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At least 1,297 records · Page 72Linked to original sources
PubMed1990

The OKT3 immunosuppressive effect. In situ antigenic modulation of human graft-infiltrating T cells.

OKT3 exerts its in vivo immunosuppressive effects by inducing major peripheral T cell depletion as well as antigenic modulation of the T3/Ti T cell receptor complex. Modulated cells, which reversibly lose the expression of the CD3 T cell receptor molecular complex but still share the CD4 and CD8 antigens, have been shown to be functionally immunoincompetent. Antigenic modulation is maintained as long as significant OKT3 serum levels are present. Cells infiltrating renal allografts from seven OKT3 treated patients were studied by double immunofluorescence to assess whether antigenic modulation could affect cells located in profound organs such as renal allografts. Needle biopsies were obtained in patients given OKT3 (5 mg/day) for at least 10 consecutive days in association with conventional immunosuppressive drugs for treatment of a rejection episode (5 cases) or prophylactically (2 cases). In all patients at the time of biopsy, CD3 positive cells were absent from the circulation, significant OKT3 serum levels were present, and neither IgG nor IgM anti-OKT3 antibodies were detected. Infiltrating cells were double-labeled using a combination of either anti-CD3 and anti-CD4 or anti-CD3 and anti-CD8 monoclonal antibodies. Following 7-14 consecutive days of treatment, all patients given OKT3 for a rejection episode showed a significant decrease in the number of graft-infiltrating lymphocytes. Importantly, all T cells still infiltrating the allograft were CD3-CD4+ or CD3-CD8+ cells, which is exactly the same phenotypical pattern of CD3 circulating modulated T cells. In 6 out of the 7 patients, this phenotypical pattern was associated with clinically normal graft function. These results further underline the fact that antigenic modulation is an important mechanism mediating the immunosuppressive effect of OKT3 both in peripheral blood and in renal allografts.

Antibodies, Monoclonal↗
PubMed1989

[Modulation of the jaw muscle activity during the rhythmical jaw movement by stimulation of the cortical masticatory area and amygdala in the rabbit].

The effect of each stimulus pulse to the digastric and masseter muscles activities was examined during the rhythmic jaw movement evoked by repetitive electrical stimulation of the cortical masticatory area and amygdala in the rabbit. The stimulus pulse evoked facilitation and suppression in the digastric muscle activity, and suppression and slight facilitation in the masseter muscle activity. No obvious difference in the pattern of the modulation was appeared between the stimulation of the anterior and posterior cortical masticatory area in the digastric muscle activity. In masseter muscle, the stimulation of the anterior cortical masticatory area showed remarkable suppression only, whereas the stimulation of the posterior cortical masticatory area evoked both suppression and facilitation. Lager motor units were received conspicuous modulation than smaller motor units in both muscles. The time course of these modulation was resembled with those of the masseteric and digastric reflexes by stimulation of the cortical masticatory area. We concluded that the modulation evoked by repetitive electrical stimulation of the cortical masticatory area might be occurred by stimulation of the same pathway as evoking the modulation of reflexes. The repetitive electrical stimulation of the amygdala induced rhythmical jaw movement. In the digastric and masseter muscles, the stimulus pulse evoked facilitation, whereas no obvious suppression was appeared. Lager motor unit was modulated remarkably than smaller unit.

Amygdala↗
PubMed1989

The induction of T cell unresponsiveness by rapidly modulating CD3.

