Two recent studies (1, 2) have identified cells in human blood that fully resemble the dendritic cells described previously in mice and rats (3). Among other similarities, the human equivalent is Ia positive and Fc receptor negative, occurs in trace numbers (<1% of blood mononuclear cells), and acts as a potent stimulator of T cell proliferation in vitro. For example, preparations enriched in dendritic cells are 10-100 times more active than monocytes or lymphocytes in stimulating the syngeneic and allogeneic mixed leukocyte reactions (MLR) ~ as well as oxidative mitogenesis--the proliferation of periodate-modified T cells (1, 2). Therefore the prevailing concept that monocytes are the principal accessory cells in man must be reexamined.Monoclonal antibodies that distinguish macrophages from dendritic cells provide new probes for accessory or stimulator cells in the immune response. Selective depletion of murine dendritic cells, with specific antibody and complement, decreases accessory function dramatically (4-6). In man, antidendritic cell antibodies are not available, but alternative and useful reagents have been obtained. For example, 3C10 and 1 D9 are related antimacrophage antibodies that do not react with dendritic cells, while 9.3F10 is an anti-HLA class II reagent (7) that reacts with both cell types. In this paper, we use these monoclonals to study the requirements for T cell proliferation. T cell growth is severely reduced when accessory cells are depleted with 9.3F10 and complement, or when an Fab fragment of 9.3F10 is added to the culture. Positive and negative monocyte selection experiments, with the fluorescence-activated cell sorter and with complement-mediated cytolysis, indicate that monocytes contribute little if at all to accessory function. In contrast, highly enriched and monocyte-depleted dendritic cells are potent stimulators of the syngeneic and allogeneic MLR and the response to soluble tetanus toxoid. Monocytes and dendritic cells express similar levels of Ia antigens, however, indicating that class II products need to be expressed on dendritic cells to induce several T cell-proliferative responses in man.

BackgroundSRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD+-dependent deacetylase involved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucose metabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age-related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderly volunteers.MethodsOral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days. Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamic endpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI) for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magnetic resonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity.ResultsSRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally. Mean Tmax was 2–4 hours with elimination half-life of 15–20 hours. Serum cholesterol, LDL levels and triglycerides decreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for more rapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent with increased mitochondrial oxidative phosphorylation.ConclusionsSRT2104 can be safely administered in elderly individuals and has biological effects in humans that are consistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful in dose selection for future clinical trials in patients.Trial RegistrationClinicalTrials.gov NCT00964340

Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines. Neuroactive steroids (NAS), such as allopregnanolone, retain anticonvulsant activity in rodent models of benzodiazepine-resistant SE, perhaps because they modulate a broader variety of GABA receptor subtypes. SGE-516 is a novel, next generation NAS and a potent and selective GABA receptor positive allosteric modulator (PAM). The present study first established that SGE-516 reduced electrographic seizures in the rat lithium-pilocarpine model of pharmacoresistant SE. Then the anticonvulsant activity of SGE-516 was investigated in the soman-intoxication model of OPNA-induced SE. SGE-516 (5.6, 7.5, and 10mg/kg, IP) significantly reduced electrographic seizure activity compared to control when administered 20min after SE onset. When 10mg/kg SGE-516 was administered 40min after SE onset, seizure activity was still significantly reduced compared to control. In addition, all cohorts of rats treated with SGE-516 exhibited significantly reduced neuronal cell death as measured by FluoroJade B immunohistochemistry. These data suggest synthetic NASs that positively modulate both synaptic and extrasynaptic GABA receptors may be candidates for further study in the treatment of OPNA-induced SE.

The adjuvant properties of Micropolyspora faeni, an important source of antigenic material in the production of farmer’s lung, were evaluated by comparing antibody- and cell-mediated immune responses of rabbits to bovine serum albumin (BSA) incorporated in complete Freund’s adjuvant (CFA), incomplete Freund’s adjuvant (IFA) and incomplete Freund’s adjuvant with 5–10 mg/ml homogenized M. faeni (MFA). Rabbits immunized with BSA in CFA or MFA developed significantly increased antigen-induced macrophage migration inhibition, lymphocyte stimulation, and delayed skin reactivity when compared to those immunized with BSA in IFA. No similar adjuvant effect on specific antibody production was observed in rabbits immunized using BSA in MFA. These data suggest that M. faeni can act as a selective immunologic adjuvant for delayed hypersensitivity. This adjuvant property might be important in the induction of mononuclear cell infiltrates seen in human hypersensitivity pneumonitis.