CD44-Associated Tn Antigen as a New Biomarker of Tumor Cells with Aberrant Glycosylation.

Tn antigen is a tumor-associated antigen that appears on cancer cells as a result of aberrant O-glycosylation. The most studied form of Tn antigen is found in mucins, in particular, in mucin 1 (MUC1). Antibodies against this form of Tn antigen are used to diagnose tumors, as well as to generate T-killers with a chimeric receptor. Some carcinomas do not carry MUC1 and antibodies of a different specificity are required to detect Tn antigen on these cells. In our work, we searched for anti-Tn antibodies without preliminary assumptions about the proteins that may be carriers of the Tn antigen. For this purpose, we obtained several pairs of isogenic cell lines with the wild type and knockout of the Cosmc gene, which is essential for correct protein O-glycosylation. Using the created lines as immunogens, we generated a monoclonal antibody AKC3, which reacted with the Cosmc-deficient A549 lung adenocarcinoma cells and did not bind to the wild-type cells. Using mass spectrometry, as well as co-immunoprecipitation, it was shown that the AKC3 antibody recognized the Tn antigen in the context of CD44 protein - a protein important for tumor growth. The AKC3 antibody can be used for tumor diagnosis, and to generate T cells with a chimeric receptor for treatment of tumors that do not express mucins.

Pharmaceutical grade synthetic peptide Thr-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val-Glu-Arg-Glu-Lys-Glu ameliorates DSS-induced murine colitis by reducing the number and pro-inflammatory activity of colon tissue-infiltrating Ly6G+ granulocytes and Ly6C+ monocytes.

A pharmaceutical grade synthetic tetradecapeptide Thr-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val-Glu-Arg-Glu-Lys-Glu (GEPON) that mimics the ezrin protein hinge region was studied in dextran sodium sulphate-induced murine experimental colitis (DSS colitis). We report that GEPON intraperitoneal injections significantly attenuated DSS-induced pathological manifestations in the large intestine, bloody diarrhoea, and body weight loss in C57BL/6 mice. GEPON markedly inhibited the transcription rate of pro-inflammatory Il1b, Il6, and Nos2 genes in the colon tissue, in contrast with those encoding anti-inflammatory factors, such as Tgfb1, I10, and Arg1, whose transcription rate did not change significantly. Using flow cytometry, we found that GEPON treatment significantly reduced the accumulation of Ly6G+ granulocytes and Ly6C+ monocytes in the colon infiltrate of DSS colitis mice. Analysis of the mRNA level in myeloid cells sorted from the colon tissue revealed that GEPON had decreased the expression of pro-inflammatory genes in both colon-infiltrating Ly6G+ granulocytes and Ly6C+ monocytes, but not in Ly6C-CD64+ macrophages of DSS-treated mice. The direct anti-inflammatory impact of GEPON was shown in an in vitro culture of Ly6C+ monocytes, as evidenced by an inhibition of IL-1 beta and IL-6 mRNA expression. Taken together, our results demonstrated that GEPON had a pronounced therapeutic effect on ulcerative colitis in a laboratory mice model and provided evidence of its curative efficacy via inhibition of colon tissue inflammation by decreasing Ly6G+ granulocyte and Ly6C+ monocyte infiltration and by reducing their pro-inflammatory activities.

An asymptotic higher-order theory for rectangular beams.

A direct asymptotic integration of the full three-dimensional problem of elasticity is employed to derive a consistent governing equation for a beam with the rectangular cross section. The governing equation is consistent in the sense that it has the same long-wave low-frequency behaviour as the exact solution of the original three-dimensional problem. Performance of the new beam equation is illustrated by comparing its predictions against the results of direct finite-element computations. Limiting behaviours for beams with large (and small) aspect ratios, which can be established using classical plate theories, are recovered from the new governing equation to illustrate its consistency and also to illustrate the importance of using plate theories with the correctly refined boundary conditions. The implications for the correct choice of the shear correction factor in Timoshenko's beam theory are also discussed.

The TLR4 Agonist Immunomax Affects the Phenotype of Mouse Lung Macrophages during Respiratory Syncytial Virus Infection.

