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Biomedical subjects

M H Frank

Publications and source records attributed to M H Frank.

12 recordsLinked to original sources
PubMed2006

P-glycoprotein functions as a differentiation switch in antigen presenting cell maturation.

P-glycoprotein (P-gp) expressed on human antigen presenting cells (APC) regulates alloantigen-dependent T-cell activation, but the associated mechanisms are not well understood. Here we demonstrate that P-gp functions in IL-12-dependent monocyte differentiation into dendritic cell (DC) lineages during APC maturation, thereby regulating the capacity of myeloid-derived APCs to elicit alloimmune Th1 responses. Human CD14+ monocytes cultured in vitro in the presence of IL-4/GM-CSF differentiated into CD14(-) CD1A+ APCs of the immature DC phenotype. In contrast, P-gp blockade during differentiation inhibited CD1a induction, down-regulated CD80 expression, enhanced CD86 expression and induced CD68 expression. APCs differentiated in the presence of P-gp blockade stimulated alloimmune T-cell proliferation significantly less than controls and this effect was associated with 97% inhibition of Th1 IFN-gamma production, but preserved Th2 IL-5 secretion. MAb-mediated blockade of the P-gp transport substrate IL-12 in the course of APC differentiation also inhibited IFN-gamma production, while addition of rIL-12 to P-gp-blocked APC differentiation cultures significantly reversed this effect, demonstrating that P-gp functions in APC differentiation in part via IL-12 regulation. Our findings define a novel role for P-gp as a differentiation switch in APC maturation and resultant alloimmune Th1 responses, thereby identifying P-gp as a potential novel therapeutic target in allotransplantation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

[Coagulation abnormalities and the dentist].

Defects in the coagulation system increase the risk of excessive bleeding during and after invasive dental procedures. This increased risk of bleeding is irrespective whether the coagulation disorder is inherited or acquired, for example by using anticoagulant medication. However, the cause of the coagulation disorder dictates preventive measures to be taken. Therefore, a careful medical history is crucial to identify and characterize patients with coagulation abnormalities. Recently, the insight in the mechanism of coagulation has increased considerably. This has resulted in specific procedures to adapt the level of coagulation required for specific invasive dental procedures. The dentist must discuss this temporary alteration of the coagulation level with the medical specialist of the patient.

Blood Coagulation↗
PubMed2005

Investigation of multidrug resistance in cultured human renal cell carcinoma cells by 31P-NMR spectroscopy and treatment survival assays.

KTCTL-26 and KTCTL-2 are renal cell carcinoma (RCC) lines with high and low expression of P-170 glycoprotein, respectively. Inherent differences between the two cell lines in terms of phosphate metabolites and growth characteristics in culture were examined for possible association with multidrug resistance (MDR). Differences in response to drug treatment were investigated for 40 h incubations with various doses of vinblastine (VBL) alone or as cotreatments with various concentrations of the calcium antagonist diltiazem (DIL) and/or interferon-alpha (IFN-alpha). Treatment effects were quantitated using the MTT survival assay and 31P magnetic resonance spectroscopy (MRS) to determine phosphate metabolite profiles in intact cells. KTCTL-2 and KTCTL-26 cells exhibited significant inherent differences in phosphocholine, glycerophosphocholine, glycerophosphoethanolamine, and phosphocreatine levels. KTCTL-26 cells were more sensitive than KTCTL-2 to 0.011 mircroM VBL alone (87% vs. 102% survival) or to 0.011 microM BL + 10 microM DIL (55% vs. 80% survival). The latter treatment resulted in a significant decrease in the ratio of phosphocholine to glycerophosphocholine in KTCTL-26 cells but no significant changes in phosphate metabolites in KTCTL-2 cells. Metabolomic 31P MRS detects different metabolite profiles for RCC cell lines with different MDR phenotypes and may be useful for noninvasive characterization of tumors in a clinical setting.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

P-glycoprotein--a novel therapeutic target for immunomodulation in clinical transplantation and autoimmunity?

