High-dose Ag Research Articles

Ion emission from solid electrolyte CsAg4Br2.68I2.32 film deposited on Ag-tip: Characteristics and applications

We have developed a solid electrolyte ion source (SEIS) with CsAg4Br2.68I2.32 film deposited on a silver tip. In the paper, Ag+ ion emission was significantly enhanced and the ion current of 1.6 μA was obtained at 168 °C temperature and 20 kV accelerating voltage. I-T and I-U characteristics were well described by the field evaporation (FEV) model, and the surface potential barrier was estimated to be 0.19 eV. Experimental investigations of the Ag+ ion emission mechanisms revealed that the solid electrolyte film plays an important role of ion-transport system, and the emitted Ag+ ions were compensated by the ions diffusing from the silver reservoir (Ag-tip). The developed SEIS was exploited for the synthesis of Ag nanoparticles on Si surface. The average size of these nanoparticles was estimated 15.5 ± 0.3 nm, and the projected range Rp of the low-energy high-dose Ag+ ions implanted Si sample was found to be less than 5 nm using TOF-SIMS depth profiling. The future application of SEISs in ion propulsion systems of miniature spacecraft with limited on-board payloads was discussed, and the thrust was estimated within μN range.

Porous germanium formed by low energy high dose Ag+-ion implantation

A technical approach is proposed for the synthesis of thin porous PGe layers with Ag nanoparticles based on low-energy high-dose implantation of single-crystal c-Ge metal ions. To demonstrate a successes of this technique, we performed an Ag+-ion implantation of a polished c-Ge substrates with an energy of 30 keV at a dose of 1.5⋅1017 ion/cm2 and a current density of 5 μA/cm2. Methods of scanning electron and atomic force microscopy, as well as EDX analysis and electron backscattered diffraction was shown that as a result of the implantation on the c-Ge surface a porous amorphous PGe layer is formed of a spongy structure consisting of a network of intersecting Ge nanowires with an average diameter of ∼10–20 nm. At the ends of the nanowires, the synthesis of Ag nanoparticles is observed. It was found that the formation of pores during Ag+-ion implantation is accompanied by efficient spattering of the Ge surface.

Pulsed laser annealing of high-dose Ag+-ion implanted Si layer

The formation of a crystalline composite Ag:Si material with Ag nanoparticles by low-energy (E = 30 keV) high-dose (D = 1.5 × 1017 ion cm−2) Ag+ implantation into a monocrystalline c-Si substrate followed by nanosecond pulsed laser annealing (PLA) is demonstrated. Compared to traditional thermal annealing, PLA allows us to perform local heating of the sample both for its depth and area, and eliminate implantation-induced defects more efficiently, due to rapid liquid-phase recrystallization. Moreover, dopant diffusion during a nanosecond laser pulse is mainly limited by the molten region, where the dopant diffusion coefficient is several orders of magnitude higher than in the solid state. During PLA by a ruby laser (λ = 0.694 µm), the optical probing of the irradiated zone at λ = 1.064 µm with registration of time-dependent reflectivity R(t) was carried out. By scanning electron microscopy, it was established that Ag+ implantation leads to the creation of a thin amorphous Ag:Si layer of porous structure, containing Ag nanoparticles with sizes of 10–30 nm. PLA with energy density W = 1.2–1.8 J cm−2 results in the melting of the implanted layer (d ~ 60 nm) and the topmost layers of the c-Si substrate (d < 400 nm), followed by the rapid recrystallization of the Si matrix containing Ag nanoparticles with dominate sizes of 5–15 nm and some fraction of larger particles of 40–60 nm. Energy dispersive x-ray (EDX) spectroscopy did not show a noticeable change of Ag atomic concentration in the implanted layer after PLA. Spectral dependence R(λ) of Ag:Si layers showed the partial recovery of c-Si bands with maxima at 275 and 365 nm with simultaneous weakening of plasmon band for Ag nanoparticles in Si at 835 nm.

