Effect of γ-butyrolactone derivative on an artificial membrane

trans-2-(6'Methylheptanol-1'-yl)-3-hydroxymethyl-4-butanolide(II) was shown to increase the passive flux of cations such as Co²⁺ through a black lipid membrane made from ox brain phospholipids. This membranotropic effect appears to be involved in the activity of II towards blocked mutants of streptomycetes as an autoregulator of cytodifferentiation.     

Calmodulin kinase II chimeras used to investigate the structural requirements for smooth muscle myosin light chain kinase autoinhibition and calmodulin-dependent activation

Segments of the autoregulatory domain of MK, a catalytically active fragment of the monomeric smooth muscle myosin light chain kinase (smMLCK) (residues 472-972), were replaced with their counterparts from a homologous but multimeric enzyme, calmodulin-dependent protein kinase II (CaM KII). Chimeric proteins in which both the autoregulatory and oligomerization domains of CaM KII (residues 281-478) were substituted for residues 781-972 of smMLCK, MK(CK281-478), or only the autoregulatory domain of CaM KII (residues 281-315) was exchanged for residues 781-813 of smMLCK, MK(CK281-315), exhibited significant enzymatic activity in the absence of Ca(2+)/CaM. In contrast, both MK and a chimeric protein in which the C-terminal half of the autoregulatory domain of smMLCK was replaced with CaM KII residues 301-315, MK(CK301-315), were inactive in the absence of Ca(2+)/CaM. These results indicate that the sequence of the N-terminal half of the autoregulatory domain of smMLCK is important for complete autoinhibition of its enzymatic activity. All proteins bound to Ca(2+)/CaM, and the chimeric proteins MK(CK281-478) and MK(CK281-315) were activated by Ca(2+)/CaM with activation constants (K(CaM)) and maximal enzymatic activities comparable to those of the wild-type MK enzyme. This demonstrates that the entire autoregulatory domain of CaM KII can replace that of smMLCK in its ability to promote efficient CaM-dependent activation of the smMLCK enzyme. However, the inability of the chimeric protein MK(CK301-315) to be activated by Ca(2+)/CaM suggests that replacement of only the C-terminal half of the autoregulatory domain of smMLCK, while still retaining the ability to bind Ca(2+)/CaM, also substitutes residues that prevent activation of the enzyme by Ca(2+)/CaM.     

The lipopolysaccharide-induced stimulation of peritoneal macrophages involves at least two signal pathways. Partial stimulation by lipid A precursors

Bacterial lipopolysaccharides (LPS) stimulate the ability of macrophages to convert arginine into ornithine. This effect is inhibited by the cycloxygenase inhibitor indomethacin and reconstituted by application of exogenous prostaglandin E2 (PGE2) or cholera toxin, i.e. two substances which are known to raise the intracellular concentration of cyclic AMP. Moreover, the LPS-mediated effect is augmented in a synergistic manner by PGE2, cholera toxin and the dibutyryl-derivative of cyclic AMP. Lipid A precursor IA, which lacks lauric, myristic and palmitic acids, and lipid A precursor IB, which is devoid of lauric and myristic acids of the complete lipid A structure, are capable of augmenting PGE2 synthesis but do not stimulate the conversion of arginine into ornithine. Taken together, our experiments suggest that the LPS-induced production of PGE2 and the PGE2-induced increase of the intracellular cAMP concentrations are essential elements of an autoregulatory loop that controls the LPS-mediated stimulation of the ornithine production by macrophages. The stimulation of the autoregulatory loop is necessary but not sufficient for this effect, indicating that an additional signal is required which is provided by the complete lipid A structure but not by the incomplete lipid A structures IA and IB. This additional signal can be provided by a lipid A structure containing the 3-acyloxyacyl residues with lauric and myristic acids.     

Incommensurate frequencies of major vascular regulatory mechanisms.

