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PubMed1992

Influence of glucose on metabolism and growth of rat glioma cells (C6) in multicellular spheroid culture.

The metabolism and growth of rat glioma C6 cells in multicellular spheroid culture depended strongly on the glucose supply. A low glucose level (0.1 g/l) in the culture medium reduced lactate production, increased oxygen consumption and diminished hydrogen ion production under normoxia as well as hypoxia. A high glucose level (10 g/l glucose) increased lactate production, had no significant influence on oxygen consumption and increased the hydrogen ion production under hypoxia. Hydrogen ion release from cells under normoxic and hypoxic conditions could be significantly diminished by amiloride (l mM), indicating the involvement of the Na+/H+ exchanger. The growth of the C6 spheroids was enhanced under low glucose conditions, possibly due to the more physiological extracellular pH in the deeper regions of the spheroids. The growth was inhibited under high glucose conditions, which seemed to be toxic due to a massive hydrogen production giving acidosis. The glucose supply strongly influenced the local hydrogen ion production inside the C6 spheroids and this might in turn lead to changes in the response to different therapeutic modalities.

Animals↗
PubMed1992

Production of stable phenotypes from 9L rat brain tumor multicellular spheroids treated with 1,3-bis(2-chloroethyl)-1-nitrosourea.

During chemotherapy and regrowth of brain tumors, tumor-cell heterogeneity, and possibly tumor progression, may change as a result of both the selective forces and mutagenic effects of treatment. We have isolated and characterized drug-response variants of multicellular rat 9L brain-tumor spheroids exposed to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Ten colonies were isolated from spheroids disaggregated immediately after treatment, and 10 colonies were isolated from treated spheroids disaggregated after 1 week in suspension culture. The sensitivity to BCNU was determined by assays of sister chromatid exchange and colony-forming efficiency in monolayer cultures of each subline after a 1-hr exposure to graded doses of BCNU. Three classes of response were found: BCNU sensitivity increased, decreased, or was comparable to that of uncloned, parent 9L cells. Resistant phenotypes were predominant (8/10) in sublines from spheroids disaggregated immediately after treatment, whereas hypersensitive phenotypes (4/8) were isolated only from spheroids disaggregated after 1 week of regrowth. Since subpopulations isolated immediately after treatment do not have the same biological characteristics as those isolated after a period of regrowth, these data suggest that tumor-cell heterogeneity may be generated by distinct processes at various times during therapy. The predominance of hypersensitive sublines obtained by the regrowth protocol may have resulted from the recovery of cells that would have died if isolated but were instead able to repair the drug-induced damage when left in contact with neighboring, possibly resistant cells. Two resistant and two hypersensitive sublines were studied further.

Animals↗
PubMed1994

Cytoreductive effects of anti-transferrin receptor immunotoxin in a multicellular tumor spheroid model.

We have evaluated the sensitivity to immunotoxins (IT) of monolayer and of 200-250 microns multicellular tumor spheroid (MTS) cultures obtained with human breast (MCF7) and glioblastoma (U118) tumor cells and with rat glioblastoma (9L) cells. Monolayer MCF7 and U118 cells were highly sensitive to antitransferrin receptor (anti-TfnR) ricin A chain (RTA)-IT (Tfn-RTA and MAb OKT9-RTA) treatment in the presence of the intracellular RTA-IT enhancing agent human serum albumin-monensin (HSA-Mo) conjugate. A 790- to 2000-fold higher concentration of anti-TfnR IT was instead required to reduce by 50% the volume of individually treated MCF7 spheroids, as evaluated by applying the Gompertz growth model. Monolayer 9L cells showed 230- to 5700-fold lower sensitivity to Tfn-RTA IT than MCF7 and U118 monolayers, yet 9L spheroid cells were almost as sensitive to anti-TfnR IT as monolayer 9L cultures. Binding studies performed with [125I]-Tfn and FITC-labelled anti-TfnR MAb revealed that 9L monolayers and MTS expressed 4.1-fold and 8.8-fold lower amounts of TfnR than MCF7 monolayers and MTS, respectively. However, Tfn bound to TfnR sites of 9L and of MCF7 cells with comparable affinity. Experiments carried out with the diphtheria toxin mutant CRM107 linked to Tfn confirmed the pattern observed with RTA-IT. Monolayers and spheroids showed no considerable differences in sensitivity to ricin toxin. Collectively, these results indicated that the efficacy of IT against 3-D tumors is heavily influenced by the number of target Ag expressed by the tumor cells, as well as by the affinity of IT/toxin-cell interaction.