The formation of diffraction gratings by the deposition of SiO2 colloidal microspheres

A simple way of fabrication of diffraction gratings with the help of deposition of SiO2 colloidal particles on vertical glass substrate has been proposed. The method is based on an intermittent, “stick–slip” motion of the suspension meniscus during liquid evaporation. The deposition was carried out at different temperatures (from 27 to 50 °C). Ethanol-based suspensions with a SiO2 concentration in the range of 0.2–0.83 g/L, both narrow-dispersed with SiO2 particle diameter of about 200–300 nm and polydisperse, were used. As a result, the structures consisting of parallel ridges of deposited SiO2 microspheres repeating with a period of 140–200 μm and empty gaps between them have been prepared. The diffraction gratings formation is possible only at temperatures higher than the critical value of about 30 °C, and their period enhances with the temperature increase. The real diffraction patterns of light have been obtained for such structures for the first time. Further modification of prepared structures with the purpose of their strengthening has been realized with the help of high-dose Ag+ implantation (4 × 1016 ions/cm2, ion energy of 30 keV) followed by sonication.

T follicular helper, but not Th1, cell differentiation in the absence of conventional dendritic cells.

Development of long-lived humoral immunity is dependent on CXCR5-expressing T follicular helper (Tfh) cells, which develop concomitantly to effector Th cells that support cellular immunity. Conventional dendritic cells (cDCs) are critical APCs for initial priming of naive CD4(+) T cells but, importantly, also provide accessory signals that govern effector Th cell commitment. To define the accessory role of cDCs during the concurrent development of Tfh and effector Th1 cells, we performed high-dose Ag immunization in conjunction with the Th1-biased adjuvant polyinosinic:polycytidylic acid (pI:C). In the absence of cDCs, pI:C failed to induce Th1 cell commitment and IgG2c production. However, cDC depletion did not impair Tfh cell differentiation or germinal center formation, and long-lived IgG1 responses of unaltered affinity developed in mice lacking cDCs at the time point for immunization. Thus, cDCs are required for the pI:C-driven Th1 cell fate commitment but have no crucial accessory function in relation to Tfh cell differentiation.

Raman spectra observation of silver nanoparticles in porous silicon fabricated by ion implantation

Porous silicon layers fabricated by the low-energy high-dose Ag+-ion implantation of crystalline silicon with doses from 7.5 × 1016 to 1.5 × 1017 ion/cm2 are studied by Raman spectroscopy. Pores with sizes from ∼100–180 nm formed on irradiated silicon surface are controlled by scanning electron microcopy. Synthesized silver nanoparticles are observed in the structure of porous silicon. The sizes of pour and nanoparticles are increased with an increase in implantation dose. Acoustic vibrations generated by laser irradiation in silver nanoparticles of various sizes are registered by low-temperature Raman spectra of composite material.

The effects of salvianolate on NE、Ang-II and T-N？Finrats during the development of congestive heart failure

