Biomedical subjects
M L Blue
Publications and source records attributed to M L Blue.
Class II major histocompatibility complex molecules regulate the development of the T4+T8- inducer phenotype of cultured human thymocytes.
We demonstrate that a variety of Ia+ cells has the ability to promote the development of human T4+T8- thymocytes in vitro. Prolonged thymocyte culture in the absence of Ia+ accessory cells results in a predominantly T8+T4- cell population. The generation of T4+ cells in the presence of irradiated Ia+ cells could be suppressed up to 70% by a monoclonal antibody directed against a nonpolymorphic epitope on HLA-DR. Using two-color fluorescence sorting techniques, we were able to identify the activated T4+T8+ thymocyte as the cell that interacts with Ia and gives rise to the T4+T8- cell subset. These results directly and specifically implicate class II major histocompatibility complex molecules in the differentiative pathway of the human thymocyte.
Coexpression of T4 and T8 on peripheral blood T cells demonstrated by two-color fluorescence flow cytometry.
Using two-color fluorescence flow cytometry, we were able to detect the presence of small numbers of T4+T8+ cells (about 3%) in freshly isolated peripheral T cell populations derived from normal healthy donors. Coexpression of T4 and T8 was predominantly found on large blastlike cells and appeared to be related to activation. Stimulation of peripheral T cells with concanavalin A (Con A) for 5 days resulted in the generation of up to 60% of T4+T8+ cells. Coexpression was accompanied by a twofold increase in the number of T8 antigenic sites per cell. The T4+T8+ cells in lectin-stimulated cultures expressed high levels of the activation antigens T9, T10, and the IL-2 receptor but lacked T6, an antigen found on a majority of stage II thymocytes. Coexpression of T4 and T8 appeared to be a transitory process, because prolonged culture of T cells in the absence of lectin resulted in the loss of the T4+T8+ phenotype. Our data suggest that T cell activation in peripheral blood results in the generation of a T4+T8+ cell population which is distinct from previously described thymic and peripheral blood cells. Because T4 and T8 molecules may interact directly with MHC antigens, coexpression of these molecules may have an important role in immune function.
Diabetes induction by subdiabetogenic doses of streptozotocin in BALB/cBOM mice. Noninvolvement of host B-lymphocyte functions.
Multiple subdiabetogenic doses of streptozotocin induce an insulin-dependent progressive hyperglycemia in genetically susceptible strains of mice. We have shown previously that T-cell-dependent autoimmune mechanisms play an obligatory role in this model of diabetogenesis by demonstrating that athymic nude mice and lethally irradiated euthymic mice are selectively resistant to diabetes induction and that the susceptibility can be reconstituted by grafting thymus in nude mice or by giving B-cell-depleted splenic lymphocytes to the irradiated mice. In this report we investigate more directly the possible role of host B-cell functions in the induction of hyperglycemia. Mice were rendered selectively deficient in functional B lymphocytes by repeated injections of a polyclonal antiserum against mouse IgM, starting immediately after birth. These B-cell-suppressed mice had no detectable ability to produce antibodies against a test antigen but appeared to have normal levels of T cells. When treated with multiple low doses of streptozotocin, they developed progressive hyperglycemia in a manner indistinguishable from control mice with normal B-cell functions. These results suggest that host B cells, in contrast to host T cells, are not etiologically involved in the development of diabetes induced by multiple subdiabetogenic doses of streptozotocin.
Use of immunodeficient mice in the study of experimental diabetes mellitus.
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Apolipoprotein E synthesis in human kidney, adrenal gland, and liver.
Human tissues were incubated in vitro with radiolabeled amino acids to determine whether plasma apolipoproteins are synthesized in human kidney. Subsequently, tissue extracts were screened with antisera directed against apolipoprotein E (apo E), apolipoprotein B (apo B), apolipoprotein AI (apo AI), and bulk apolipoproteins of high density lipoprotein (HDL). Newly synthesized apo E, but not apo AI or apo B, was identified in kidney and adrenal cortex. Estimates of relative rates of apo E synthesis in vitro suggest that a substantial portion of adrenal and kidney protein synthesis is committed to apo E synthesis. The relative rate of apo E synthesis was 4-6 times greater in kidney cortex than in kidney medulla. Analysis of immunoreactive apo E showed that kidney and adrenal apo E species have the same electrophoretic mobility in NaDodSO4/polyacrylamide gels as does plasma apo E. Further characterization by high resolution two-dimensional gel analysis indicated that the isoforms of newly synthesized kidney and adrenal apo E correspond to specific isoforms of plasma apo E. These findings suggest that apolipoproteins arising from peripheral tissues may play an important role in lipid transport and metabolism.
Synthesis of apolipoprotein AI by peripheral tissues of the rooster. A possible mechanism of cellular cholesterol efflux.
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Diabetes susceptibility of BALB/cBOM mice treated with streptozotocin. Inhibition by lethal irradiation and restoration by splenic lymphocytes.