In the study, the effect of the TLR4 agonist Immunomax was investigated in vitro and in vivo. In particular, Immunomax was shown to polarize mouse bone marrow macrophages from the M0 and M2 states into the M1 state (ARG1 and iNOS mRNA expression levels were used to identify the mouse M1 and M2 phenotypes). Next, we investigated the prophylactic antiviral effect of Immunomax in both a model of mouse respiratory syncytial virus (RSV) infection and a model of RSV-induced bronchial asthma (BA) exacerbation. In the experiment with RSV-induced BA exacerbation, Immunomax-treated mice were characterized by a significant decrease of the viral load in lung homogenates, an increased amount of M1 macrophages in the lung, a tendency toward Th2-dependent ovalbumin-specific IgG1 antibodies decrease in blood serum, a significant increase in RSV-activated CD4+ T cells secreting IFNγ (Th1 cells), and a simultaneous significant decrease in the amount of CD4+ cells secreting IL-4 (Th2 cells) in the mouse spleen, which were detected by ELISPOT 1.5 months after experiment. These findings suggest that treatment with the TLR4 agonist Immunomax polarizes the immune response towards antiviral Th1 and may be used for short-term antiviral prophylaxis to prevent acute respiratory viral infections in asthmatics.

Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling.

Essentials Roles of the two thrombin receptors in platelet signaling are poorly understood. Computational systems biology modeling was used together with continuous flow cytometry. Dual-receptor system has wide-range sensitivity to thrombin and optimal response dynamics. Procoagulant platelet formation is determined by donor-specific activities of the two receptors. SUMMARY: Background Activation of human platelets with thrombin proceeds via two protease-activated receptors (PARs), PAR1 and PAR4, that have identical main intracellular signaling responses. Although there is evidence that they have different cleavage/inactivation kinetics (and some secondary variations in signaling), the reason for such redundancy is not clear. Methods We developed a multicompartmental stochastic computational systems biology model of dual-receptor thrombin signaling in platelets to gain insight into the mechanisms and roles of PAR1 and PAR4 functioning. Experiments employing continuous flow cytometry of washed human platelets were used to validate the model and test its predictions. Activity of PAR receptors in donors was evaluated by mRNA measurement and by polymorphism sequencing. Results Although PAR1 activation produced rapid and short-lived response, signaling via PAR4 developed slowly and propagated in time. Response of the dual-receptor system was both rapid and prolonged in time. Inclusion of PAR1/PAR4 heterodimer formation promoted PAR4 signaling in the medium range of thrombin concentration (about 10 nm), with little contribution at high and low thrombin. Different dynamics and dose-dependence of procoagulant platelet formation in healthy donors was associated with individual variations in PAR1 and PAR4 activities and particularly by the Ala120Thr polymorphism in the F2RL3 gene encoding PAR4. Conclusions The dual-receptor combination is critical to produce a response combining three critical advantages: sensitivity to thrombin concentration, rapid onset and steady propagation; specific features of the protease-activated receptors do not allow combination of all three in a single receptor.

Regulation of the target protein (transgene) expression in the adenovirus vector using agonists of toll-like receptors.

Replication-defective adenoviral vectors are effective molecular tools for both gene therapy and gene vaccination. Using such vectors one can deliver and express target genes in different epithelial, liver, hematopoietic and immune system cells of animal and human origin. The success of gene therapy and gene vaccination depends on the production intensity of the target protein encoded by the transgene. In this work, we studied influence of Toll-like receptors (TLR) agonists on transduction and expression efficacy of adenoviral vectors in animal and human antigen-presenting cells. We found that agonists of TLR2, 4, 5, 7, 8 and 9 significantly enhance a production of the target protein in cells transduced with adenoviral vector having the target gene insert. The enhancement was observed in dendritic cells and macrophages expressing cytoplasmic (GFP), membrane (HA) or secretory (SEAP) proteins encoded by the respective rAd-vectors. Experiments in mice showed that enhancement of the transgene expression can be achieved in the organism of animals using a pharmaceutical-grade TLR4-agonist. In contrast to other TLR-agonists, the agonist of TLR3 substantially suppressed the expression of transgene in cells transduced with adenoviral vectors having insert of GFP or SEAP target genes. We propose that the enhancement of transgene expression is linked to the activation of MyD88→ NF-kB, while the inhibition of transgene expression depends on TRIF→ IRF signaling pathways. Both of these pathways jointly exploited by TLR4-agonists lead to the enhancement of transgene expression due to the dominant role of the MyD88→ NF-kB signaling.