Animals↗
PubMed1994

Oxygen consumption rate and mitochondrial density in human melanoma monolayer cultures and multicellular spheroids.

Rate of oxygen consumption per cell has been shown in previous studies to decrease with increasing depth in the viable rim of multicellular spheroids initiated from rodent cells, human colon-carcinoma cells, and human glioma cells, due to progressive accumulation of quiescent cells during spheroid growth. The purpose of our work was to determine oxygen-consumption profiles in human melanoma spheroids. Monolayer cultures of 4 lines (BEX-c, COX-c, SAX-c, and WIX-c) and spheroid cultures of 2 lines (BEX-c and WIX-c) were subjected to investigation. Spheroids were initiated from monolayer cell cultures and grown in spinner flasks. Rate of oxygen consumption was measured with a Clarke-type electrode. Mitochondrial density was determined by stereological analysis of transmission electron micrographs. Thickness of viable rim and cell packing density were assessed by light microscopy of central spheroid sections. Cell-cycle distribution was determined by analysis of DNA histograms measured by flow cytometry. Cell volume was measured by an electronic particle counter. Rate of oxygen consumption per cell differed by a factor of approximately 1.8 between the 4 cell lines and was positively correlated to total volume of mitochondria per cell. Rate of oxygen consumption per cell and total volume of mitochondria per cell were equal for monolayer cell cultures, 600-microns spheroids and 1,200-microns spheroids of the same line. Mitochondrial density and location in the cell did not differ between cells at the spheroid surface, in the middle of the viable rim and adjacent to the central necrosis. Cell-cycle distribution, cell volume, and cell-packing density in the outer and inner halves of the viable rim were not significantly different. Consequently, the rate of oxygen consumption per cell in inner regions of the viable rim was probably equal to that at the spheroid surface, suggesting that oxygen diffusion distances may be shorter in some melanomas than in many other tumor types.

Humans↗
PubMed1995

Effects of 1,25-dihydroxyvitamin D3 on transformed C3H/10T1/2 fibroblasts grown as multicellular spheroids.

We have previously shown that 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is able to modulate proliferation of C3H/10T1/2 fibroblasts grown in monolayer cell culture. The aim of this study was to investigate the effects of the hormone in a 3-dimensional culture system, which is considered to better reflect the cellular environment that is found in vivo. Two transformed cell lines of C3H/10T1/2 fibroblasts (C116 and TPA 482) were grown as multicellular spheroids, whereas the nontumorigenic C3H/10T1/2 C18 cells failed to form spheroids. The hormone had no effect on spheroids made of TPA 482 cells but had a biphasic effect on C116 spheroid growth with stimulation at low and inhibition at higher concentrations. In C116 spheroids, 10(-8) M 1,25-(OH)2D3 induced complete arrest of spheroid growth. Light and electron microscopic studies and immunocytochemistry showed that 10(-8) M 1,25-(OH)2D3 induced morphological changes in C116 spheroids, with a marked reduction in expression of fibronectin, laminin and the gap junction protein connexin 43. These effects were followed by a loosening of the spheroid structure, detachment of viable cells, and finally disaggregation of the spheroids. The results of this study, together with the data previously obtained in monolayer cell cultures, indicate that the effects of 1,25-(OH)2D3 may be conditioned by the cellular environment. Therefore, the spheroid model is an interesting tool for investigation of the antineoplastic effect of the hormone.

Animals↗
PubMed1984

In situ oxygen consumption rates of cells in V-79 multicellular spheroids during growth.

The rate of consumption of oxygen by V-79 cells in multicellular spheroids was measured as a function of the spheroid diameter. In situ consumption was equal to that of exponentially growing cells for spheroids less than 200 micron in diameter. The rate of oxygen consumption decreased for cells in spheroids between 200 and 400 micron diameter to a value one-fourth the initial, then remained constant with further spheroid growth. Comparison of consumption rates for spheroid-derived cells before and after dissociation from the spheroid structure indicated that the spheroid microenvironment accounted for only 20% of the change in oxygen consumption rate. Cell-cell contact, cell packing, and cell volume were not critical parameters. Plateau-phase cells had a fivefold lower rate of oxygen consumption than exponential cells, and it is postulated that the spheroid quiescent cell population accounts for a large part of the intrinsic alteration in oxygen consumption of cells in spheroids. Some other mechanism must be involved in the regulation of cellular oxygen consumption in V-79 spheroids to account for the remainder of the reduction observed in this system.