The immunomodulatory effects of an IgM anti-CD3 mAb (38.1) were investigated. 38.1 was distinct from other anti-CD3 mAb, in that it was rapidly modulated from the cell surface in the absence of a secondary antibody. Although 38.1 induced an immediate increase in intracellular free calcium [Ca2+]i by highly purified T cells, it did not induce entry of the cells into the cell cycle in the absence of accessory cells (AC) or a protein kinase C-activating phorbol ester. Clearing of 38.1 from the surface of AC-depleted T cells, documented both by immunofluorescence and by functional activity, was rapid, with markedly reduced levels of initially bound mAb observed after a 1 to 2 h incubation at 37 degrees C and complete modulation noted after a 5-h incubation. Despite rapid modulation of 38.1, the T cells continued to express substantial amounts of surface CD3, suggesting there is a rapid rate of turnover of CD3 molecules on resting T cells. After modulation of 38.1 bound CD3, T cells were markedly inhibited in their capacity to respond to PHA. Inhibition could be overcome by culturing the cells with supplemental AC or IL-2. The inhibitory effects of 38.1 could be mimicked by briefly pulsing cells with the calcium ionophore, ionomycin, that had no effect on surface expression of CD3. 38.1- or ionomycin-pulsed cells were inhibited in their subsequent response to PHA even when exposures were carried out in the presence of EGTA to prevent increases in [Ca2+]i from extracellular sources. Inhibition could not be accounted for by an inability of the ionomycin-treated or 38.1-modulated T cells to increase [Ca2+]i in response to PHA. These studies demonstrate that a state of T cell nonresponsiveness can be induced by modulating CD3 with an anti-CD3 mAb in the absence of co-stimulatory signals. A brief increase in [Ca2+]i resulting from mobilization of internal calcium stores appears to be sufficient to induce this state of T cell nonresponsiveness.

Adult↗
PubMed1989

Modulation, shedding, and serum titers of the chronic lymphatic leukemia-associated antigen: characterization and clinical correlations.

The fate of the common chronic lymphatic leukemia antigen (cCLLa), a leukemia-associated antigen selectively expressed by clonal cells in chronic lymphatic leukemia (CLL) was examined in 31 patients. cCLLa was detected by immune precipitation assay in extracts of metabolically labeled CLL culture cells, in CLL cell culture supernatants, and in patients' sera. In vitro shed membrane cCLLa was comparable in all patients (n = 15) on a per cCLLa-positive cell basis but was independent of cCLLa density (r = .46), absolute lymphocyte count ([ALC] r = .46) and stage (r = .44). In contrast, serum cCLLa (n = 31) correlated with absolute cCLLa-positive cell count (r = .92) and to a lesser extent with stage (r = .67), but was independent of cCLLa density (r = .47). cCLLa modulation was assessed from changes in membrane density estimated by radioreceptor assay before and after in vitro exposure to anti-cCLLa monoclonal antibody (MoAb) CLL2. Immune precipitation studies of metabolically labeled CLL cells showed that modulated cCLLa was internalized as judged by its detection within modulated cells but not in their supernatants. Intact cCLLa-CLL2 complexes were not detected within the modulated cells nor in their supernatants. Regeneration of modulated cCLLa was rapid with return to baseline density levels within 24 hours of antibody removal. Modulation was specific and depended on exposure time, medium temperature, and on antibody titer; correlated with extent of disease (versus absolute lymphocyte count, r = .79; versus stage, r = .66; n = 22); was independent of cCLLa density or affinity (r = .44 to r = .57; n = 11); and was unaffected by T cells or by monocytes (n = 14).

Antigen-Antibody Complex↗
PubMed1988

Expression of a 33-kDa antigen Tm 1 on lymphocyte surface after modulation of cell surface antigens by IgM monoclonal antibody.

The mAb Tm 1 was obtained from a fusion of SP2/O tumor cells with spleen cells from CF1 mouse immunized with T cells modulated by an IgM anti-CD3 mAb.mAb Tm 1 reacted with IgM anti-CD3 modulated T cells (66.6%) but not with unmodulated T cells (4.4%). Tm 1 was not expressed on T cells modulated with either IgG2a or IgG1 anti-CD3 mAb. Immunoprecipitation from 125I-labeled CD3-modulated T cells showed that Tm 1 Ag is a single polypeptide of 33 kDa under reducing and nonreducing conditions. Kinetic studies revealed that Tm 1 was detectable on T cells 10 min after incubation and maximally expressed after 4 h of incubation with IgM anti-CD3 mAb. CD3 expression was markedly modulated by this anti-CD3 mAb after the same period of incubation. Studies with cycloheximide revealed that Tm 1 expression on T cells does not require new protein synthesis. Tm 1 expression persisted long after CD3-reexpression 24 h later. Tm 1 was present on a small fraction of circulating T cells, B cells, and monocytes and absent from granulocytes, platelets, E, and thymocytes. Tm 1 was not expressed on T cells after various activation stimuli but was expressed on B cells upon activation. Additional studies indicate that IgM mAb against other T cell differentiation Ag and IgM mAb against B cell Ag also lead to the expression of Tm 1 on these cells. Thus, modulation of surface Ag by IgM mAb externalizes this cytoplasmic Ag. However, one exception has been noted. Purified mAb Tm 1 was not mitogenic and was unable to block either the T cell proliferation induced by 12-O-tetradecanoyl phorbol-13-acetate plus anti-CD3 mAb and other T cell stimuli, or the B cell proliferation induced by B cell mitogens. The role of Tm 1 on lymphocyte function remains to be determined.