The dynamic relationship among three major vascular control mechanisms that operate on large fractions of cardiac output: arterial baroreflex and renal and mesenteric autoregulation, was investigated in conscious rats. Wistar and spontaneously hypertensive rats were studied in their home cages 10 days after implantation of pulsed Doppler flow probes. There was an oscillation of blood pressure centered at 0.45 Hz that is associated with operation of arterial baroreflexes. Hindquarters blood flow displayed a featureless, "1/f' power spectrum, in which no autoregulatory or baroreflex signatures could be discerned, although active control of resistance over a wide range of frequencies was evident. The renal pressure - flow transfer function was dominated by an autoregulatory mechanism with a resonance peak at 0.25 +/- 0.01 Hz. In the mesenteric circulation an autoregulatory mechanism was seen with a resonance peak at 0.15 +/- 0.01 Hz and another active mechanism was seen above 0.2 Hz that appeared from its negative admittance phase to be a baroreflex. The center frequencies of mesenteric and renal autoregulation and of the arterial baroreflex were related in a ratio of 1 : 1.7 +/- 0.1 : 3.0 +/- 0.2 (approximately 4:7:12). Such relatively high order ratios can be expected to minimize the possibility of phase locking and (or) entrainment among the various control mechanisms.     

Effects of mesenchyme of the embryonic urogenital sinus and neonatal seminal vesicle on the cytodifferentiation of the Dunning tumor: ultrastructural study.

The aim of the present study was to examine the effects of mesenchyme on the cytodifferentiation of the Dunning tumor (DT, R3327), a transplantable rat prostatic adenocarcinoma developed spontaneously from the dorsolateral prostate of a Copenhagen rat. Small pieces of DT were combined with mesenchyme of the rat urogenital sinus (18-day fetal, UGM) or seminal vesicle (0-day neonatal, SVM). Both types of combinations were grown under the kidney capsule of male athymic nude mice for 4 weeks. At harvest, the tissue recombinants were fixed and processed for electron microscopy. Grafts of parental DT were similarly processed for electron microscopy. The tumor was characterized by tubules lined by 2-3 layers of undifferentiated cells lacking secretory granules. The basal lamina was reduplicated, and epithelioid cells traversing gaps in the basal lamina were frequently observed. The stroma was composed of a mixture of fibroblastic and large epithelioid cells derived from the ductal lining epithelium through a process of micrometastasis. In UGM or SVM+DT combinations the mesenchyme influenced the differentiation and secretory activity of the DT epithelium. The induced DT epithelial cells exhibited a well-developed granular endoplasmic reticulum, a large Golgi apparatus and prominent secretory granules which were never observed in the parental DT. The basal lamina returned to normal, while the incidence of micrometastasis was decreased. The collagen content of the stroma was increased with a concurrent appearance of smooth muscle cells surrounding those tubules where secretory cytodifferentiation had occurred. While the mechanism involved in the mesenchyme-induced change in cytodifferentiation remains unknown, it is evident that the DT epithelial cells when associated with normal embryonic or neonatal mesenchyme can express a more normal cytodifferentiation and function. It is concluded (a) that the DT cells can be induced by mesenchyme to express more highly differentiated ultrastructural patterns and secretory cytodifferentiation, (b) that the induced secretory cytodifferentiation is associated with a reduction in invasiveness (micrometastasis) and a more normal-appearing basal lamina and (c) that the increased abundance of collagen fibers and the differentiation of smooth muscle in the stromal compartment are associated with secretory cytodifferentiation suggesting that reciprocal epithelial-mesenchymal interactions are involved in the regulation of the pathobiology of the DT.     

Embryonic mouse lung morphogenesis and type II cytodifferentiation in serumless, chemically defined medium using prolonged in vitro cultures

The timing, position and mechanism(s) for determining type II cytodifferentiation during mammalian lung development are not known. To approach this problem, we have cultured Theiler stage 16 embryonic B10.A strain mouse lung primordia (12-days gestation, E12) in serumless, chemically defined medium in the presence or absence of dexamethasone (DEX) for periods up to 27 days in vitro. Morphogenesis and cytodifferentiation were evaluated by light and transmission electron microscopy and immunochemical techniques. Pulmonary surfactant-associated apoproteins (PSAP) were initially expressed by type II cells at 16.5-day gestation in vivo. DEX-supplementation to the culture medium resulted in the accelerated expression of PSAP; the apoprotein isoforms (A1, A2, and A3) produced in vitro were comparable to those synthesized during fetal and postnatal in vivo development by high resolution, two-dimensional gel electrophoresis coupled with immunoblot staining. Cultures without DEX produced PSAP A2 and A3 isoforms, but did not produce A1 (26-31 kDa, pI 5.2-5.3). DEX-treated cultures produced more lamellar bodies within type II cells than non-treated controls. The results demonstrate that long-term cultures of embryonic lung primordia express morphogenesis, cytodifferentiation and the synthesis and secretion of PSAP in the absence of exogenous hormones or growth factors. The data set further supports the hypothesis that morphogenesis and type II cytodifferentiation are regulated by autocrine and paracrine factors intrinsic to the embryonic lung developmental program and independent of exogenous hormone controls.     