[Comparative analysis of the immune response to DNA constructions encoding hepatitis C virus nonstructural proteins].

A promising approach to construction of antiviral vaccines consists in activation of cellular immunity with the DNA vaccines. The goal of this work was to evaluate the efficacy of genetic immunization of mice with DNA pcNS3-NS5B encoding five hepatitis C virus (HCV) nonstructural proteins: NS3, NS4A, NS4B, NS5A, and NS5B in comparison with plasmids containing genes of same individual nonstructural proteins. The DNA constructions were injected intramuscularly in DBA mice three times. The humoral immune response was assessed with ELISA; cellular immune response--in blast transformation reaction, by quantitation of CD4+ and CD8+ T cell proliferation using flow cytofluorometry, by intracellular synthesis and secretion of IFN-gamma and IL-2 in ELISpot and ELISA. It was found that the functionally active T cell response was achieved to antigens presenting NS3, NS4, NS5A, and NS5B epitopes of different HCV genotypes in response to pcNS3-NS5B plasmid and was stronger than that to plasmids carrying individual genes. A high proliferation rate of CD4+ T cells, secretion of IL-2 and IFN-gamma, induction of anti-NS3 and anti-NS5B IgG2a were demonstrated. These findings indicate that DNA construction pcNS3-NS5B is one of promising candidates for anti-HCV vaccine developing.

[Postinfection irritable bowel syndrome].

AIM: To characterize pathogenesis, clinicolaboratory criteria and treatment of postinfection irritable bowel syndrome (PICS). MATERIAL AND METHODS: The examination including histological study of the small and large intestine mucosa, polymerase chain reaction (PCR), coagglutination reaction using shigella, salmonella, yersinia, campilobacter jejuni diagnosticums, indirect hemagglutination reaction for identification of antibodies to these agents in the blood serum was conducted in 750 patients with PICS. Fecal seeding on selective media was made as well as the respiratory test for bacterial growth in the small intestine. Immune status was studied with laser cytometry, chemiluminescence, immunodiffusion, immunofluorescence, flow laser cytofluorometry. Personality profile was assessed by MMPI. RESULTS: PICS was diagnosed in 599 (79.9%) of 750 patients. Most of them had diarrhea, abnormal fecal microflora, antigens of acute intestinal infection agents in circulating immune complexes of the serum and coprofiltrates. Immune system was characterized by low phagocytic activity, attenuation of cell and humoral immunity. Etiotropic and pathogenetic treatment including intestinal antiseptics, probiotics and immunomodulators produced persistent remission during a year in 79.3% PICS patients. CONCLUSION: PICS is described which differs from ICS by registration of markers of acute intestinal infections in biological media, bacterial overgrowth in the small intestine and dysbiosis in the large intestine, immunodeficiency. A positive response was observed to treatment with intestinal antiseptic and enterosorbent drugs, probiotics and immunomodulators.

Extensional edge modes in elastic plates and shells.

The recently discovered undamped localized mode at the end of an elastic strip is demonstrated to be particularly relevant in the plane stress setting, where it exists for the Poisson ratio 0.29. This paper also emphasizes the difference between low-frequency edge modes, typically characterized by low variation across the plate (or shell) thickness, and high-frequency edge modes, whose natural frequencies are of the order of thickness resonance frequencies.

Multigenic control of tuberculosis resistance: analysis of a QTL on mouse chromosome 7 and its synergism with sst1.

Tuberculosis remains a significant global health problem: one-third of the human population is infected with Mycobacterium tuberculosis (MTB) and 10% of those are at lifetime risk of developing tuberculosis. In the majority of individuals infected, genetic determinants of susceptibility remain largely unknown due to complex multigenic control and the influence of genes--environment interactions. Genetic variation of host resistance to MTB in animal models reflects heterogeneity among humans. Stepwise dissection of these interactions will permit the deciphering of MTB's complex virulence strategy. Previously, we have characterized a mouse supersusceptibility locus (sst1) controlling antituberculosis immunity. In this study, eight host resistance quantitative trait loci (QTLs) were mapped that counter-balance the devastating effect of sst1, among which a QTL on chromosome 7 (Chr7) was most prominent. The Chr7 and sst1 loci independently control distinct resistance mechanisms to MTB, but their effects apparently converge on macrophages in remarkable synergy. Combining these resistance alleles on a C3HeB/FeJ-susceptible background reduced the lung pathology and improved survival after MTB challenge accounting for half of the difference between susceptible and resistant parental strains. These data reveal novel gene interactions controlling MTB resistance and will enable the identification of resistance gene(s) encoded within Chr7 locus.

