Fumimaro Oseko

The suppressive effect of deoxyspergualin on the differentiation of human B lymphocytes maturing into immunoglobulin-producing cells.

Deoxyspergualin, an analog of spergualin, has been known as a novel immunosuppressive agent with strong immunosuppressive activity in in vivo experimental systems. In the present study, we examined the effect of deoxyspergualin (DSG) and methyldeoxyspergualin (MeDSG) on the proliferation and differentiation of human B lymphocytes in vitro. Highly purified B cells from human tonsil samples were isolated by Percoll density gradient from nonrosetted cells and were used as target cells. Both agents had little effect on the proliferative response of resting or activated B lymphocytes. However, they suppressed the immunoglobulin synthesis of B lymphocytes not only in a T cell—dependent, but also in a T cell-independent system. The inhibition of antibody synthesis was manifested in the early stage of B cell differentiation. Both drugs also suppressed Ig secretion, but not proliferation, of an EBV-transformed human B lymphoblastoid cell line. These results indicate that DSG and MeDSG have a selective immunosuppressive effect on the differentiation pathway of B lymphocytes.

Bladder carcinoma associated with ectopic production of gonadotropin

A rare incidence of a primary gonadotropin‐producing bladder carcinoma in which gynecomastia appeared in the terminal stage was encountered in a 76‐year‐old Japanese male. There was a good probability that the symptoms of hormonal activity were due to chorionic gonadotropin (hCG), since its whole molecule, β‐ and α‐subunits were detected by radioimmunoassay in the blood, urine, and the tissue from the malignant neoplasm, and the plasma and urine estrogens were elevated. Recent papers concerning the synthesis of hCG‐like material by neoplastic cells are reviewed and the implication of the measurement of β‐ and α‐subunits of hCG in various neoplastic diseases are discussed. Other characteristic profiles of plasma hormonal levels are also discussed in this case. Cancer 42:2773–2780, 1978.

The distinct effects of FK506 on the activation, proliferation, and differentiation of human B lymphocytes

We examined the effect of FK506 on the activation, proliferation and differentiation of human B lymphocytes in vitro. FK506 inhibited the proliferative response of resting B cells induced by Staphylococcus aureua Cowan strain I (SAC) and phorbol myristate acetate (PMA) in a dose-dependent manner. Inhibition of cell proliferation by FK506 was caused by a selective block of GO to G1 phase transition leading to cell arrest. In addition, the proliferative response of in vivo–activated B cells and lymphokine-driven B cell proliferation were also found to be sensitive to FK506. Interestingly, FK506 did not affect the expression of activation antigens such as CD23, IL-2 receptor (CD25), and transferrin receptor (CD71). Finally, FK506 had little effect on B cell antibody generation in a T cell-independent system. Conversely, FK506 suppressed neither proliferation nor immunoglobulin secretion in a human B lymphoblastoid cell line. These results indicate that FK506 has discrete effects on the different stages of the B cell maturation.

A Role for Ferritin in Hematopoiesis and the Immune System

Elevated serum ferritin levels have been reported in a number of pathological states. These observations indicate that cells of the immune system can participate in the prevention of potential tissue toxicity from iron accumulation, and iron and iron-binding protein have important effects on immune systems. Ferritin is generally regarded as an intracellular iron storage protein. However, small amounts of ferritin circulate in the serum of normal individuals, and the physiological role of serum ferritin remains obscure. Although the function of ferritin is inevitably linked to iron metabolism, a role for ferritin in hematopoiesis and the immune system has drawn attention for years. Ferritin has an inhibitory effect on the in vitro growth of human hematopoietic progenitor cells and on the proliferation of T lymphocytes in vitro. Recently we report that ferritin may directly suppress the differentiation of human B lymphocytes maturing into antibody producing cells in vitro. In the present review, we summarise this field of research.

G-CSF enhances the immunoglobulin generation rather than the proliferation of human B lymphocytes

Abstract: The effect of granulocyte‐colony stimulating factor (G‐CSF) on human B‐cell function was studied in in vitro cultures. G‐CSF alone had no effect on the proliferative response of resting B cells, but it slightly enhanced the proliferative response of these cells in the presence of polyclonal B‐cell mitogen, Staphylococcus aureus Cowan strain I (SAC) at concentrations of 0.2 to 25 μg/ml (1.5‐fold increase in the DNA synthesis). In contrast, immunoglobulin (Ig) secretion of activated B cells was increased approximately three‐fold to four‐fold by adding G‐CSF to the cultures. The neutralization of G‐CSF bioactivity with anti‐G‐CSF antibody abrogated this effect. Though cytoplasmic Ig‐positive cells or plasma cell marker‐positive cells did not change, the expression of IgM mRNA in antibody‐producing B cells increased in the presence of G‐CSF in the cultures. Interestingly, human B lymphocytes are shown to express the binding to biotin‐conjugated G‐CSF preparation, but not to biotin‐conjugated GM‐CSF preparation when examined by flow cytometry. These data suggest that G‐CSF may influence B‐cell function in special circumstances.