P-glycoprotein, the human MDR1 gene product and cancer multidrug resistance-associated ATP-binding cassette transporter, is physiologically expressed on peripheral blood mononuclear cells, but its role in cellular immunity is only beginning to be elucidated. A role of P-glycoprotein in the secretion of several T cell- and antigen presenting cell-derived cytokines has been described, and additional functions of the molecule have been identified in lymphocyte survival and antigen presenting cell differentiation. Taken together, these findings provide compelling evidence that P-glycoprotein serves several distinct functions in the initiation of primary immune responses, and a critical role of the molecule in functional immune responses is now established. Here, we will review the current understanding of P-glycoprotein function in T cell activation and antigen presenting cell function, which are relevant to the fields of clinical transplantation and autoimmunity, and summarize the evidence for in vitro and in vivo immunomodulatory actions of several known P-glycoprotein-inhibiting agents currently in clinical use for other indications. We suggest that it is the P-glycoprotein-inhibitory function of many of these agents that underly their immunoregulatory capacities. Thus, the established immunoregulatory function of P-glycoprotein and the availability of P-glycoprotein-inhibitory drugs raise the possibility that P-glycoprotein may represent a promising novel therapeutic target for immune modulation in acute and chronic allograft rejection, and cell-mediated autoimmune disorders.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Specific MDR1 P-glycoprotein blockade inhibits human alloimmune T cell activation in vitro.

MDR1 P-glycoprotein (P-gp), the multidrug resistance-associated transmembrane transporter, is physiologically expressed by human peripheral immune cells, but its role in cell-mediated immunity remains poorly understood. Here, we demonstrate a novel role for P-gp in alloantigen-dependent human T cell activation. The pharmacologic P-gp inhibitor tamoxifen (1-10 microM) and the MDR1 P-gp-specific mAb Hyb-241 (1-20 microg/ml), which detected surface P-gp on 21% of human CD3(+) T cells and 84% of CD14(+) APCs in our studies, inhibited alloantigen-dependent, but not mitogen-dependent, T cell proliferation in a dose-dependent manner from 40-90% (p < 0.01). The specific inhibitory effect on alloimmune T cell activation was associated with >85% inhibition (p < 0.01) of IL-2, IFN-gamma, and TNF-alpha production in 48-h MLR coculture supernatants. Addition of recombinant human IL-2 (0.1-10 ng/ml) restored proliferation in tamoxifen-treated cocultures. Pretreatment of purified CD4(+) T cells with Hyb-241 mAb before coculture resulted in inhibition of CD4(+) T cellular IFN-gamma secretion. Also, blockade of P-gp on allogeneic APCs inhibited IL-12 secretion. Taken together these results demonstrate that P-gp is functional on both CD4(+) T cells and CD14(+) APCs, and that P-gp blockade may attenuate both IFN-gamma and IL-12 through a positive feedback loop. Our results define a novel role for P-gp in alloimmunity and thus raise the intriguing possibility that P-gp may represent a novel therapeutic target in allograft rejection.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Interferon alpha2b differentially affects proliferation of two human renal cell carcinoma cell lines differing in the P-glycoprotein-associated multidrug-resistant phenotype.

PURPOSE: Interferon alpha (IFNalpha) has been used in the immunotherapy of renal cell carcinoma (RCC), but the various mechanisms of its antiproliferative effects are poorly understood. Recent evidence suggests that IFNalpha is involved in the up-regulation of multidrug resistance (MDR) gene expression, and that the MDR gene product, P-glycoprotein (Pgp). facilitates the transport of several cytokines, some of which have been implicated in mediating tumor antiproliferative effects. We hypothesized that IFNalpha-induced antiproliferative activity may require Pgp-mediated transport, and that susceptibility to IFNalpha may thus correlate with Pgp expression. METHODS: Pgp expression by the human RCC cell lines KTCTL-2 and KTCTL-26 was characterized by immunofluorescence staining, using the Pgp-specific primary antibodies C219 and JSB1. KTCTL-2 and KTCTL-26 cell lines were subsequently treated with IFNalpha2b, and growth kinetics of treated and control cell cultures were determined daily by cell counting. RESULTS: KTCTL-2 expresses Pgp at low levels, whereas KTCTL-26 is a highly expressing cell line. IFNalpha2b treatment abrogated cell proliferation in KTCTL-26, whereas proliferation of KTCTL-2 was only partially inhibited. CONCLUSIONS: We have identified two RCC cell lines that differ in the MDR phenotype and exhibit different responses to the antiproliferative activity of IFNalpha2b. These preliminary findings raise the possibility that susceptibility to the antiproliferative effects of IFNalpha2b may correlate with Pgp expression, and further studies are warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1982

Effect of ramp slope on determination of aerobic parameters from the ramp exercise test.

