Main topics

Population dynamics

Mutations, immunity, anti-tumor immunity

Nonlinear excitations in DNA

Photosyntetic reactions

Transport of Electrons in Photosynthetic Reaction Centers

 

Modeling of anti-tumor immunity

Investigators: V. Osipov, O. Issaeva

It is well established that likewise foreign agents (viruses, bacteria, distinct protein molecules) tumor cells can stimulate immune response directed to destroy them. There are two types of reactions to the presence of foreign agent - antigen. The first is non-specific immune reactions. Elements of non-specific anti-virus and anti-tumor defense are both NK (natural killer) cells and LAK-cells populations. They can kill tumor cells without preliminary recognizing certain antigen. The mechanism of non-specific immune response is described more detail in [1].

As non-specific immune reaction usually is not sufficient to destroy the tumor cells population, clone of lymphocytes specific to tumor antigen is formed. This is specific immune reaction.

The are two forms of specific immune response - humoral and cellular. The first is concluded with production of specific protein molecules - antibodies by mature B cells, plasma cells. Antibodies bind to foreign antigens forming complex that is eliminated from an organism [2]. This immune reaction is effective to fight infection disease caused by viruses and bacteria. Antibodies produced in response to tumor cells formation can bind to tumor antigens. As tumor cell can lose its surface antigens, complex antigen-antibody leaves tumor cell before process of antibody dependent lysis develops. Anti-tumor antibodies block antigens of tumor cells and T cell receptors, preventing tumor cells from cytolytic impact [1]. Thus these immune complexes worse development of disease.
The cellular form of specific immune response is used by an organism mainly against foreign cells (cells of transplanted tissues and organs, in tumor transformation). In process of cellular immune response clone of T lymphocytes (CD8+ T cells) specific to foreign antigen is formed. By means of T cell receptors CD8+ T cells bind to antigen determinants presented on the surface of tumor cell and kill them.

Differentiation of both B lymphocytes and T lymphocytes specific to tumor antigen into plasma cells and cytotoxic T lymphocytes respectively is consists of some similar stages [1,3,17]. Let us briefly describe the process T lymphocyte differentiation. Three stages can be singled out: presentation of both tumor antigen with MHC-II and antigen with MHC-I molecules by antigen-presenting cells to helper T cell and T lymphocyte precursor respectively; production of interleukine-2 by helper T cells in response to antigen presentation and activation T lymphocyte precursor proliferation; proliferation and differentiation into cytotoxic T lymphocytes under influence of interleukine-2. Cytotoxic T lymphocytes recognize tumor antigens with MHC-I molecule on the surface of tumor cells bind to tumor cells and kill them [1,3,17].

During process of differentiation all intercellular interactions are mediated by system of interleukins. There are more then 20 interleukins. All of them carry out different functions in forming of anti-tumor defense [1]. However tumor growth results in a disbalance between the production and regulation of cytokins as well as in a reduction of corresponding receptors. For example, amounts of interleukine-2 (Il-2) and interleukine-12 (Il-12) decrease markedly during the malignant growth. As a result, the activity of killer cells and, accordingly, the strength of the anti-tumor immune response become weaker [4].

The methods for enhancement of both the anti-tumor resistance and the general condition of the immune system in tumor-bearing organisms are of current interest. In particular, one of the modern methods in the immunotherapy refers to the use of cytokins [5,6]. Interleukine-2 is considered as the main cytokine responsible for the proliferation of cells containing Il-2 receptors and their following differentiation [7]. Il-2 is mainly produced by activated CD4+ T cells. Many investigations give evidence that Il-2 plays an important role in specific immunological reactions to foreign agents including tumor cells. Besides, this cytokine provides enhancement of natural killer (NK) cell cytotoxic activity [1]. Clinical trials show that there are positive treatment effects at low doses of Il-2 [6,8,9]. At the same time, at high doses of Il-2 treatment may cause serious hematological violations revealed by anemia, granulocytopenia, thrombocytopenia, and lymphocytosis.