Objective To investigate the effects of salvianolate on noradrenaline（NE）, angiotension-Ⅱ（Ang-Ⅱ）and tumor necrosis factor-α（TNF-α）in rats with congestive heart failure. Methods Sixty male SD rats were randomly divided into 6 groups, the normal control group（NCG）, the model group, the captopril group（CAG）, the low dosage of salvianolate group（LSG）, the high dosage of salvianolate group（HSG）, the captopril and high doseage of salvianolate group（CSG）. The rats of Congestive Heart Failure were established＆amp;nbsp;with peritoneal injection of adriamycin except the rats in normal control group. The rats in normal control group were injected with the equal volume of normal saline once per week for 6 weeks. The medication was started in every group at the same time. Eight weeks later, the Left Ventricular Systolic Pressure（LVSP）, Left Ventricular End-diastolic Pressure（LVDP）, ＋dp/dtmax, -dp/dtmax were measured. The serum levels of NE, Ang-Ⅱ and TNF-αwere measured. Protein expressions of Ang-Ⅱ and TNF-αin cardiac muscle were detected by Western blot. Results Compared with the model group[（90.77±14.75）mmHg, （22.52±2.58）mmHg, （3 290.16± 109.61）mmHg/s, （3 114.07±112.39）mmHg/s], HSG[（114.10±13.71）mmHg, （19.97±1.14）mmHg, （3 504.97 ± 163.94）mmHg/s, （3 303.02 ± 121.98）mmHg/s ] and CSG [ （141.18 ± 15.42）mmHg, （15.58 ± 1.46）mmHg, （3 766.56±159.93）mmHg/s, （3 566.70±154.57）mmHg/s]had significant difference in LVSP, LVDP, ＋dp/dtmax, -dp/dtmax（P〈0.05 or 0.01）. Compared with the model group[（85.06±9.07）ng/ml, （180.11±25.45）pg/ml, （205.80±15.73）pg/ml], the serum levels of NE, Ang-Ⅱand TNF-αwere decreased in groups of HSG[（75.33±8.60）ng/ml, （149.21±25.39）pg/ml, （188.84±13.79）pg/ml], CAG[（71.49± 6.21）ng/ml, （139.15 ± 24.83）pg/ml, （183.73 ± 10.99）pg/ml ] and CSG [ （60.02 ± 7.38）ng/m, （110.68 ± 28.63）pg/ml, （165.93±16.22）pg/ml]in different degree（P〈0.05 or 0.01）, those of CSG were significantly lower than CAG（P〈0.05）. Compared with the model group[（1.043±0.044）, （1.167±0.048）], the expression of protein in Ang-Ⅱand TNF-α were decreased in groups of HSG[（0.981±0.024）, （1.069±0.055）]CAG [（0.954±0.031）, （1.046±0.053）]and CSG[（0.886±0.044）, （0.955±0.038）]in different degree（P〈0.05 or 0.01）, those of CSG were significantly lower than CAG（P〈0.05）. Conclusion Salvianolate can reduce the serum levels of NE, Ang-Ⅱand TNF-αin rats with congestive heart failure, decrease the expression of Ang-Ⅱand TNF-αin its cardiac muscle, improve the cardiac function. Key words: Salvianolate： Heart failure; NE; Ang-Ⅱ; TNF-α

Cytoprotective Effect of American Ginseng in a Rat Ethanol Gastric Ulcer Model

Panax quinquefolium L. (American Ginseng, AG) is one of the most popular herbal medicines in the World. We aimed to investigate whether chronic (28-day) supplementation with AG could protect against ethanol-induced ulcer in gastric tissue. Furthermore, we investigated the possible molecular mechanisms leading to AG-mediated gastric mucosal protection. We randomized 32 male Wistar rats into four groups for treatment (n = 8 per group): supplementation with water (vehicle) and low-dose (AG-1X), medium-dose (AG-2X) and high-dose (AG-5X) AG at 0, 250, 500, and 1250 mg/kg, respectively. In the first experiment, animals were fed vehicle or AG treatments for 4 weeks. At day 29, 75% ethanol was given orally to each animal at 10 mL/kg to induce gastric ulceration for 2 h. In a second experiment, animals were pretreated orally with each treatment for 1 hr before a single oral administration of ethanol (70%, 10 mL/kg). Trend analysis revealed that AG treatments inhibited ethanol-induced gastric mucosal damage. AG supplementation dose-dependently decreased the pro-inflammatory levels of interleukin 1β and cyclooxygenase 2 and the expression of pro-apoptotic proteins tBid, cytochrome C, and caspases-9 and -3 and increased the levels of anti-apoptotic proteins Bcl-2, Bcl-xL and p-Bad. AG could have pharmacological potential for treating gastric ulcer.