Animals↗
PubMed1989

Regrowth kinetics of cells from different regions of multicellular spheroids of four cell lines.

A basic understanding of the recruitment of quiescent tumor cells into the cell cycle would be an important contribution to tumor biology and therapy. As a first step in pursuing this goal, we have investigated the regrowth kinetics of cells from different regions in multicellular spheroids of rodent and human origin. Cells were isolated from four different depths within the spheroids using a selective dissociation technique. The outer cells were proliferating and resumed growth after replating with a 0-8-hour lag period, similar to cells from exponentially growing monolayers. With increasing depth of origin, the lag periods prior to regrowth increased to 2-3 times the monolayer doubling time; cells from plateau-phase monolayers showed a lag period of 1-1.5 times the doubling period. After resuming growth, all cells of a given cell line grew with the same doubling time and achieved the same confluency level. The inner spheroid cells and cells from plateau-phase monolayers had reduced clonogenic efficiencies. The inner cells were initially 1.5-3 times smaller than the outer cells, but began to increase in volume within 4 hours of replating. The fractions of S-phase cells were greatly decreased with increasing depth of origin in the spheroids; there were long delays prior to S-phase recovery after plating, to a maximum of 1-1.5 times the normal doubling time. These results suggest that those quiescent cells from spheroids and monolayers which are able to reenter the cell cycle are predominantly in the G1-phase. However, quiescent cells from the innermost spheroid region require approximately twice as long to enter normal cell cycle traverse as cells from plateau-phase monolayers. The selective dissociation method can isolate very pure populations of proliferating and quiescent cells in a rapid and nonperturbing manner; this system will be valuable in further characterizing quiescent cells from spheroids.

Animals↗
PubMed1990

Effects of beta-all-trans retinoic acid on growth, proliferation, and cell death in a multicellular tumor spheroid model for squamous carcinomas.

The growth of multicellular tumor spheroids, MTSs, from squamous carcinoma line MDA 886Ln was inhibited by beta-all-trans retinoic acid (RA). Inhibition occurred within 3 to 5 days of treatment, and MTS size then remained static for up to 2 weeks. Although their growth stopped, 10-day-treated MTSs incorporated [3H]thymidine into trichloroacetic acid-precipitable material, and the [3H]thymidine labeling index, determined by autoradiography, was equivalent between control and RA-treated MTSs. Bivariate flow cytometric analysis of bromodeoxyuridine-labeled MTSs showed equivalent S phase progression of labeled cells over an 8-hour chase. MTS growth stasis was not related to RA-induced cell cycle effects. Monitoring of MTSs for cell sloughing showed no significant cell shedding that could account for stasis. Quantitation of cell number and DNA content per MTS showed an RA-induced decrease. This was confirmed by histological analysis, which demonstrated the temporal appearance of acellular areas. MTS growth statis is thus related to an RA-induced cell loss in this MTS model for squamous carcinomas.

Autoradiography↗
PubMed1981

Ultrasonic effects on mammalian multicellular tumor spheroids.

Mammalian multicellular tumor spheroids (MTS), grown in liquid culture medium, 0.23 to 0.32 mm in diameter and consisting of 4,500 to 12,100 cells, were exposed to three ultrasonic machines: a clinical diagnostic device with an emitted intensity of 13 mW/cm2, a therapeutic machine with emitted intensities of 1 to 3.5 W/cm2, and a laboratory emitting 12 to 50 W/cm2. (All intensities are temporal and spatial average.) Four measures of ultrasonic effect on MTS were made: decrease in diameter after treatment, damage to subsequent growth outright kill, and number of cells detached from the MTS. There was no loss in MTS size from diagnostic or therapeutic exposures. None of the exposures from any of the three machines caused any damage to subsequent growth or survival. There was no significant detachment of cells from the MTS by any of the diagnostic exposures (at 13 mW/cm2, out of 40 minutes). With the laboratory machine, a significant number of cells were detached, about 0.02% of the MTS (approximately one cell per MTS) per W/cm2 in a ten-minute exposure. Cells detached by therapeutic exposure increased linearly with exposure. On the average, 1 W/cm2 detaches about 0.5 cells per minute, per MTS, or about 0.006% of the cells in the MTS.