Recently, a recovery of IL-2 production after the exposure of tumor-bearing mice to low-intensity centimeter waves was experimentally observed [10]. This indicates that exposure to centimeter electromagnetic waves can be used for an enhancement of the anti-tumor immune response. This finding stimulates our interest to study the influence of exposure on tumor-immune dynamics.

A theoretical investigation of cancer growth under immunological activity has a long history [11]. Most of the known models consider dynamics of two main populations: effector cells and tumor cells. The behavior of cancer growth under the effect of immunity as well as the effect of therapy was the central point of these investigations. The effect of cytokines on the disease dynamics has been considered only in few models [12,13] .

In the framework of our research we have formulated the dynamical model for the anti-tumor immune response based on a scheme of intercellular cytokine-mediated interactions [7] with the interleukine-2 taken into account [16]. The production of Il-2 is considered to depend on the antigen presentation. Our study shows that the production rate of Il-2 has a distinct influence on the tumor dynamics. At low production of Il-2 a progressive tumor growth to a highest possible value occurs. At high production rate of Il-2 there is a regression of tumor to a small value when the dynamical equilibrium between the tumor and the immune system is achieved. In the case of the medium production of Il-2 both these regimes can be realized depending on the initial tumor size and the condition of the immune system. The influence of low-intensity electromagnetic microwaves is considered as a parametric perturbation of the dynamical system. The pronounced immunomodulating effect is found with the suppression of tumor growth and the normalization of Il-2 concentration in good agreement with the recent experimental results on immunocorrective effects of centimeter electromagnetic waves in tumor bearing mice.

Nowadays in the framework of proposed model we consider strategies for combining chemotherapy and immunotherapy of tumors. Different methods of chemotherapy alone certainly provide increase of progression free survival time as well as complete remission of tumor in few percent of cases. Enhancement of the chemotherapeutic effect by increase of drug dose is not possible. As chemotherapeutic drugs usually kill cells in the process of division, beside tumor cells dividing much more rapidly than most normal cells, fast-growing cells are also killed by chemotherapy. Normal cells susceptible to drugs are marrow cells, hair, stomach lining, and immune cells [14]. Therefore it is necessary to find out method of combining destructive chemotherapy and immunotherapy. Clinical trials show that of all the currently employed treatment modalities, cisplatin-based (chemical drug) regimens combined with biologic agents such as interferon-a and interleukine-2, have attained the highest clinical response [15]. The mechanism of biochemotherapy's enhanced activity against cancer is not known, but a large amount of preclinical data points to some biological interactions that may be involved. One of hypotheses for the mechanism of this therapeutic action is enhancement of the chemotherapeutic effect by induction of local NO (nitric oxide) production, which would inhibit the repair of chemotherapy-induced DNA damage [15]. NO production is induced by interferon-g [1,15]. Beside this it might be suggested that TNF-a (tumor necrosis factor a) production induced by interleukine-2 is increased by immunotherapeutic interleukine-2 [1,15]. As TNF-a induce apoptosis (programming cell destruction), increase of its production can enhance the chemotherapeutic effect. Following this facts and taking into account that in the process of division cells are more susceptible to drugs [14] we add our system with corresponding terms and equation describing chemotherapeutic drug dynamics. Preliminary results of calculations show that the use of sequential a biochemotherapy strategy concluded in chemotherapy followed immediately by biotherapy allows to enhance the time, for which tumor size riches dangerous value, by approximately 20-25 days. Received results are in qualitative agreement with clinical observations.