Pulmonary and Cardiovascular Responses of Rats to Inhalation of Silver Nanoparticles

Exposure to wet aerosols generated during use of spray products containing silver (Ag) has not been evaluated. The goal was to assess the potential for cardiopulmonary toxicity following an acute inhalation of wet silver colloid. Rats were exposed by inhalation to a low concentration (100 μg/m3 ) using an undiluted commercial antimicrobial product (20 mg/L total silver; approximately 33 nm mean aerodynamic diameter [MAD]) or to a higher concentration (1000 μg/m3) using a suspension (200 mg/L total silver; approximately 39 nm MAD) synthesized to possess a similar size distribution of Ag nanoparticles for 5 h. Estimated lung burdens from deposition models were 0, 1.4, or 14 μg Ag/rat after exposure to control aerosol, low, and high doses, respectively. At 1 and 7 d postexposure, the following parameters were monitored: pulmonary inflammation, lung cell toxicity, alveolar air/blood barrier damage, alveolar macrophage activity, blood cell differentials, responsiveness of tail artery to vasoconstrictor or vasodilatory agents, and heart rate and blood pressure in response to isoproterenol or norepinephrine, respectively. Changes in pulmonary or cardiovascular parameters were absent or nonsignificant at 1 or 7 d postexposure with the exceptions of increased blood monocytes 1 d after high-dose Ag exposure and decreased dilation of tail artery after stimulation, as well as elevated heart rate in response to isoproterenol 1 d after low-dose Ag exposure, possibly due to bioavailable ionic Ag in the commercial product. In summary, short-term inhalation of nano-Ag did not produce apparent marked acute toxicity in this animal model.

Oral administration of Ag suppresses Ag-induced allergic conjunctivitis in mice: critical timing and dose of Ag

Background/aimsTo investigate the effect of Ag doses and administration time points on oral tolerance induction in experimental allergic conjunctivitis (EAC).MethodsBALB/c mice were actively sensitised twice with ovalbumin (OVA) in alum,...

Supressor T cell–derived miRNA that acts in part via attached antigen specific Immunoglobulin and Prostaglandin-E2 (PGE2) (89.10)

Abstract Soluble antigen (Ag)-specific T cell-derived suppressive factor (TsF) of contact sensitivity (CS) is a small RNA, not a protein, induced in suppressor cells of spleen and nodes by high dose Ag iv tolerance; and is not IL-10 nor TGF-beta. The RNA TsF inhibits effector Th1 cells that elicit classical cutaneous CS and in vitro inhibits responsiveness of T cell lines to rIL-2; both in a paracrine manner; like exosomes containing specific mRNA and miRNA (Nature Cell Biol 9:654, '07). The TsF obtained by phenol chloroform extraction of cell supernatants, is degraded by RNase A, and RNase III (specific for ds RNA like pre-miRNA), but not DNase. It is in the RNA fraction from a Quiagen DNA/RNA separation column and about 75bp size (like pre-miRNA) on denaturing electrophoresis. The suppressive RNA TsF likely is associated with Ig (likely kappa light chain, Nat Med 8:694, '02) and PGE2 (Jo Im 150:2102, '93), that may account for Ag specificity and some suppression. The miRNA part of TsF, after uptake by target cells, may block translation via degrading mRNA encoding a protein in the IL-2 pathway, that is needed by CS Th1 effector cells. Thus, an Ag-specific TsF is dsRNA, associated with Ig light chain and inhibitory PGE2. This complex, released by a suppressor cell mix, perhaps via exosomes acts in a paracrine manner to target the effector T cells of CS, to intracellularly degrade mRNA translating protein of the IL-2 pathway, needed for effector T cells to elicit CS. Supported by grants from NAID, NIH, the Yale Molecular Hematology program, and the Polish Ministry of Science and Higher Education.