Animals↗
PubMed2003

Biology of the basic multicellular unit and the pathophysiology of osteoporosis.

Bone structural integrity is maintained by removal of old bone by osteoclasts and synthesis of new bone in its place by osteoblasts. This process, called bone remodeling, is accomplished by assembly of osteoclasts and osteoblasts into discrete temporary anatomic structures called basic multicellular units (BMUs). The lifespan of osteoclasts and osteoblasts is short compared to the lifespan of the BMU; therefore, they must be continually replenished for BMU progression to occur. Osteoclasts develop from hematopoeitic progenitors; and osteoblasts are derived from mesenchymal stem cells, also known as marrow stromal fibroblasts. Circulating hormones together with locally produced cytokines and growth factors modulate the replication and differentiation of osteoclast and osteoblast progenitors. The most important locally produced pro-osteoclastogenic cytokine is receptor activator of NF-kappaB (RANK) ligand. It is expressed by stromal/osteoblastic cells, and binds to its receptor (RANK) on osteoclast progenitors to stimulate differentiation. The development of mature osteoblasts is promoted by growth factors released from the bone matrix during resorption, as well as by growth factors produced by osteoblast progenitors themselves. Many of these same locally produced factors and cytokines also govern the lifespan of osteoclasts and osteoblasts by their effects on apoptosis. The orderly genesis and apoptosis of both osteoclasts and osteoblasts is essential for normal bone homeostasis during bone remodeling. Bone loss caused by sex steroid deficiency or glucocorticoid excess is caused by alteration of bone cell production, and by prolonging osteoclast lifespan and shortening osteoblast lifespan. Therapies that prevent or reverse osteoporosis act at least in part by preventing osteoblast apoptosis and/or stimulating osteoclast apoptosis.

Animals↗
PubMed1990

Proton NMR microscopy of multicellular tumor spheroid morphology.

We report proton NMR images obtained at microscopic (less than 30 microns) resolution of EMT6/Ro and HT1080 multicellular tumor spheroids 1.2-1.7 mm in diameter. T1-weighted images showed little contrast across a slice through the spheroid. There was also no difference between the inner and outer spheroid regions when signal intensity was measured as a function of the repetition time (TR), showing that T1 was the same across the spheroid. Conversely, T2-weighted and multi-echo images clearly revealed the central necrosis that occurs as the spheroids develop. Measurements of the thickness of the viable cell zone made on NMR images agreed with those made on standard histology sections for two different cell lines. The basis for the NMR discrimination of the necrotic region from the viable rim cells was found to be a shortened apparent T2 in the necrotic region (132 +/- 17 ms) with respect to that in the viable cells (173 +/- 9 ms). These results illustrate the applicability of NMR microscopy to assaying conditions inside intact tumor spheroids and suggest that this technology will allow the use of spheroids to investigate several important questions in tumor biology and pathophysiology.

Animals↗
PubMed1990

A system for viably maintaining a stirred suspension of multicellular spheroids during NMR spectroscopy.

We have developed a system for the perfusion of a stirred suspension of multicellular spheroids during nuclear magnetic resonance spectroscopy. Measurement of the medium temperature, pH, oxygen tension, and glucose and lactate concentrations demonstrated that the macroenvironmental conditions around the spheroids during perfusion matched those in standard spinner culture flasks. Spheroids cultured in the NMR perfusion chamber for up to 48 h were virtually identical to spheroids cultured under standard conditions in terms of volume and cell number growth, the extent of central necrosis, cellular clonogenicity, and proliferative status. To avoid problems in interpreting the NMR spectra, we have used a medium containing 10% of the normal inorganic phosphate concentration; comparative growth and NMR studies showed that this medium had no effect on the results reported. 31P NMR spectroscopic analysis demonstrated that the mean pH, nucleotide triphosphate (NTP) to inorganic phosphate (Pi) ratio, the total amount of NTP, and the total energy charge were essentially constant over 8 h of analysis. Stopping the stirring of the spheroid culture during analysis resulted in depletion of the nucleotide phosphate pool in 30 min, with an accumulation of Pi and a shift to a more acid intracellular pH. This effect could be reversed if stirring was resumed within 30 min. Stopping the perfusion while maintaining stirring resulted in a deterioration of the 31P spectra until no high energy phosphates remained at 120 min and the pH fell to approximately 6. This effect was also partially reversible after 30 min of reperfusion, with recovery to a normal 31P spectrum requiring 10 h. The combination of the spheroid model system with 31P NMR spectroscopic analysis will provide a powerful tool for investigating basic questions about the regulation of tumor cell energy metabolism and viability.