Reliability of autoregulatory mechanisms of biosystems as affected by ionizing radiation

Reliability of biosystems in processes of adaptation and homeostasis after whole-body irradiation of rats with different doses was determined in terms of the stochastic process theory developed for the autoregulatory systems with random parameters. Fluctuations in the rate of spontaneous chemiluminescence of blood serum and accumulation of lipid peroxidation products by erythrocyte membranes of rat blood were taken as the initial material. The analysis of fluctuations of peculiar parameters permitted to predict the adaptability of the system and to make timely corrections.     

The effects of nimodipine and L-NAME on coronary flow and oxidative stress parameters in isolated rat heart

The aim of this study was to assess the effects of Ca2+ channel antagonist nimodipine (in concentration which competitive inhibited phosphodiesterase 1--PDE1) on oxidative stress alone or under inhibition of nitric oxide synthase by L-NAME in isolated rat heart. The hearts from male Wistar albino rats (n=18, BM about 200 g, age 8 weeks) were retrograde perfused according to the Langendorff technique at gradually increased constant perfusion pressure conditions (CPP, 40-120 cm H2O). The experiments were performed under control conditions, in the presence of Nimodipine (2 microM) or Nimodipine (2 microM) plus L-NAME (30 microM). Coronary flow (CF) varied in the autoregulatory range from 3.7 +/- 0.4 ml/min/g wt at 50 cm H2O to 4.35 +/- 0.79 at 90 cm H2O. Basal nitrite outflow, index of lipid peroxidation (measured as TBARS release) and superoxide anion release (O2-) (at 60 cm H2O) were 0.64 +/- 0.18 nmol/min/g wt, 0.55 +/- 0.13 micromol/min/g wt and 19.72 +/- 3.70 nmol/min/g wt, respectively. Nimodipine induced significant vasodilation at all values of CPP (from 26% at 40 cm H2O to 36% at 120 cm H2O) accompanied with significant decrease of nitrite outflow (from 59% at 40 cm H2O to 40% at 120 cm H2O), significant increase of TBARS above autoregulatory range (about 40%) and significant increase of O2- release (from 186% at 40 cm H2O to 117% at 120 cm H2O). However, perfusion with L-NAME completely reversed the effects of Nimodipine. Nimodipine-induced flow changes were decreased under L-NAME (from 3% at 40 cm H2O to 11% at 120 cm H2O) without changes in the autoregulatory range, accompanied with significantly increased nitrite outflow (from 69% at 40 cm H2O to 36% at 120 cm H2O) and TBARS release (almost 50%), as well as significantly decreased O2- release (from 50% at 40 cm H2O to 43% at 120 cm H20). Our findings show that effect of nimodipine on coronary flow should be significantly influenced by NO, TBARS and O2- release in isolated rat heart.     

Lipid modification during cytodifferentiation of Tetrahymena vorax. Whole cell phospholipids and triacylglycerols of microstomal and macrostomal phenotypes

Microstomal cells of the ciliate Tetrahymena vorax V2S can be induced to undergo cytodifferentiation to form an alternate phenotype known as the macrostomal cell; however, sublines of T. vorax exist that respond differently to methods that induce macrostomal cell formation. The phospholipid- and triacylglycerol-bound fatty acid compositions of microstomal and macrostomal cells of a high-transforming subline (designated 3-C) were determined and compared to similar data from cells of a low-transforming subline (designated Ala). Differences in fatty acid composition were found between the two phenotypes as well as between the different sublines. Some change in the distribution of radioactive acetate and lauric acid into phospholipid classes of the different subline was observed, and evidence was also obtained that indicated changes in the relative amounts of the sterol-like pentacyclic triterpenoid tetrahymanol. A limited analysis of the lipid composition of stomatin revealed the presence of small amounts of tetrahymanol, phospholipid and free fatty acid. Stomatin is the naturally produced material obtained from T. pyriformis that triggers differentiation in T. vorax. The existence of a low-transforming subline provides a powerful experimental tool for elucidating the underlying biochemical and molecular mechanisms that control cytodifferentiation in T. vorax and possibly in other eukaryotic cells.     