Animals↗
PubMed1987

Modulation of T3 antigen in systemic lupus erythematosus (SLE).

One of the first steps in the T cell activation is modulation of T3-Ti complex from the cell membrane. This process was studied in patients with SLE by immunofluorescence staining and measured in a cell sorter. The modulation of T3 antigen was impaired in a number of patients. The mitogen-induced proliferation was also decreased in these cases, but decreased blast transformation occurred also with efficient modulation. Pretreatment of normal T lymphocyte with sera from patients with decreased modulation caused only moderate inhibition of T3 antigen modulation. Modulation in vitro was not influenced by steroids.

Antibodies, Monoclonal↗
PubMed1986

Modulation of IgM anti-lymphocyte antibody-reactive T cell surface antigens in systemic lupus erythematosus.

Cold-reactive lymphocytotoxic autoantibodies are present in the serum of most patients with active systemic lupus erythematosus (SLE) and may be important for the development of the lymphopenia and T cell dysfunction characteristic of this disorder. Neither the mechanisms of autoantibody action in this regard, nor the nature of the relevant T cell membrane target molecules have been defined, however. In the present investigation, preincubation of T cells with SLE serum at 37 degrees C reduced their reactivity with SLE IgM anti-lymphocyte autoantibodies, as demonstrated by indirect immunofluorescence and complement-dependent cytotoxicity. Modulation was restricted to SLE IgM autoantibody-reactive antigen; monoclonal antibody staining of various T cell differentiation and activation antigens remained unchanged. Loss of antigen from the surface membrane was rapid, but transient. A nadir was reached after approximately 120 min of 37 degrees C incubation, followed by essentially complete reexpression of antigen several hours later. Although modulation occurred spontaneously at 37 degrees C in the absence of SLE serum, loss of antigen was enhanced by IgM anti-lymphocyte autoantibodies, despite their low thermal amplitude. Modulation was inhibited by sodium azide, by fixation of cells with paraformaldehyde, and by low incubation temperatures. Colchicine and cytochalasin D had no effect on this process, suggesting that the integrity of the cytoskeleton was not essential. Cycloheximide did not prevent loss of antigen, but inhibited its reexpression. In experiments to determine the fate of modulated antigen, both intracytoplasmic accumulation and shedding from the cell surface were demonstrated. Only shedding was increased by the presence of anti-lymphocyte antibodies, however. These studies delineate modulation of T cell membrane antigen as a new mechanism for anti-lymphocyte autoantibody action in SLE. The occurrence of modulation at physiologic temperatures in vitro suggests that a similar phenomenon of potential relevance to T cell dysfunction may obtain in patients with this disorder.

Antigen-Antibody Reactions↗
PubMed1988

[Role of calcium ions in the processes of modulation of serotonin responses of Helix pomatia neurons to the application of serotonin].

Role of calcium ions in modulating action of serotonin on acetylcholine (ACh) responses in nonidentified and identified (LPa3, RPa3) neurons of Helix pomatia was studied using the voltage-clamp method. An exposure for 1 min to serotonin before ACh application decreased the ACh response in the LPa3 neuron and increased it in the RPa3 neuron. Extracellular administration of theophylline and dibutyryl-cAMP produced analogous effects in these neurons. The injection of calcium ions into LPa3 neuron increased the ACh-induced current in the presence of serotonin, i.e. changed the type of the modulating action of serotonin on the ACh response in this neuron. The injection of calcium ions into the RPa3 neuron enhanced modulating action of serotonin on the ACh response without any change in a type of modulation, while EDTA injection elicited opposite effects. The increase of extracellular calcium concentration inhibited modulating action of serotonin on acetylcholine responses in RPa3 neuron. The regulatory role of calcium ions in the modulating action of serotonin on acetylcholine responses in tested neurons and participation of cAMP are discussed.