In genetically susceptible strains of mice, repeated injections of a subdiabetogenic dose of streptozotocin induces the development of progressive insulin-dependent hyperglycemia. We showed previously that host T-cell functions play an obligatory etiologic role in this experimental disease by demonstrating that the athymic nude mouse is resistant to diabetes induction unless its T-cell functions are reconstituted by thymus graft (Paik et al., Proc. Natl. Acad. Sci. USA 77:6129-33, 1980). Here we show that lethal irradiation of euthymic (+/nu) mice of BALB/cBOM background causes selective resistance of the mice to the diabetogenic effects of the multiple low doses of streptozotocin without affecting their sensitivity to a high pharmacologic dose of the toxin. We also show that reconstitution of the irradiated mice with splenic lymphocytes causes the restoration of diabetes susceptibility. Lethally irradiated mice thus represent a useful experimental model for analyzing the host functions involved in the development of this disease. These results provide an additional support for the hypothesis that the induction of diabetes in this model system is mediated by an autoimmune amplification mechanism.
Induction of avian serum apolipoprotein II and vitellogenin by tamoxifen.
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Estrogen receptor and the development of estrogenic responses in embryonic chick liver.
We have examined the development of responsiveness to estrogen by embryonic chick liver with a view to determining common and unique factors involved in the establishment of different genomic responses to th e hormone. The major apoproteins of chick VLDL, apo VLDL-B and apo VLDL-II, both appear to be estrogen inducible at an earlier stage of of embryonic development than is vitellogenin. Apo VLDL-B, but not vitellogenin, exhibits a significant level of hepatic synthesis in the absence of estrogen treatment. This basal synthesis in the absence of estrogen treatment. This basal synthesis is tamoxifen-resistant and is detectable at very early stages of hepatic development, well before estrogen responsiveness is seen. Immunological cross-reactivity, electrophoretic behavior and the results of limited proteolysis mapping suggest that the apo VLDL-B synthesized under basal and estrogen-stimulated conditions is the same (or a very similar) protein. Inducibility of the VLDL apoproteins appears to parallel the appearance of the hepatic estrogen receptor system at days 10-12 while vitellogenin induction is delayed by several days. Cytosol receptor concentration undergoes a gradual increase up to the 19th day of development and thereafter declines. The properties of the 19-day receptor are very similar to those of cytosol receptor in hatched chickens, but the fall in concentration does not appear to be proportionately related to inducibility of estrogenic responses, as measured by the relative rates of synthesis in vitro.
Differential ontogeny of estrogen responsiveness in the chick embryo liver.
The development of estrogen responsiveness in embryonic chicken liver has been studied in terms of specific genomic responses to the hormone. Embryonated eggs were injected with estradiol at various stages of development, and after 48 h the hepatic synthesis of the apoproteins II and B of very low density lipoprotein (VLDL) was determined by incubation of liver slices with [3H]leucine and analysis of the tissue supernatant by specific immunoprecipitation. Significant estrogen induction of synthesis of apoprotein II of VLDL could be seen by the 11th day of embryonic development. The induction of apoprotein B, the other major apolipoprotein of VLDL, paralleled that of apoprotein II. It was reported earlier that the synthesis of vitellogenin did not become estrogen inducible until about the 15th day of embryonic development. The dissociation of the vitellogenin and apoprotein B responses can be confirmed by direct electrophoretic analysis of [3H]serine-labelled liver homogenates. The results are discussed in relation to the ontogeny of the estrogen receptor and the possible involvement of other controlling factors.
Biosynthesis of apolipoprotein B in rooster kidney, intestine, and liver.
After in vitro incubation with radiolabeled amino acids, extracts of various chicken tissues were screened for newly synthesized proteins reactive with antibody to plasma apolipoprotein B (apo B). An immunologically related protein was found in kidney as well as liver and intestine. This kidney protein showed the same mobility upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis as plasma apo B or pulse-labeled apo B made by liver or intestine. Partial proteolysis mapping with porcine elastase or V8 protease revealed nearly identical partial cleavage maps of pulse-labeled apo B from kidney, intestine, and liver. These data show that the kidney is a site of apo B synthesis and suggest that the kidney may be a significant source of plasma lipoproteins. Apo B synthesis was also detected in the distal small intestine and colon as well as in the proximal small intestine. The relative rate of apo B synthesis was 5% of total protein synthesis in the duodenum and decreased progressively to about 1% of protein synthesis in the colon. The synthesis of apo B in the distal small intestine and colon may indicate a similar capacity for dietary fat absorption via lipoprotein particles in all intestinal regions. The large intestine may be an additional source of plasma lipoproteins.
Possible mechanisms of emphysema in cigarette smokers. Release of elastase from human polymorphonuclear leukocytes by cigarette smoke condensate in vitro.
Human polymorphonuclear leukocytes, when incubated in vitro with cigarette smoke condensate, release beta-glucuronidase, acid phosphatase, and elastase and fail to exclude trypan blue. The released elastase is active on an elastin substrate even in the continuing presence of cigarette smoke condensate. When mixtures of human polymorphonuclear leukocytes and cigarette smoke condensate are instilled into rat lungs in vivo, the elastase is also released and can be traced to conneective tissue targets by immunohistochemical and enzyme-histochemical techniques.
Persistence of group A streptococci as related to penicillinase-producing staphylococci: comparison of penicillin V potassium and sodium nafcillin.
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