Bactericidal and corrosive properties of silver implanted TiN thin films coated on AISI317 stainless steel

The bactericidal and corrosive property of Ag +-implanted AISI317 stainless steel and TiN thin films coated on AISI317 substrate were investigated using Gram positive bacteria Staphylococcus aureus ( S. aureus) and electrochemical measurements. The silver ion implantation was performed with the dose ranging from 5 × 10 16 to 5 × 10 18 ions/cm 2 at an energy of 70 keV. The samples were characterized by X-ray Photoelectron Spectroscopy (XPS). The results indicate that the high dose Ag +-implanted samples show the antibacterial activity obviously but high dose implantation reduced the corrosion resistance correspondingly. There is an optimum ion dose of 1 × 10 18 ions/cm 2 at which both bactericidal and anticorrosion properties are kept complement. Based on some results on surface characterization, the mechanism of the antibacterial properties and corrosion resistance are discussed.

Aged Garlic Extract Has Potential Suppressive Effect on Colorectal Adenomas in Humans

Epidemiological and animal studies suggest AGE and its organosulfur constituents, such as S-allylcysteine and S-allylmercaptocysteine have anticarcinogenic effects. To confirm these effects in humans, a preliminary double-blind, randomized clinical trial using high-dose AGE (AGE 2.4 mL/d) as an active treatment and low-dose AGE (AGE 0.16 mL/d) as a control was performed on patients with colorectal adenomas-precancerous lesions of the large bowel. The study enrolled 51 patients who were diagnosed as carrying colorectal adenomas. The patients were randomly assigned to the two groups after adenomas larger than 5 mm in diameter were removed by polypectomy. The number and size of adenomas right before intake (0 mo) and at 6 and 12 mo after intake were measured using colonoscopy. Thirty-seven patients (19 in the active group, 18 in the control group) completed the study and were evaluated for the efficacy of AGE. The number of adenomas increased linearly in the control group from the beginning (the baseline), but AGE significantly suppressed both the size and number of colon adenomas in patients after 12 mo of high-dose treatment (P=0.04). The results suggest AGE suppresses progression of colorectal adenomas in humans. It appears that AGE has multiple pathways to reduce cancer incidence and suppress its growth and proliferation.

T cell hyporesponsiveness induced by oral administration of ovalbumin is associated with impaired NFAT nuclear translocation and p27kip1 degradation.

Oral tolerance is an important physiological component of the immune system whereby the organism avoids dangerous reactions such as hypersensitivity to ingested food proteins and other luminal Ags which may cause tissue damage and inflammation. In addition, it has been shown in animal models and in humans that oral tolerance can be applied to controlling undesired immune responses, including autoimmune diseases, allergies, and organ transplant rejections. However, the molecular mechanisms of oral tolerance have been poorly defined. In this study, we investigated the molecular basis underlying the hyporesponsiveness of orally tolerant CD4 T cells using a TCR transgenic mouse system in which oral tolerance was induced by long-term feeding with high dose Ag. We demonstrate that the hyporesponsive state of the CD4 T cells was maintained by a selective impairment in the TCR-induced calcium/NFAT signaling pathway and in the IL-2R-induced degradation of p27(kip1) and cell cycle progression. Thus, physiological mucosal tolerance is revealed to be associated with a unique type of T cell hyporesponsiveness which differs from previously described anergic T cells.

Immunomodulatory effects of the liver: deletion of activated CD4+ effector cells and suppression of IFN-gamma-producing cells after intravenous protein immunization.

