Bcl11b is required for differentiation and survival of alphabeta T lymphocytes

The gene Bcl11b, which encodes zinc finger proteins, and its paralog, Bcl11a, are associated with immune-system malignancies. We have generated Bcl11b-deficient mice that show a block at the CD4-CD8- double-negative stage of thymocyte development without any impairment in cells of B- or gammadelta T cell lineages. The Bcl11b-/- thymocytes showed unsuccessful recombination of V(beta) to D(beta) and lacked the pre-T cell receptor (TCR) complex on the cell surface, owing to the absence of Tcrb mRNA expression. In addition, we saw profound apoptosis in the thymus of neonatal Bcl11b-/- mice. These results suggest that Bcl11b is a key regulator of both differentiation and survival during thymocyte development.     

Blood flow velocity in the common carotid artery in humans during graded exercise on a treadmill

Cerebral blood volume flow and flow velocity have been reported to increase during dynamic exercise, but whether the two increase in parallel and whether both increases occur as functions of exercise intensity remain unsettled. In this study, blood flow velocity in the common carotid artery was measured using the Doppler ultrasound method in eight healthy male students during graded treadmill exercise. The exercise consisted of stepwise progressive increases and decreases in exercise intensity. The peak intensity corresponded to approximately 85% of maximal oxygen consumption. During this exercise, the heart rate (f _c), mean blood pressure (BP) in the brachial artery and mean blood flow velocity (_cc) in the common carotid artery increased as functions of exercise intensity. At the peak exercise intensity, (f _c), BP and _cc increased by 134.5%, 20.5% and 51.8% over the control levels before exercise (P < 0.01), respectively. The resistance index (RI) and pulsatility index (PI) were determined from the velocity profile and were expected to reflect the distal cerebral blood flow resistance. The RI and PI increased during the graded exercise, but tended to decrease at the highest levels of exercise intensity. As _cc increased with increases in exercise intensity it would be expected that cerebral blood flow would also increase at these higher intensities. It is also suggested that blood flow velocity in the cerebral artery does not proportionately reflect the cerebral blood flow during dynamic exercise, since the cerebral blood flow resistance changes.     

Immunohistological study of senile brains by using a monoclonal antibody recognizing β amyloid precursor protein: significance of granular deposits in relation with senile plaques

Summary Immunochemical analyses revealed that a monclonal antibody Am-3 recognized amyloid precursor protein (APP) in senile plaques extracted from Alzheimer's brain, but did not recognize amyloid protein. Immunohistochemically, however, the staining pattern of Am-3 in frozen section of Alzheimer's brain was almost the same with that of rabbit polyclonal antibody to amyloid peptide which could recognize both amyloid protein and APP. In other words, APP was present in senile plaques of various types, cerebrovascular amyloid and granular deposits. The granular deposits were 5–10 m in size and laminarily distributed in the 1st, 3rd and 4th layers of cerebral cortex. They were especially abundant in 1st and 4th layers where senile plaques were usually fewer in number. Although the distribution in the cerebral cortex was different between the senile plaques and the granular deposits, the number of the granular deposits was well correlated with that of senile plaques. The granular deposits were negative in Congo-red birefringence, but contained amyloid protein as well as APP fragment judging from positive staining by both Am-3 and polyclonal antibody to synthetic amyloid peptide. Thus, they could be regarded as pre-amyloid.     

The effect of sequential multiple grafting of syngeneic newborn thymus on the immune functions and life expectancy of aging mice

Enhancement of the immune functions and extension of the mean life expectancy were successfully performed in aging mice by sequential multiple grafting of syngeneic newborn thymus. In the first experiment, 2-month-old female C57BL/6 mice were grafted with either syngeneic newborn thymus or newborn spleen every 2 months, 5 or 6 times. A significant enhancement of T cell dependent immune functions were observed in the group sequentially grafted with newborn thymus, in comparison to that grafted with multiple sequential newborn spleen or with a single newborn thymus and that without a graft. In the second experiment, the same sequential grafting protocol was performed in middle aged mice at monthly interval for 4-5 consecutive months and the immune functions and survival rate were compared between the experimental and control groups. The immune functions were only partially rejuvenated, but an extension of the mean remaining life expectancy was observed in the experimental group (312 +/- 38 days) as compared with control (214 +/- 42 days), although maximal life-span was the same in both groups (1100 days).     

Radiation-induced-thymic lymphoma occurs in young,but not in old mice

Young mice exposed to fractionated whole-body irradiation develop thymic lymphoma. By using young and old mice, we examined the effect of age on the occurrence of radiation-induced thymic lymphoma in mice. In the first experiment, young and old mice were grafted with newborn thymus under kidney capsule and then treated with fractionated whole-body irradiation (FWI). In the second and third experiments, four combinations of bone marrow chimeras were constructed by transplanting bone marrow cells from young and old mice into young and old mice. Then these chimera mice were grafted with newborn thymus and treated with fractionated whole-body irradiation. The results in the present study indicate that the incidence of thymic lymphoma is influenced by age factors of thymic microenvironment, bone marrow, and host environment. If they are all young, the incidence of thymic lymphoma is high. If one of these is old, the incidence definitely decreases. Thymic lymphoma never occurred in old thymic environment even in the presence of young thymocytes. In conclusion, age advantage is present in the induction of thymic lymphoma after the treatment with FWI and the incidence definitely decreases in the presence of old factors.     

Hypertrophy of the thymus and restoration of immune functions in mice and rats by gonadectomy

Hypertrophy of the thymus was observed in aging C57BL/6 mice, ranging in age from 4 to 20 months, which had been gonadectomized 2 months before the sacrifice, and the magnitude of thymic regeneration was more pronounced in male than in female. However, enhancement of anti-SRBC antibody response was observed only in female, but not in male mice regardless of age. Gonadectomy brought about not only thymic hypertrophy but also an increase in T cells and B cells in the spleen. An increase in T cell subpopulations was proportional in female mice, but disproportional in male. The disproportional increase of T cell subpopulations could account for the failure to enhance the anti-SRBC antibody response in male mice. Gonadectomy also resulted in the thymic hypertrophy in male and female young Wistar rats, but not in those which had been previously hypophysectomized.     

Spontaneous development of autoimmune sialadenitis in aging BDF1 mice.

This study reports that spontaneous autoimmune sialadenitis developed in aging female, rather than male, BDF1 mice. The lesions first appeared in 6-month-old female BDF1 mice and were aggravated with advancing age, especially in 24-month-old and 30-month-old senescent mice. In contrast, significant inflammatory changes did not develop in aging male BDF1 mice. The presence of antisalivary duct antibody was found in sera from mice with sialadenitis. The infiltrating cells in the lesions of submandibular salivary glands were mainly composed of T cells, especially Lyt 1+ and L3T4+ cells. Moreover, mild inflammatory lesions were observed in parotid, sublingual salivary glands, pancreas, or kidneys in some mice that developed spontaneously occurring sialadenitis.