References

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  3. Liu, Y., Ng, Y., and Lillehei, K.O. 2003. Cell mediated immunotherapy: a new approach to the treatment of malignant glioma. Cancer Control. 10(2), 138-147
  4. Berezhnaya, N.M., Chekhun, V.F., 2000. Interleukines system and cancer. DIA, Kiev, 224pp. (in Russian).
  5. Gause, B.L., Sznol, M., Kopp, W.C., Janik, J.E., Smith II, J.W., Steis, R.G., Urba, W.J., Sharfman, W., Fenton, R.G., Creekmore, S.P., Holmlund, J., Conlon, K.C., VanderMolen, L.A. and Longo, D.L. 1996. Phase I study of subcutaneously administered interleuking-2 in combination with interferon alfa-2a in patients with advanced cancer. J. of Clin. Oncol., 14(8), 2234-2241.
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  7. Wagner, H., Hardt, C., Heeg, K., Pfizenmaier, K., Solbach, W., Bartlett, R., Stockinger, H. and Rollingoff, M. 1980. T-T cell interactions during CTL response: T cell derived helper factor (interleukin 2) as a probe to analyze CTL responsiveness and thymic maturation of CTL progenitors. Immunoll. Rev. 51, 215.
  8. Rosenberg, S. A. and Lotze, M. T. 1986. Cancer immunotherapy using interleukin-2 and interleukin-2-activated lymphocytes. Annual Review of Immunology, 4, 681-709.
  9. Rosenberg, S. A., Yang, J. C., Toplian, S. L., Schwartzentruber, D. J., Weber, J. S., Parkinson, D. R., Seipp, C. A., Einhorn, J. H. and White, D. E. 1994. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2, JAMA, 271(12), 907-913.
  10. Glushkova, O. V., Novoselova, E. G., Sinotova, O. A., Fesenko, E. E. Immunocorrective effects of Ultrahigh-frequency Waves on tumor-bearing mice. 2003. Biophysics. 48(2), 281-288.
  11. Adam, J.A. and Bellomo, N. 1996. A survey of Models for Tumor-Immune System Dynamics. Birkhauser, Boston, MA.
  12. De Boer, R.J., Hogeweg, P., Dullens, F.J., De Weger, R.A., Den Otter, W. 1985. Macrophage T lymphocyte interactions in the anti-tumor immune response: a mathematical model. J. of Immunology. 134(4), 2748-2758.
  13. Kirschner, D., Panetta, J. C. 1998. Modeling immunotherapy of the tumor-immune interaction. J. of Mathematical Biology. 37, 235-252.
  14. W. Chang, L. Crowl, E. Malm, K. Todd-Brown, L. Thomas, M. Vrable. 2003. Analyzing immunotherapy and chemotherapy of tumors through mathematical modeling. Summer Student-Faculty Research Project
  15. Antonio C. Buzaid. 2000. Strategies for combining chemotherapy and biotherapy in melanoma. 7(2), 185-197.

Publications

  1. O.G. Issaeva and V.A. Osipov. Modeling of interleuline-2 mediated anti-tumor immune response: immunocorrective effect of centimeter electromagnetic waves. q-bio. CB/0506006. Submitted to the Journal of Mathematical Biology (2005).
  2. O.G. Isaeva.2005 Intercellular interactions mediated by cytokines in immune cellular respone. Bulletin of Dubna International University for nature, society, and man. 1(12), 57-63.

Transport of Electrons in Photosynthetic Reaction Centers

Investigators: R. Pincak, M. Pudlak

In plants and bacteria the energy of light is stored in the energy of the electric potential later used to form chemical bonds. The reaction center complex from the anoxygenic purple photosynthetic bacteria are the best understood of all photosynthetic organisms, from both a structural and a functional point of view. Photosynthesis begins when light is absorbed by an antenna pigment. The photons from the antenna pigment procced to the reaction centers (RC). The photosynthetic reaction centers is a special pigment-protein complex, that functions as a photochemical trap. The precise details of the charge separations reactions and subsequent dark electron transport (ET) form the central question of the conversion of solar energy into the usable chemical energy of photosynthetic organism. The function of the reaction center is to convert solar energy into biochemical amenable energy.

Despite the striking symmetry of the cofactors into 2 branches of RC, there arisses very big asymmetry in ET. The electron transfer proceeds only along the one branch from two possible at least with 10:1 ratio. Our understanding of the primary processes in photosynthesis is not complete without explanation of the strong asymmetry in ET. This is the first step to a better understanding of the process of electron transfer and thus the transport of energy in photosynthetic organisms. Consequently, it could open a way for using the solar energy more efectively. We present some models to elucidate the unidirectionality of the primary charge-separation process in the bacterial reaction centers.


See more about the photosynthesis in bacteria at the gallery section here.

References

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    Publications

 

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