Functional analysis of clonally expanded CD8,TCRγδ T cells in a patient with chronic T-Gamma lymphoproliferative disease

Abstract Leukemic cells from a patient with T-gamma lymphocytosis were found to have the surface phenotype, CD3 + , CD4 − , CD8 + , Leu19 + , TCRδ1 + , WT31. The clonal nature of the TCRγδ T cell proliferation was documented by flow cytometry and Southern blot analysis. Morphologically, they were large to medium-sized mature lymphocytes with cytoplasmic granules. Functionally, the cells revealed strong cytotoxic activities against NK-sensitive target cells, but had neither killer T cell activity nor suppressive activity on PWM-driven immunoglobulin synthesis by B cells. Interestingly, both suppressive and cytotoxic T cell activities were recovered with the depletion of CD8 + T cells. These studies may suggest some functions of the CD8 + population of human TCRγδ T cells in a normal immune system.

Effects of chronic bromocriptine-induced hypoprolactinemia on plasma testosterone responses to human chorionic gonadotropin stimulation in normal men

To study the role played by normal levels of plasma prolactin (PRL) in the secretion of testosterone (T) in the testes, we induced hypoprolactinemia with a daily dose of 5 mg bromocriptine administered orally in five normal men 20 to 35 years of age for 8 weeks. The basal PRL, T, luteinizing hormone, follicle-stimulating hormone, and maximum responses of plasma T to human chorionic gonadotropin (hCG) stimulation were measured every 2 weeks. Basal levels of plasma T were reduced in the 1st 2-week-long period of hypoprolactinemia. In the 4-week-long period of hypoprolactinemia, the maximal response of plasma T to hCG stimulation was significantly reduced. The findings suggest that normal levels of plasma PRL may play an important role in the secretion of T in the human testes in vivo.

Bestatin, an inhibitor of aminopeptidase B, suppresses the proliferation and differentiation of human C-cells in vitro

Bestatin, an inhibitor of aminopeptidase B, was examined for its effect on B-cell activation. Small, dense B-cells from human tonsil samples were isolated by Percoll density gradients from non-rosetted (E-) cells and were used as target cells. Although bestatin was not cytotoxic towards B-cells, it inhibited the proliferative response of B-cells induced by SAC- or PMA-stimulation. The inhibition of cell proliferation by bestatin was manifested as cell arrest caused by the selective block of G1b to S phase transition. This inhibitory effect was prevented by the addition of B-cell growth factor (BCGF) or interleukin-2 (IL-2). The presence of BCGF or IL-2 at the initiation of the culture prevented the bestatin-mediated suppressive effect on B-cell proliferation. Bestatin also has a direct inhibitory effect on the differentiation of B-cells independent of its suppressive effect on B-cell proliferation, which was not relieved by T-cell help. Conversely, bestatin suppressed neither proliferation nor Ig secretion of human B lymphoblastoid cell lines, although aminopeptidase activities on the membrane of these cell lines were strongly inhibited by bestatin. These results indicated that bestatin selectively suppressed normal B-cell proliferation and differentiation. Although several studies have demonstrated that bestatin has immunopotentiating effects in tumor-bearing subjects, the above results indicated that the mechanism of immunopotentiation by bestatin is not a direct stimulatory effect on B-cells.

Influence of chronic hyperprolactinemia induced by sulpiride on the hypothalamo-pituitary-testicular axis in normal men

For elucidation of the effects of hyperprolactinemia on the hypothalamic-pituitary-testicular axis, five healthy men were exposed to sulpiride (300 mg/day by mouth); four among the five maintained hyperprolactinemia (71.6 to 95.3 ng/ml) for 78 days. Clomiphene citrate (CC), luteinizing hormone (LH)-releasing hormone, and human chorionic gonadotropin tests were performed before and after sulpiride treatment. The CC test, given as a measure of hypothalamic function, was carried out in each of the five volunteers before sulpiride treatment (control) and on days 14 (2 weeks) and 60 (2 months) of sulpiride administration. Each value of plasma LH stimulated by CC was integrated and expressed as a ratio of the integrated value obtained after administering CC at 2 weeks and 2 months to that from each control experiment. The mean ratio in the four subjects at 2 months (mean +/- standard deviation, 0.769 +/- 0.121) was significantly lower than that at 2 weeks (0.942 +/- 0.073; P less than 0.05) and before sulpiride treatment (1.000; P less than 0.01). Impairment of LH responses to CC by 2-month long sulpiride-induced hyperprolactinemia suggests that chronic hyperprolactinemia in men partly suppresses LH secretion by its inhibitory action on the hypothalamus.

Diabetic Retinopathy in Acromegaly

A study was made of diabetic retinopathy in acromegaly. 10 of 15 patients with acromegaly had diabetes mellitus, and 3 of the 10 showed diabetic retinopathy. 2 of them had a diabetic family history. 1 patient with a diabetic family history had retinopathy of state IIIa in Scotts classification, and the other 2 showed a few microaneurysms and/or punctate hemorrhages in the macula. Diabetes mellitus and diabetic retinopathy in acromegaly showed no correlation with the duration of acromegaly and diabetes mellitus, age, or growth hormone level. No diabetic cataract was found in the present series. It was concluded that diabetic retinopathy due to secondary diabetes mellitus is usually slight or moderate. Diabetes mellitus with severe retinopathy is probably primary diabetes due to a genetic defect, and secondary diabetes may be different in nature from the primary disease.