I/St mice hypersusceptible to Mycobacterium tuberculosis are resistant to M. avium.

We previously demonstrated that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis, as well as to the taxonomically distant intracellular bacteria Chlamydia pneumoniae and Salmonella enterica. To broaden our knowledge about the control of susceptibility to intracellular pathogens, we studied the infection caused by Mycobacterium avium virulent strain 724 in a panel of inbred mouse strains and found that I/St mice are resistant to M. avium. By comparing I/St mice with B6 mice, we demonstrated that (i) B6 mice are much more susceptible to infection caused by M. avium in terms of bacterial multiplication in the lung tissue and severity of lung pathology; (ii) in B6 mice but not in I/St mice infection leads to prolonged leukocyte infiltration of the lung tissue, development of necrotic lung granulomata, and lethality; and (iii) the unfavorable infectious course in B6 mice is accompanied by elevated production of gamma interferon, tumor necrosis factor alpha, and especially interleukin-12 in the lungs. Importantly, M. avium-resistant I/St mice carry a functional r allele of the Slc11a1 (formerly Nramp1) gene, while B6 mice have the Slc11a1(s) genotype. Segregation genetic analysis of (I/St x B6) F2 hybrids demonstrated that susceptibility or resistance to infection caused by M. avium largely depended upon the Slc11a1 genotype and that other genetic traits had a relatively weak influence. This close-to-monogenic pattern differs sharply from the host control of many other intracellular bacterial infections, for which the involvement of numerous quantitative trait loci has been ubiquitously observed.

Trophic venous ulcers and their relationship with the immune status.

This paper describes the results of an original study into the systemic and local immunity in 25 patients with trophic venous ulcers. The authors discovered a number of significant parameters demonstrating the influence of the immune status on the formation of venous ulcers and tempo of their healing. They revealed previously unknown relationships between the immune status, clinical manifestations arid natural history of venous ulcers. Presented herein are the first results of the local use of the immunomodulator gepon and evidence for its efficacy in the treatment of chronic trophic venous ulcers.

[Immune status of patients with cardiac arrhythmias: idiopathic and in primary heart disease].

AIM: A detailed description of immune status abnormalities of adult patients with heart arrhythmia either idiopathic or in combination with primary heart disease such as chronic myocarditis and dilated cardiomyopathy (DCMP). MATERIAL AND METHODS: Eighty two consecutive patients aged 16-57 years admitted to the L.A. Myasnikov Institute of Clinical Cardiology (Moscow) for heart arrhythmia were studied. Among them 35 patients had idiopathic heart arrhythmia (IHA, group 1) with no evidence of any primary heart disease, while other 47 patients (group 2) had heart arrhythmia combined with primary heart disease (chronic myocarditis or DCMP). In group 1 ventricular arrhythmia was recorded in 27 patients (12 cases with ventricular tachyarrhrythmia ?VTA, 15 cases with ventricular extrasystolia- VE). Supraventricular heart arrhythmia was found in 6 patients (3 cases of constantly recurring supraventriccular tachycardia, 2 cases of paroxysmal and 1 with constant atrial fibrillation). The intermittent atrioventricular block of the second-third degree was recorded in 2 patients. The patients of group 2 were divided into subgroups 2a, 2b and 2c. In subgroup 2a (patients with DCMP without signs of heart failure) ventricular arrhythmia was found in 7 patients (VT ? 5, VE ? 2). Supraventricular arrhythmia was recorded in 7 patients 5 of which had constantly recurring supraventricular tachycardia, 1 ? paroxysmal and 1 constant atrial fibrillation. In subgroup 2b (DCMP patients with obvious signs of heart failure) ventricular arrhythmia was recorded in 12 patients, among them 6 had VT and 6 ? VE, 2 ? constant atrial fibrillation). In subgroup 2c (patients with chronic myocarditis) ventricular arrhythmia was in 7 patients (VT ? 5, VE ? 2), constant atrial fibrillation ? in 2, heart conduction abnormalities ? in 3 patients, atrioventricular block of the first or second degree ? in 2, sick sinus syndrome ? in 1. To verify the diagnosis, all the patients have undergone physical examination, blood cell counts and biochemical tests, urine clinical analysis, ECG and ultrasound heart examination as well as 24h ECG monitoring. On demand, bicycle exercise test or treadmill test, coronaroangiography, endomyocardial biopsy and invasive electrophysiological examination were made. RESULTS: Immune status abnormalities found in patients with heart arrhythmia both idiopathic and combined with primary heart diseases such as chronic myocarditis and DCMO correspond to immune defense response during chronic infection. Activation of different anti-infection defense mechanisms was recorded in patients with idiopathic heart rhythm and conductivity abnormalities. Immune deficiency was found in arrhythmia and conductivity abnormalities combined with primary heart diseases (chronic myocarditis or DCMP). A positive correlation exists between the degree of immune defense failure and reduction of myocardial contractility. CONCLUSION: There exists a characteristic pattern of immune status abnormalities in patients with arrhythmia, both idiopathic or combined with primary heart disease (myocarditis, DCMP). The abnormalities depend on severity of arrhythmia, intensity of inflammatory processes in the myocardium and on the degree of left ventricular contractility dysfunction in patients with primary heart diseases.