Animals↗
PubMed1995

The cell and the organism: the role of subdivisional cell replication in the development and maintenance of the multicellular organism.

Evidence of new cell formation from nucleoli (subdivisional cell replication) was observed in vitro and in vivo. Mouse melanoma cells, human fibroblasts, and rat mast cells were observed in tissue culture with phase contrast time-lapse cinematography. Evidence of subdivisional cell replication seen in tissue culture was supported by observations of mast cells, cervical epithelial cells, melanoma cells, keratinocytes, and fungal spores in vivo. Indirect evidence for subdivisional cell replication was the presence of differentiated form and function in nuclei and nucleoli. Synergism between subdivisional replication and mitotic replication (subdivisional expansion) is believed to be a key to morphogenesis, whereby cellular and subdivisional zones act as biologic "molds". It is believed that subdivisional cell replication has a key role in maintenance of differentiated form in multicellular organisms, as well as in morphogenesis.

Animals↗
PubMed2001

Dosage-dependent gene regulation in multicellular eukaryotes: implications for dosage compensation, aneuploid syndromes, and quantitative traits.

Evidence from a variety of data suggests that regulatory mechanisms in multicellular eukaryotes have evolved in such a manner that the stoichiometric relationship of the components of regulatory complexes affects target gene expression. This type of mechanism sets the level of gene expression and, as a consequence, the phenotypic characteristics. Because many types of regulatory processes exhibit dosage-dependent behavior, they would impact quantitative traits and contribute to their multigenic control in a semidominant fashion. Many dosage-dependent effects would also account for the extensive modulation of gene expression throughout the genome that occurs when chromosomes are added to or subtracted from the karyotype (aneuploidy). Moreover, because the majority of dosage-dependent regulators act negatively, this property can account for the up-regulation of genes in monosomics and hemizygous sex chromosomes to achieve dosage compensation.

Aneuploidy↗
PubMed1999

Differential effects of the insulin-like growth factor I receptor on radiosensitivity and spontaneous necrosis formation of human glioblastoma cells grown in multicellular spheroids.

The purpose of this study is to investigate how the insulin-like growth factor I receptor (IGF-IR) affects cellular radiosensitivity when cells are cultured under different growth conditions. For this, A7(R) and A7(puro) cells were established from human glioblastoma GB A7 cells. The former were derived from the parent cells by stable cotransfection with plasmids carrying human IGF-IR cDNA and a puromycin resistance gene and the latter had the marker gene alone. The cells were either grown exponentially in monolayer cultures or grown in multicellular spheroids as an in vitro model for solid tumors. Spheroids were formed in the two different methods, liquid-overlay (LOC) and spinner (SPC) cultures. Although the growth rate of both cell lines in monolayer was exactly the same, the growth rate of A7(R) spheroids formed in LOC was higher than that of A7(puro) spheroids. A central necrosis region was histologically observed in A7(puro) spheroids, but the corresponding region in A7(R) spheroids was almost completely filled with intact cells in both LOC and SPC spheroids. Both cell lines showed the same radiosensitivity in monolayer cultures in terms of cell viability and clonogenic cell survival. When the spheroids formed in LOC were X-irradiated, the radiosensitivity of A7(R) and A7(puro) cells assayed for cellular clonogenicity was also the same. However, in the spheroids formed in SPC, A7(R) cells were significantly more radiosensitive than A7(puro) cells. The results indicate that overexpression of the IGF-IR could induce radiosensitization of human tumor cells in spheroids while inhibiting spontaneous necrosis formation. This may open a possibility to explore the novel function of the IGF-IR.

Cell Cycle↗
PubMed2000

Amino acid uptake and regulation in multicellular hepatoma spheroids.