The effect of ramp slope on determination of aerobic parameters from the ramp exercise test. Med. Sci. Sports Exercise, Vol. 14, No. 5, pp. 339-343, 1982. We have previously demonstrated that the four parameters of aerobic function (maximal oxygen uptake (muVO2), VO2 at the anaerobic threshold (theta an), the time constant for VO2 kinetics (tau VO2), and work efficiency (eta)) may all be determined reliably from a single test in which the work rate increases continuously at a constant rate, i.e., ramp. That study, however, utilized a single ramp slope of 50 W X min-1, which may not be appropriate for subjects with very low or very high work tolerances. We therefore studied the effect of different ramp slopes on the determination of these parameters. Ramp slopes of 20, 30, 50, and 100 W X min-1 were generated on a cycle ergometer, and each was assigned randomly to 14 healthy subjects. Ventilatory and gas exchange variables were measured breath-by-breath utilizing on-line digital computation. Ramp slopes of 20, 30, and 50 W X min-1 yielded the same values for each aerobic parameter. The 100 W X min-1 ramp yielded muVO2 and eta an values that were the same as those found for the other ramp slopes, but tau VO2 and eta could not be discerned validly from this ramp slope. We conclude that valid assessment of the four parameters of aerobic function is possible with ramp slopes between 20 and 50 W X min-1; no further information on the parameters is to be gained by prolonging the tests with ramps slower than 20 W X min-1.

Adult↗
PubMed1979

Anaerobic threshold alterations caused by endurance training in middle-aged men.

Nine previously sedentary middle-aged males underwent cycle endurance training 45 min/day for 9 wk with an average attendance of 4.1 days/wk. Seven males served as controls. Before and after the training period, the subjects performed three cycle ergometer tests. Work rate was incremented by 15 W/min, to the limit of the subjects' tolerance, in the first two tests; the third test consisted of contant-load cycling at an O2 uptake (VO2) just below the pretraining anaerobic threshold (AT). After training, the AT increased significantly by 44%, expressed as absolute VO2, and by 15%, expressed relative to VO2 max. Significant increases were also noted in VO2max (25%), maximal minute ventilation (19%), and maximal work rate (28%). The test-retest correlation coefficients for the AT (%VO2max) were 0.91, pre- and posttraining. Training did not alter steady-state VO2 during the submaximal exercise test whereas significant decreases occurred in CO2 output, VE, respiratory quotient, and VE/VO2. No changes occurred in the control subjects during this period. These results demonstrate that the AT is profoundly influenced by endurance training in previously sedentary middle-aged males.

Adult↗
PubMed1975

Cardiovascular chemoreflexes from the perfused innervated ileum of the cat.

The vascular supply of innervated segments of ileum in urethan-anesthetized cats was perfused by an electrolyte-glucose solution, containing heparinized cat blood. Addition of acetylcholine or nicotine to the perfusion inflow was followed by increases of systemic arterial pressure. Calculated mean concentrations of 32 mug/ml acetylcholine or 35 mug/ml nicotine in the perfusion fluid induced mean pressor responses of 19 and 23 mmHg. These responses began within 2-6 s, reached a maximum within 20 s, were unaffected by vagotomy, and were frequently accompanied by cardiac acceleration and increase in rate and depth of respiration. Evans blue in the perfusion fluid did not enter the general circulation. Systemic responses were abolished or markedly decreased after perfusion of 40-180 mg procaine through the innervated gut segments or by cooling the nerve fibers between the perfused ileum and the body of the animal. In itself, procaine injected into the isolated circulation or nerve cooling commonly induced decreases of arterial pressure. The vascular isolation of the perfused segments and the dependence of the systemic responses on the nervous connections indicate that the effects were reflex.

Acetylcholine↗