Mycobacterium tuberculosis-susceptible I/St mice develop severe disease following infection with taxonomically distant bacteria, Salmonella enterica and Chlamydia pneumoniae.

Mice of I/St strain develop severe lung inflammation and die shortly following infection with virulent mycobacteria. To find out whether tuberculosis (TB)-susceptible I/St mice are susceptible to other intracellular bacteria, we investigated two different taxonomically distant pathogens, Chlamydia pneumoniae and Salmonella enterica serovar Typhimurium. Comparison of I/St and TB-resistant A/Sn mice (both Nramp1(r)) demonstrated that the former are more susceptible to both salmonella and chlamydia, displaying a significantly shortened survival time following challenge. Lung pathology develops more rapidly in I/St compared to A/Sn mice following infection with chlamydia, despite their similar ability to control bacterial multiplication. Following infection with salmonella, substantial ( approximately 3 log) but very short (second day post-infection) interstrain differences in bacterial loads were observed, accompanied by higher levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha in the peritoneal cavities of I/St mice. I/St macrophages were more permissive for salmonella growth during the first 24 h following infection in vitro. Because the prominent differences in survival time did not correlate with permanent differences in bacterial multiplication, we suggest that both infections trigger fatal pathological processes whose dynamics depend strongly upon the host genetics.

[Use of the Gepon immunomodulator for ulcerative colitis treatment].

The efficacy of the Gepon immunomodulator was studied in 36 patients with ulcerative colitis (UC) having distal lesions in the resistant form. Taking into account the fact that immunological abnormalities play the main role in UC pathogenesis, the drug with immunomodulatory action was used for overcoming resistance to basic anti-inflammatory drugs. The clinical and immunological reaction to the used drugs was found to be ambiguous. Most of the patients (83.3%) had clinical and endoscopic amelioration after taking Gepon and managed to overcome the resistance to basic anti-inflammatory drugs.

[Apoptosis of immune system cells in tuberculosis infection].

The review summarizes information on the role of apoptosis in distinct cell subsets in tuberculosis infection. It is emphasizes that the apoptotic death of Mycobacterium-infected macrophages and immune T cells may have differences for the protection of the host. Macrophageal apoptosis may be considered as an important mechanism involved in defense against Mycobacterium tuberculosis, by reducing the viability of mycobacteria and inhibiting their spread in the organs. In contrast, elimination of mycobacteria-specific T cells through the apoptotic mechanism of activation-induced cell death rather prevents the long-term responsiveness to mycobacterial antigens, leading to the persistence of infection and unfavorable tuberculosis progression. The findings suggest the complexity of host-pathogen interactions and emphasize the importance of studies of the molecular mechanisms involved in protection and pathology.

Comparative analysis of T lymphocytes recovered from the lungs of mice genetically susceptible, resistant, and hyperresistant to Mycobacterium tuberculosis-triggered disease.