The liver is tolerogenic in many situations, including as an allograft and during the response to allogeneic MHC expressed on hepatocytes. The majority of data that address this issue focus on endogenous Ags. Little is known about CD4(+) T cells and their fate under tolerizing conditions, especially with respect to fully differentiated CD4(+) effector T cells. In this study, we used the adoptive transfer of populations of TCR-transgenic CD4(+) T cells, skewed toward the Th1 or Th2 phenotype, to test whether either apoptotic or immune deviation mechanisms apply to cytokine-producing CD4(+) T cells that enter the liver. After transfer, Th1 and Th2 cells could be detected up to 25 days in lymphoid organs and the liver. Intravenous high dose Ag application resulted in accumulation, proliferation, and subsequent deletion of effector cells within the liver. Th1 cells lost their capacity to produce cytokines, whereas IL-4 expression was sustained within Th2 cells from the liver. However, there was no evidence for a deviation of Th1-programmed cells toward a Th2 (IL-4) or regulatory T cell (IL-10) pattern of cytokine expression. We used isolated populations of liver-derived APCs to test whether the liver had the capacity to impose a bias toward IL-4 expression in T cells. These experiments showed that liver sinusoidal endothelial cells selectively suppress the expansion of IFN-gamma-producing cells, yet they promote the outgrowth of IL-4-expressing Th2 cells, creating an immune suppressive milieu within this organ. These data suggest that presentation of Ags in the liver leads to modulation of immune response in terms of quantity and quality.

Molecular mechanisms of high-dose antigen therapy in experimental autoimmune encephalomyelitis: rapid induction of Th1-type cytokines and inducible nitric oxide synthase.

High-dose Ag administration induces apoptotic death of autoreactive T cells and is an effective therapy of experimental autoimmune diseases of the nervous system. To explore the role of cytokines in Ag-specific immunotherapy, we analyzed mRNA induction and protein expression for the proinflammatory cytokines TNF-alpha and IFN-gamma, the anti-inflammatory cytokine IL-10, and the cytokine-inducible NO synthase (iNOS) during high-dose Ag therapy of adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE) in the Lewis rat. Using semiquantitative and competitive RT-PCR, we found 5- to 6-fold induction of TNF-alpha mRNA and 3-fold induction of IFN-gamma mRNA in the spinal cord that occurred within 1 h after i.v. injection of Ag and was accompanied by a 2-fold increase of iNOS mRNA. Both IFN-gamma and iNOS mRNA remained elevated for at least 6 h, whereas TNF-alpha mRNA was already down-regulated 6 h after Ag injection. A comparable time course was found for circulating serum levels of TNF-alpha and IFN-gamma. IL-10 mRNA levels did not change significantly following Ag injection. Neutralization of TNF-alpha by anti-TNF-alpha antiserum in vivo led to a significant decrease in the rate of T cell and oligodendrocyte apoptosis induced by high-dose Ag administration, but did not change the beneficial clinical effect of Ag therapy. Our data suggest profound activation of proinflammatory but not of anti-inflammatory cytokine gene expression by high-dose Ag injection. Functionally, TNF-alpha contributes to increased apoptosis of both autoaggressive T cells and oligodendrocytes in the target organ and may thereby play a dual role in this model of Ag-specific therapy of CNS autoimmune diseases.

Gamma/delta T cells from tolerized alpha/beta-TCR-deficient mice antigen specifically inhibit contact sensitivity in vivo and IFN-gamma production in vitro.

Contact sensitivity (CS) responses to reactive hapten antigens (Ag), such as picryl chloride, are classical examples of T-cell-mediated immune responses in vivo. There is also abundant evidence that T cells exposed in vivo to high intravenous doses of Ag can downregulate CS (high-dose Ag tolerance). To clarify cell types that effect CS and mediate its downregulation, we have studied CS in mice congenitally deficient in alpha/beta T cells (alpha-/- mice). We show that alpha-/- mice cannot mount CS, implicating alpha/beta T cells as critical CS effector cells. However, after high-dose Ag tolerization, these alpha-/- mice can downregulate alpha/beta CS effector cells adoptively transferred to them. The active cells in tolerized alpha-/- mice are gamma/delta TCR+ cells which downregulate CS effector alpha/beta T cells Ag-specifically upon adoptive cell transfer. Moreover, gamma/delta cells can Ag-specifically downregulate IFN-gamma production by CS effector cells in vitro. These findings establish that gamma/delta T cells are not CS effector cells but downregulate CS, in agreement with recent reports that gamma/delta T cells downregulate IgE responses.