Cone cells fail to develop normally in transgenic mice showing ablation of rod photoreceptor cells

Transgenic mice were derived containing the cytotoxic dt-α gene driven by opsin promoter sequences. Mice expressing this construct showed progressive degeneration of rod photoreceptor cells commencing at birth, with obvious depletion of such cells by postnatal day 7. Ablation of rod photoreceptor cells in the transgenic retina was accompanied by the failure of developing cone cells to elaborate outer segments, although all other aspects of cone cell cytodifferentiation appeared normal. The results suggest that the 1.0-kb opsin promoter segment contains rod cell type specificity and that cone cells require maturation of rod cells to complete the late stages of their terminal differentiation and for their maintenance and cellular integrity.     

Studies on dentin 2. transient vasodentin in the incisor teeth of a rodent (perognathus longimembris).

Vascular inclusions regularly occur in the lingual dentin of the constantly erupting teeth of the pocket mouse (P. longimembris). The inclusion of a capillary loop and surrounding perivascular tissues is associated with odontoblasts whose cytodifferentiation is relatively immature. These same cells produce dentinal tubules which are more irregular in their course, more arborescent, with more lateral branches, wider in diameter and less numerous than are the tubules of the labial orthodentin. The patent vascular inclusions are surrounded by a broad halo of incompletely mineralized dentin. With further maturation complete obliteration of the vessels occurs, accompanied by complete dental matrix mineralization. A literature review supports the contention that vasodentinogenesis is related operationally to lower stages of odontoblastic cytodifferentiation although the processes by which this occurs are not yet clear.     

Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: insights into autoregulation of a bifunctional enzyme.

The hepatic bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF-2-K/Fru-2,6-P2ase), E.C. 2.7-1-105/E.C. 3-1-3-46, is one member of a family of unique bifunctional proteins that catalyze the synthesis and degradation of the regulatory metabolite fructose-2,6-bisphosphate (Fru-2,6-P2). Fru-2,6-P2 is a potent activator of the glycolytic enzyme 6-phosphofructo-1-kinase and an inhibitor of the gluconeogenic enzyme fructose-1,6-bisphosphatase, and provides a switching mechanism between these two opposing pathways of hepatic carbohydrate metabolism. The activities of the hepatic 6PF-2-K/Fru-2,6-P2ase isoform are reciprocally regulated by a cyclic AMP-dependent protein kinase (cAPK)-catalyzed phosphorylation at a single NH2-terminal residue, Ser-32. Phosphorylation at Ser-32 inhibits the kinase and activates the bisphosphatase, in part through an electrostatic mechanism. Substitution of Asp for Ser-32 mimics the effects of cAPK-catalyzed phosphorylation. In the dephosphorylated homodimer, the NH2- and COOH-terminal tail regions also have an interaction with their respective active sites on the same subunit to produce an autoregulatory inhibition of the bisphosphatase and activation of the kinase. In support of this hypothesis, deletion of either the NH2- or COOH-terminal tail region, or both regions, leads to a disruption of these interactions with a maximal activation of the bisphosphatase. Inhibition of the kinase is observed with the NH2-truncated forms, in which there is also a diminution of cAPK phosphorylation to decrease the Km for Fru-6-P. Phosphorylation of the bifunctional enzyme by cAPK disrupts these autoregulatory interactions, resulting in inhibition of the kinase and activation of the bisphosphatase. Therefore, effects of cyclic AMP-dependent phosphorylation are mediated by a combination of electrostatic and autoregulatory control mechanisms.     

Residual morphogenetic competence in the proximal core region of stage 25 chick limbs: Zwilling's hypothesis revisited

Morphogenetic competence (MC) exists in embryonic limb tissue once thought to have lost this property as a consequence of cytodifferentiation. By stage 25 of chick embryonic development, cells in the proximal core of the limb have committed to the cartilage phenotype and are producing their characteristic extracellular matrix. Recombinant limb-bud grafts constructed using isolated fragments of this tissue produce outgrowths with a limb-like skeletal pattern. Inclusion of proximal peripheral tissue in the grafts (with or without the polarizing tissue) inhibits outgrowth and skeletal morphogenesis, explaining the failure of earlier studies to reveal the MC of the proximal core (chondrogenic) cells. Since definitive chondroblasts express MC in more permissive surroundings, it appears that Zwilling's assertion, that the onset of cytodifferentiation causes the loss of MC, is an oversimplification and that complex tissue interactions are probably involved.     

Developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. I. Stomach. A relationship to gastric carcinoma.

Studies were undertaken to provide information regarding cell-specific expression of mucin genes in stomach and their relation to developmental and neoplastic patterns of epithelial cytodifferentiation. In situ hybridization was used to study mRNA expression of eight mucin genes (MUC1-4, MUC5AC, MUC5B, MUC6, MUC7) in stomach of 13 human embryos and fetuses (8-27 weeks' gestation), comparing these with normal, metaplastic, and neoplastic adult tissues. These investigations have demonstrated that MUC1, MUC4, MUC5AC, MUC5B, and MUC6 are already expressed in the embryonic stomach at 8 weeks of gestation. MUC3 mRNA expression can be observed from 10.5 weeks of gestation. MUC2 is expressed at later stages, concomitant with mucous gland cytodifferentiation. Normal adult stomach is characterized by strong expression of MUC1, MUC5AC, and MUC6, less prominent MUC2, and sporadic MUC3 and MUC4, without MUC5B and MUC7. Intestinal metaplasia is characterized by an intestinal-type pattern with MUC2 and MUC3 mRNA expression. Gastric carcinomas exhibit altered mucin gene expression patterns with disappearance of MUC5AC and MUC6 mRNAs in some tumor glands, abnormal expression of MUC2, and reappearance of MUC5B mRNAs. In conclusion, we have observed that patterns of mucin gene expression in embryonic and fetal stomach could show similarities with some gastric carcinomas in adults. Differences in mucin gene expression in developmental, metaplastic, and neoplastic stomach compared to normal adult stomach suggest a possible regulatory role for their products in gastric epithelial cell proliferation and differentiation.     

In vitro studies on xylogenesis in citrus fruit vesicles. II. Effect of pH of the nutrient medium on the induction of cytodifferentiation

The initial pH of the nutrient medium influenced the type of cytodifferentiation occurring in cultured isolated fruit vesicles of Citrus limon (L) Burmann var. Assam lemon. Neither callus formation nor cytodifferentiation was found at pH values below 3.0. Three types of cytodifferentiation were found after 30 days culture in the presence of a liquid Murashige and Skoog (MS) basal medium supplemented with MS vitamins, indoleacetic acid (IAA) (10 mg/l), kinetin (0.2 mg/l), and sucrose (3% w/v): sclereids, xylem fibers and tracheary elements. The greatest numbers of sclereids and tracheary elements were found in callus grown on a medium with an initial pH 5.0–6.0, whereas pH 7.0 was optimal for the formation of xylem fibers.     

Interaction between L-arginine: no system and cyclooxygenase metabolic products of arachidonic acid in coronary autoregulation.

Coronary autoregulation (CA) is the intrinsic ability of the heart to maintain its nutritive blood supply constant over a wide range of perfusion pressure. This phenomenon is regulated through several control mechanisms, while metabolic and myogenic control mechanism have dominant effects. In last few years, endothelial control mechanism, which is part of metabolic control, was intensive investigated. Dominant topic of endothelial-investigation was bioregulatory L-arginine: NO system, with his effective product--nitric oxide (NO). On the other hand, cyclooxygenase metabolic pathway products of arachidonic acid plays an important role in the control of vasomotor tone of coronary arteries. For this purpose, the aim of our study was to evaluate role of L-arginine: NO system, cyclooxygenase metabolites of arachidonic acid, as well as, their interactions in the control of CA of the isolated rat heart.. In our study rat hearts autoregulate CF between 50 and 90 cm H2O of CPP. Basal release (at 60 cm H2O) of NO (as nitrite), cAMP, cGMP and HX+X (i.e. adenosine) amounted to 2.85+/-0.25 nmol/min/g wt, 29.45+/-2.22 pmol/min/g wt, 0.43+/-0.08 pmol/min/g wt and 37.50+/-2.89 nmol/min/g wt respectively. Release of NO, cAMP and cGMP were strictly parallel with CPP-CF curve, while release of adenosine (i.e. HX + X) was an inverse function of perfusion pressure. Inhibition of NOS (L-NAME, 30 micromol/l) significantly widened autoregulatory range (40-100 cm H2O), with significant reduction in CF and NO- and cGMP release, while release of cAMP was completely reversed in the presence of L-NAME. However, inhibition of cyclooxygenase didn't influence autoregulatory range, with similar changes of NO- and cAMP-release and completely inversed values of released adenosine. When L-NAME an indomethacin (an nonspecific COX-inhibitor), 3 micromol/l where added together, they exhibit interactions between these two enzymatic systems. Namely, when L-NAME was added first, indomethacin didn't influence hemodynamic effects of NOS-inhibitor. On the other hand, when COX-inhibitor was added first, L-NAME widened autoregulatory range in small manner as after control autoregulatory experiments (40-90 cm H2O). All hemodynamic changes were followed with similar changes in NO-release, what suggest that exist interaction between L-arginine: NO system and COX-metabolites in the regulation of coronary autoregulation.     