Genetic control of susceptibility to tuberculosis (TB) is being intensively studied, and immune responses to mycobacteria are considerably well characterized. However, it remains largely unknown which parameters of response distinguish resistant and susceptible TB phenotypes. Mice of I/St and A/Sn inbred strains and (A/Sn x I/St)F(1) hybrids were previously categorized as, respectively, susceptible, resistant, and hyperresistant to Mycobacterium tuberculosis-triggered disease. In the present work we compared parameters of lung T cell activation and response following M. tuberculosis challenge. In all mice, the disease progression was accompanied by a marked accumulation in the lungs of activated CD4(+) (CD44(high)/CD45RB(low)) and CD8(+) (CD44(high)/CD45RB(+)) T cells capable of secreting IFN-gamma and of activating macrophages for NO production and mycobacterial growth inhibition. However, significantly more CD8(+) T cells were accumulated in the lungs of resistant A/Sn and F(1) compared with I/St mice. About 80% A/Sn and F(1) CD8(+) cells expressed CD44(high)/CD45RB(+) phenotype, while about 40% I/St CD8(+) cells did not express CD45RB marker at week 5 of infection. In contrast, in susceptible I/St mice lung CD4(+) cells proliferated much more strongly in response to mycobacterial sonicate, and a higher proportion of these cells expressed CD95 and underwent apoptosis compared with A/Sn cells. Unseparated lung cells and T cells of I/St origin produced more IL-5 and IL-10, respectively, whereas their A/Sn and F1 counterparts produced more IFN-gamma following infection. F(1) cells overall expressed an intermediate phenotype between the two parental strains. Such a more balanced type of immune reactivity could be linked to a better TB defense.

Capacity of murine T cells to retain long-term responsiveness to mycobacterial antigens is controlled by the H-2 complex.

It is firmly established that the allelic composition of the H-2 complex has a prominent impact on the course of tuberculosis (TB) infection in mice, including granuloma formation, mycobacterial spread in the lungs, and the dynamics of mortality. Although intuitively obvious, the role of long-term specific T cell responses in the expression of corresponding phenotypes is poorly understood. In this study we have compared polyclonal lymph node cell response (cell yield, proliferation, surface markers, IL-4/interferon-gamma (IFN-gamma) production) to Mycobacterium tuberculosis H37Rv sonicate in repeated 10-day cycles of stimulation/rest between H-2 congenic IE-negative mouse strains, categorized on the basis of mortality following lethal challenge as TB-susceptible (C57B1/6), TB-resistant (4R) and BCG non-protected (B10.M). The capacity to retain specific responsiveness to repeated stimulation by mycobacterial antigens depended upon both the H-2 haplotype of the host and the immunizing dose of the antigen. 4R lymph node cells following either 50 microg/mouse or 100 microg/mouse immunization constantly responded to sonicate, increased in numbers, and after the third stimulation/rest cycle developed into a stable CD3+CD4+ cell line. B6 cells following either 50 microg/mouse or 100 microg/mouse immunization, and B10.M cells following 100 microg/mouse (but not 50 microg/mouse) immunization, lost the capacity to incorporate methyl-3H-thymidine during the second cycle, and died. Analogous results were obtained in the in vivo experiments, when the dynamics of the response over 12 weeks following a single immunization with the antigen was studied. In response to the antigen, cells from all three mouse strains produced significant amounts of IL-2 and IFN-gamma, but not IL-4, indicating that they belong predominantly to the Th1-like subset. Among noteworthy differences between the mouse strains was a clear deficiency of CD8+ T cells in B6 cultures, and an unusually high proportion of CD3+CD4-CD8- (double-negative) T cells in B10.M cultures following a high-dose immunization.

[Regulation of human erythrocyte volume. The role of calcium channels activated by calcium]. / Reguliatsiia ob''ema éritrotsitov cheloveka. Rol' kalievykh kanalov, aktiviruemykh kal'tsiem.

A mathematical model of stabilization of erythrocytes volume which takes into account the homeostasis of univalent ions and the calcium regulation of potassium flux through the membrane has been studied. The model has the only stable solution at all actual values of parameters. The investigation of the steady-state cell volume dependence on membrane permeability for potassium and sodium ions has shown that volume is much better protected against a nonspecific change in permeability than against a specific increase in the membrane permeability for potassium or sodium ions. In the case of a nonspecific increase of the erythrocyte membrane permeability for cations the cell volume has best stabilization when the stoichiometry of sodium and potassium ions transported by a Na,K-ATPase is 3/2.