BACKGROUND: Cancer cells maintained in monolayer tissue culture are frequently used to study tumor biology and nutrient uptake, but there is a concern that this system may not fully reflect clinical tumor physiology. Because cells grown in a 3-D configuration more closely resemble an in vivo environment, a model was developed and characterized for the growth of SK-Hep human hepatoma cells in suspension as multicellular tumor spheroids (MTS). The measurement of nutrient uptake in such a system has never been established. MATERIALS AND METHODS: SK-Hep cultures were initiated as single cell suspensions and grown as MTS in siliconized spinner flasks. The transport of several individual amino acids (arginine, glutamate, leucine, alpha-(N-methylamino)isobutyric acid (MeAIB), and glutamine (GLN)) was measured in SK-Hep single cell suspensions and MTS (0. 50-0.60 mm diameter) by a radiotracer/rapid filtration technique, as was the regulation of glutamine uptake by phorbol esters. l-[(3)H]GLN uptake was also measured in larger spheroids (0.85-1.5 mm diameter). MTS cellularity was evaluated by histological examination, and single cell integrity after the transport assay was confirmed by scanning electron microscopy (SEM). RESULTS: SK-Hep MTS displayed gradients of cellular morphology and staining, with central necrosis visible at diameters >0.8 mm. Single cell suspensions endured the rapid filtration technique based on functional Na(+)-dependent uptake rates and SEM analysis. Of all amino acids tested, only GLN transport rates were visibly affected by growth format. In small MTS, Na(+)-dependent GLN uptake was diminished by 40%, but was 40-53% higher in MTS >1 mm displaying central necrosis, when compared to single cell suspensions. Likewise, slight parallel changes in glutamine transporter ATB(0) mRNA levels were observed in Northern blot analysis. Finally, phorbol ester-dependent GLN transport down-regulation (by 40-50%), previously established in SK-Hep monolayers, remained operative in all cell formats tested. CONCLUSIONS: The data suggest that the tumor microenvironment differentially impacts the uptake of specific nutrients despite the conservation of key regulatory pathways. This MTS technique may prove useful for further studies on the role of nutrient transport in nascent tumor growth.

Amino Acid Transport System ASC↗
PubMed1994

Toy models for simple forms of multicellularity, soma and germ.

Simple models for the development, maintenance, and origins of primitive, one- or two-dimensional "toy organisms" are presented. They are similar to cellular automata with the added combination of internal degrees of freedom that are genetically programmed. The growing rules are implementable by cellular mechanics, biochemistry and genetics. The forms that are dealt with are: sexual unicells, filaments with fragmentation, cell doublets with spore formation, filaments with differentiation of soma and germ, and two-dimensional colonies with early segregation of somatic cells and germ line. The minimum models presented help to understand the feasibility of several important evolutionary transitions. An explanation, supported by the models, for the fact that all three multicellular kingdoms are primarily sexual, is offered by the observation that sexuality in unicells is an excellent preadaptation for development, for the former entails programmed differentiation of cell types (relying in part on the action of homeobox genes), use of cell surface molecules, programmed arrest of cell division, etc. Relevant examples of existing biological systems are also presented.

Animals↗
PubMed2000

Modelling T-cell-mediated suppression dependent on interactions in multicellular conjugates.

Tolerance to peripheral body antigens involves multiple mechanisms, namely T-cell-mediated suppression of potentially autoimmune cells. Recent in vivo and in vitro evidence indicates that regulatory T cells suppress the response of effector T cells by a mechanism that requires the simultaneous conjugation of regulatory and effector T cells with the same antigen-presenting cell (APC). Despite this strong requirement, it is not yet clear what happens while both cells are conjugated. Several hypotheses are discussed in the literature. Suppression may result from simple competition of regulatory and effector cells for activation resources on the APC; regulatory T cells may deliver an inhibitory signal to effector T cells in the same conjugate; or effector T cells may acquire the regulatory phenotype during their interaction with regulatory T cells. The present article tries to further our understanding of T-cell-mediated suppression, and to narrow-down the number of candidate mechanisms. We propose the first general formalism describing the formation of multicellular conjugates of T cells and APCs. Using this formalism we derive three particular models, representing alternative mechanisms of T-cell-mediated suppression. For each model, we make phase plane and bifurcation analysis, and identify their pros and cons in terms of the relationship with the large body of experimental observations on T-cell-mediated suppression. We argue that accounting for the quantitative details of adoptive transfers of tolerance requires models with bistable regimes in which either regulatory cells or effectors cells dominate the steady state. From this analysis, we conclude that the most plausible mechanism of T-cell-mediated suppression requires that regulatory T cells actively inhibit the growth of effector T cells, and that the maintenance of the population of regulatory T cells is dependent on the effector T cells. The regulatory T cell population may depend on a growth factor produced by effector T cells and/or on a continuous differentiation of effector cells to the regulatory phenotype.

Antigen-Presenting Cells↗