Acetylcholine↗
PubMed1985

Role of the main immunogenic region of acetylcholine receptor in myasthenia gravis. An Fab monoclonal antibody protects against antigenic modulation by human sera.

Antigenic modulation of acetylcholine receptor (AChR), i.e., acceleration of its internalization and degradation rate by antibody-cross-linking, is considered to be one of the two main causes of AChR loss in myasthenia gravis (MG). The majority of the antibodies to AChR are directed to the main immunogenic region (MIR) on the alpha-subunit of the receptor. We here examine the relative contribution of the anti-MIR antibody fraction (as well as of another fraction) to the antigenic modulation caused by MG patients' sera. Fab fragments of an anti-MIR monoclonal antibody (mAb) or a mAb to the beta-subunit (neither of which causes antigenic modulation) were allowed to shield their corresponding regions on the AChR on the mouse muscle cell line BC3H1. The 27 MG sera subsequently added thus bound to all other regions except to the protected one, and the resulting antigenic modulation was measured. The anti-MIR mAb protected the AChR by 68 +/- 16%. This is interpreted as the contribution to antigenic modulation of the anti-MIR antibody fraction in the human sera. This percentage correlated very well with the occurrence of the anti-MIR antibodies in the same sera. The anti-beta mAb gave only small protection of the AChR. No significant pattern differences were observed between sexes, early and recent onset of the disease, or high and low antibody titers. It is concluded that as far as it concerns the one of the pathogenic mechanisms in MG, i.e., the antigenic modulation, the MIR seems to be the main pathogenic region. The observation that a single mAb can efficiently protect the AChR in this system may prove to be of therapeutic interest.

Animals↗
PubMed1985

Induction of granuloma modulation in murine schistosomiasis mansoni by enteric exposure to schistosome eggs.

Enteric administration of antigen can induce systemic tolerance. In murine schistosomiasis mansoni, blood flukes produce eggs which enter the intestine. An immunologic phenomenon associated with this disease is a spontaneous diminution in the intensity of the granulomatous response in the liver, lungs, and colonic mucosa with chronic infection, which is termed modulation. It was determined whether modulation of liver granulomas could be induced by enteric immunization with schistosome eggs. Mice infected for 4 wk were immunized by injection of 25,000 eggs into cecal pouches. This induced modulation of liver granulomas by the eighth week of infection. Neither cecal injection of normal saline nor i.p. or subcutaneous injection of eggs could induce the modulatory process. Modulation could be adoptively transferred from enterically immunized donors by injection of spleen cells into infected recipients or into uninfected recipients with synchronous liver granulomas induced by the hepatic embolization of schistosome eggs. Spleen cells treated with anti-Thy-1.2 or anti-Lyt-1.1 and complement could no longer adoptively transfer modulation. These data show that enteric immunization with schistosome eggs can induce modulation of the liver granuloma by a cellular mechanism similar to that described for the natural infection.

Animals↗
PubMed1981

Antigenic modulation of lymphocytic surface immunoglobulin yielding resistance to complement-mediated lysis. II. Relationship to redistribution of the antigen.

Experiments were carried out on guinea-pig L2C leukaemic lymphocytes to investigate the mechanism of antigenic modulation of their surface immunoglobulin (Ig) defined as the conferring by anti-Ig of resistance to lysis by anti-Ig plus complement. The phenomenon reflects, and is probably a consequence of, redistribution of the Ig molecules by bivalent antibody. Fab fragments of the antibody were completely ineffective. Parallel studies by indirect immunofluorescence of the movement of th surface antigen-antibody complexes revealed that modulation for syngeneic complement was apparent when the complexes were minimally aggregated: capping and extensive endocytosis were not necessary. Modulation for xenogeneic (rabbit) complement required more extensive movement but was still appreciable while complexes persisted on the surface. Sodium azide at 10 mM, which inhibits antibody-induced redistribution of surface molecules, diminished modulation. In experiments omitting pre-incubation with antibody alone, the presence of azide during incubations with anti-Ig plus syngeneic complement increased lysis from a low and variable to a consistently high level; there was no effect on the already high level of lysis occurring with the non-modulating anti-Ia plus syngeneic complement. This effect of azide provides further evidence that antigenic modulation can be a major factor determining a cell's survival when it is confronted simultaneously by antibody and complement.

Animals↗
PubMed1978

Circular dichroism studies on Ca2+-dependent protein modulator oxidized with N-chlorosuccinimide.

