhanced in the presence of high concentrations of ubiquitin. Facteur thymique serique (FTS) was active in the same assay, but its activity was completely inhibited by high concentrations of ubiquitin. Mixtures of thymopoietin and FTS showed activity both in the presence or absence of ubiquitin depending on the concentration of thymopoietin or FTS in the mixtures. There seemed to be an important biologic interaction of thymopoietin and FTS when presented as a mixture, suggesting that thymopoietin and FTS might interact in vitro and possibly in vivo .

T-lymphocyte differentiation in vitro in primary immunodeficiency diseases☆

Abstract The effect of thymus extract on the development of cell surface antigenicity in two patients with primary immunodeficiency was studied and compared. A stem cell fraction from bone marrow preparations of a patient with severe combined immunodeficiency failed to develop cells with antigenic markers of T-lymphocytes while that of a patient with common variable form of immunodeficiency who had both severe functional deficits of T-lymphocytes and agammaglobulinemia developed cells with such markers after treatment with thymus extract. These findings indicate that the two forms of severe combined immunodeficiency disease studied have different bases which may be reflected in differences of response to differentiative influence of thymus extract.