Gamma delta T cells from tolerized alpha beta T cell receptor (TCR)-deficient mice inhibit contact sensitivity-effector T cells in vivo, and their interferon-gamma production in vitro.

Contact sensitivity (CS) responses to reactive hapten Ag, such as picryl chloride (PCl) or oxazolone (OX), are classical examples of T cell-mediated immune responses in vivo that are clearly subject to multifaceted regulation. There is abundant evidence that downregulation of CS may be mediated by T cells exposed to high doses of Ag. This is termed high dose Ag tolerance. To clarify the T cell types that effect CS responses and mediate their downregulation, we have undertaken studies of CS in mice congenitally deficient in specific subsets of lymphocytes. The first such studies, using alpha beta T cell-deficient (TCR alpha -/-) mice, are presented here. The results clearly show that TCR alpha -/- mice cannot mount CS, implicating alpha beta T cells as the critical CS-effector cells. However, TCR alpha -/- mice can, after high dose tolerance, downregulate alpha +/+ CS-effector T cells adoptively transferred into them. By mixing ex vivo and then adoptive cell transfers in vivo, the active downregulatory cells in tolerized alpha -/- mice are shown to include gamma delta TCR+ cells that also can downregulate interferon-gamma production by the targeted CS-effector cells in vitro. Downregulation by gamma delta cells showed specificity for hapten, but was not restricted by the MHC. Together, these findings establish that gamma delta T cells cannot fulfill CS-effector functions performed by alpha beta T cells, but may fulfill an Ag-specific downregulatory role that may be directly comparable to reports of Ag-specific downregulation of IgE antibody responses by gamma delta T cells. Comparisons are likewise considered with downregulation by gamma delta T cells occurring in immune responses to pathogens, tumors, and allografts, and in systemic autoimmunity.

Induction of apoptosis by anti-CD3 epsilon F(ab')2 in antigen receptor transgenic murine T cells activated by specific peptide.

Peripheral T cell tolerance can be achieved through deletion of mature CD4+ cells activated by high dose Ag. We tested whether apoptosis of peripheral CD4+ cells could be induced by a stimulatory dose of Ag plus a soluble ligand to the nonpolymorphic epsilon-chain of the TCR-associated CD3 complex. CD4+ T cells from the DO10 mouse express a transgenic TCR-alphabeta specific for OVA peptide 323-339 presented by I-A(d). OVA alone induced clonal activation and expansion of peripheral CD4+/TCR transgene+ cells. Simultaneous exposure to specific Ag plus soluble anti-CD3 Fos, a nonmitogenic anti-CD3epsilon genetically engineered F(ab')2-like Ab, blocked expansion and induced death of CD4+/TCR transgene+ cells, but not CD4+/TCR transgene- T cells. In contrast, a mitogenic anti-CD3epsilon Ab induced polyclonal activation and nonselective T cell death. Sequential stimulation by Ag followed by anti-CD3 Fos also induced death of TCR transgene+ cells, whereas stimulation by anti-CD3 Fos followed by Ag did not affect cell viability or function. Anti-CD3 Fos-induced death was associated with DNA fragmentation characteristic of apoptosis, was facilitated by IL-2, and was initiated by stimulation during the S-G2 phases of the cell cycle. Anti-CD3 Fos could induce deletion of Ag-activated T cells by apoptosis in vivo. Thus, a soluble, non-Fc-binding anti-CD3 Ab can induce programmed cell death of Ag-activated peripheral CD4+ T cells by CD3epsilon cross-linking during S or G2. Peripheral T cell deletion by activation-driven apoptosis is under cell cycle control and can be exploited to achieve selective immunosuppression by nonmitogenic anti-CD3epsilon Abs.

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