The structural features and Ca2+-binding properties of native and N-chlorosuccinimide-oxidized modulator protein were compared by circular dichroism. In the presence of Ca2+,the far-UV spectra of native and oxidized modulator protein are virtually indistinguishable, indicating that oxidation of surface methionine residues does not alter the overall conformation of the molecule. In the absence of Ca2+, however, the circular dichroism spectra of native and oxidized modulator are different with calculated helical contents of 40% and 26%, respectively. As judged by circular dichroism titration studies, the native modulator contains both high-(Kd = 1.9 X 10(-7) M) and low-affinity (Kd = 4 X 10(-4) M) Ca2+-binding sites, whereas the modified modulator appears to possess only low-affinity sites (Kd = 3.8 X 10(-4) M). The reduced secondary structure in Ca2+-free oxidized modulator protein may account for the absence of high affinity Ca2+ binding sites.

Animals↗
PubMedDate not supplied

[Role of the inferior colliculi in the formation of conditioned reflexes to amplitude-modulated stimuli in rats].

After a bilateral ablation of the rat auditory cortex, differentiation of a tonal signal from an amplitude-modulated stimulus with 50 c/s modulation frequency is preserved, while ablation of the posterior colliculi completely abolishes differentiation of these signals, without subsequent restoration in six months after the operation. At the same time the same rats are able to elaborate a differentiation of a tonal signal from an amplitude-modulated signal with a 500 c/s modulation frequency. The results obtained show that the posterior colliculi are at the level of the auditory system, where the coding of signals with a modulation frequency of 50 c/s amplitude is accomplished, whereas stimuli with a higher frequency of amplitude modulation are coded at a lower level of the auditory system.

Animals↗
PubMed1994

Fc gamma receptor II (CD32) on malignant B cells influences modulation induced by anti-CD19 monoclonal antibody.

Antigenic modulation is one of many factors determining the effectiveness of monoclonal antibody (MoAb)-mediated therapy. To select the isotype of a CD19 MoAb most suitable for radioimmunotherapy of patients with B-cell malignancies, we studied the influence of MoAb isotype on modulation, after binding of the MoAb to different cell-line cells. The CD19-IgG1 MoAb was found to induce modulation of CD19 antigens on Daudi cell line cells more rapidly than did its IgG2a switch variant. We provide evidence that this difference in modulation rate is caused by the expression of Fc gamma receptor II (Fc gamma RII) on these cells. Experiments aimed at elucidating the mechanism of Fc gamma RII involvement in modulation induction by CD19-IgG1 showed that Fc gamma RII did not comodulate with CD19 MoAbs. However, cocrosslinking of CD19 and Fc gamma RII with CD19-IgG1 MoAb resulted in enhanced calcium mobilization in Daudi cells. This increased signal induction accompanies the enhanced capping and subsequent modulation of CD19 antigens. Because Fc gamma RII is expressed in varying densities on malignant B cells in all differentiation stages, our results have implications for the MoAb isotype most suitable for use in MoAb-based therapy of patients with B-cell malignancies.

Antibodies, Monoclonal↗
PubMed1994

Fibronectin's III-1 module contains a conformation-dependent binding site for the amino-terminal region of fibronectin.

Cultured fibroblasts express binding sites for the amino-terminal region of fibronectin on their cell surface that mediate the assembly of soluble fibronectin into disulfide-stabilized fibrils. These binding sites have been termed matrix assembly sites and have been studied in binding assays using a 125I-labeled 70-kDa fragment derived from the amino terminus of fibronectin. In an attempt to isolate the protein(s) responsible for binding the 70-kDa fragment, cell surface proteins were cleaved from fibroblast monolayers by mild trypsinization. Trypsinization of monolayers generated a series of fibronectin fragments that bound the 125I-labeled 70-kDa fragment by ligand blot assay and affinity chromatography. All of the fibronectin fragments that bound the 70-kDa fragment contained the III-1 module. In solid phase binding assays, the 125I-labeled 70-kDa fragment bound preferentially to reduced fibronectin as compared with unreduced fibronectin fragments. Binding of the 125I-labeled 70-kDa fragment to reduced fibronectin was inhibited by a monoclonal antibody directed against the III-1 domain. Isolated III-1, however, did not bind the 125I-labeled 70-kDa fragment when adsorbed to plastic tissue culture wells. Heat denaturation of III-1 prior to adsorption conferred 70-kDa fragment binding properties on the isolated module. The 125I-labeled 70-kDa fragment did not bind to heat-denatured III-2, suggesting that 70-kDa fragment binding was a property of the III-1 module and not a general characteristic of all type III modules. The binding of 125I-labeled 70-kDa fragment to III-1 was of high affinity (KD = 1.8 x 10(-8) M). These results indicate that a binding site for the 70-kDa amino terminus of fibronectin is contained within a cryptic site found in the first type III module of fibronectin. Unfolding of the III-1 module on the cell surface may control matrix assembly site expression and represent an important step in the initiation of cell-dependent fibronectin polymerization.