Temporal dissociation of developmental events in the chick eye under low temperature conditions

The chick embryonic eye is an excellent model for the study of vertebrate organogenesis. Key events in eye development involve thickening, invagination and cytodifferentiation of the lens primordium. While these events occur successively at different developmental stages, the extent to which these events are temporally related is largely unknown. Here we show that the lens invagination is highly sensitive to temperature. Lowering of incubation temperature to 29°C at embryonic day 2 delayed the onset of invagination of the lens, but not thickening and cytodifferentiation, leading to abnormal protrusion of the eye. The temperature shift also delayed the inward bending of the underlying retinal primordium, even in the absence of the lens. Taken together, our results suggest that lens invagination is initiated independently of thickening and cytodifferentiation, possibly by mechanisms associated with morphogenesis of the primordial retina.     

A BAR domain-mediated autoinhibitory mechanism for RhoGAPs of the GRAF family

The BAR (Bin/amphiphysin/Rvs) domain defines an emerging superfamily of proteins implicated in fundamental biological processes by sensing and inducing membrane curvature. We identified a novel autoregulatory function for the BAR domain of two related GAPs' (GTPase-activating proteins) of the GRAF (GTPase regulator associated with focal adhesion kinase) subfamily. We demonstrate that the N-terminal fragment of these GAPs including the BAR domain interacts directly with the GAP domain and inhibits its activity. Analysis of various BAR and GAP domains revealed that the BAR domain-mediated inhibition of these GAPs' function is highly specific. These GAPs, in their autoinhibited state, are able to bind and tubulate liposomes in vitro, and to generate lipid tubules in cells. Taken together, we identified BAR domains as cis-acting inhibitory elements that very likely mask the active sites of the GAP domains and thus prevent down-regulation of Rho proteins. Most remarkably, these BAR proteins represent a dual-site system with separate membrane-tubulation and GAP-inhibitory functions that operate simultaneously.     

On how monospecific memory-like autoregulatory CD8+ T cells can blunt diabetogenic autoimmunity: a computational approach

We have recently shown that during progression to autoimmune diabetes in NOD mice, memory autoreactive regulatory CD8(+) T cells arising from low-avidity precursors can be expanded to therapeutic levels using nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHCs). Here we examine the dynamics of memory autoregulatory CD8(+) T cells specific for islet-specific glucose-6-phosphatase catalytic subunit-related protein(206-214), a prevalent β cell autoantigen; their high-avidity counterparts (dominant effectors); and all other autoreactive non-islet-specific glucose-6-phosphatase catalytic subunit-related protein(206-214)-specific CD8(+) T cell specificities (subdominant effectors) in response to pMHC-coated nanoparticle (pMHC-nanoparticle) therapy. We combine experimental data with mathematical modeling to investigate the clonal competition dynamics of these T cell pools. To mimic the response diversity observed in NOD mice, we simulated many individual mice, using a wide range of parameters, and averaged the results as done experimentally. We find that under certain circumstances, pMHC-nanoparticle-induced expansion of autoregulatory CD8(+) T cells can effectively suppress the expansion of dominant and subdominant effectors simultaneously but, in some few cases, can lead to the substitution (or switching) of one effector population by another. The model supports the idea that disease suppression is based on the elimination of autoantigen-loaded APCs by the expanded autoregulatory CD8(+) T cells. The model also predicts that treatment strategies that operate by selectively inhibiting autoantigen-loaded APCs, such as the pMHC-nanoparticle approach, have the highest promise to blunt polyclonal, multiantigen-specific autoimmune responses in vivo without impairing systemic immunity.