Base Sequence↗
PubMed1978

Regulation of allotype expression in heterozygous rabbits. I. Concomitant modulation of cell surface allotypes on peripheral blood lymphocytes from b4b6 rabbits.

Treatment of b4b6 rabbit peripheral blood lymphocytes with b5b5 anti-b4 antibodies at 4 degrees resulted in the modulation (disappearance) ob b4 and b6 cell surface allotype after subsequent incubation in serum-free medium for 1 h at 37 degrees. A clear dose dependence on the sensitizing anti-b4 antibody was observed. Similarly, b5b5 anti-b6 treatment demonstrated a dose dependence for b6 modulation and a threshold dose effect for b4 comodulation. Cells which formed rosettes with anti-b4-coupled SRBC (anti-b4 direct antiglobulin (DAG) rosettes) also demonstrated concomitant modulation of b4 and b6 allotype when incubated at 37 degrees. When cells formed anti-b6 DAG rosettes, subsequent b6 modulation could also be demonstrated, but no b4 comodulation occurred. Concomitant modulation did not occur when cells were incubated with anti-allotype antibodies at 37 degrees. Blocking studies disclosed that the two allotypes are not contiguous in the membrane since uptake of one antiallotype antibody did not block the uptake of another at 4 degrees. We therefore propose that concomitant modulation might occur during a process similar to patch formation.

Animals↗
PubMedDate not supplied

The role of cytokines in the modulation of cell surface antigens of human melanoma.

A number of different cytokines, including IL-1 alpha and beta, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IFN-alpha, -beta and gamma, TNF-alpha -beta, and TGF-beta 1, can modulate the expression of distinct cell surface antigens of normal and neoplastic cells. Both induction/increase of expression and reduction of expression can be achieved depending on the antigen and on the cytokine. Antigens subjected to the modulating activity of cytokines include distinct families of cell surface structures such as the molecules coded by the major histocompatibility complex (MHC), the superfamily of adhesion receptors that regulate cell-cell and cell-matrix interaction, receptors for cytokines and growth factors and tumor-associated antigens. The modulating activity of cytokines is a consequence of their influence on gene expression, protein synthesis, membrane expression and shedding of antigens from the cell surface. The changes of phenotype due to the action of cytokines can influence the signalling pathways dependent on the expression and function of cell surface structures. Therefore, the antigen modulating activity of cytokines can thoroughly affect the biological behavior of normal and neoplastic cells. As described here, most of the modulating effects of cytokines on different cell surface structures and the functional consequences of antigenic modulation can be verified in human malignant melanoma cells.

Antigens, Neoplasm↗
PubMed1996

Development of a new bioartificial liver module filled with porcine hepatocytes immobilized on non-woven fabric.

We developed a new bioartificial liver module, a non-woven fabric (NWF) module, which was filled with hepatocytes immobilized on non-woven polyester fabric, and compared its efficacy with a suspension culture vessel. Porcine hepatocytes were isolated from whole pig liver, which formed spheroids in a 1L suspension culture vessel. Some of these spheroids were allowed to construct a 50 mL NWF module by inoculation onto 12 sheets of disk-shaped non-woven fabric then stuffed into a 50 mL column. The remaining spheroids were transferred to a 100 mL spinner flask and placed in suspension. The 50 mL NWF module maintained a much better metabolic and synthetic function than the 100 mL suspension culture vessel throughout the study. Based on these results, we developed a 200 mL radial-flow-type NWF module. This module filled with single hepatocytes showed promising efficiency.

Animals↗