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Researchers
  • Prof.  Michal Baniyash
Prof Michal Baniyash
 
Major research topics 
Chronic inflammation induced immunosuppression.
T and NK cell immunosuppression associated with zeta-chain down-regulation has been reported in sterile (cancer, autoimmune diseases) and pathogen-dependent (infections) pathologies. We established a mouse model that mimics the conditions of the above-mentioned pathologies and were first to show chronic inflammation and associated myeloid derived suppressor cells (MDSCs) as the causative link between these pathologies leading to T and NK cell dysfunction associated with CD247 downregulation. This phenomenon is reversible; elimination of the inflammatory response leads to normal T and NK cell function and to the recovery of CD247 expression. Based on our and others’ cumulative data, we suggest that chronic inflammation-dependent immunosuppression is the normal outcome of an exacerbated immune response aimed at its attenuation. Although immunosuppression is at times a self-regulatory mechanism, it is disadvantageous in chronic diseases, as well as in therapeutic settings based on T cell transfer and repeated vaccinations as applied today in cancer patients. In contrast, controlling overshooting immune reactions as in autoimmune diseases by inducing immuosuppression is potentially beneficial. Thus, fine-tuning the immunosuppressive environment that involves dynamic cellular interactions of various types of immune cells is critical for controlling the course of a specific disease. We are in the process of:
 
         ·       Characterizing the effector cells; MDSCs and regulatory T cells (Treg). Analyzing  the  regulatory  mechanisms controlling 
                  their functional properties under normal and chronic inflammatory conditions.
 
         ·       Studying the interrelationship between MDSC, Treg and conventional T cells.
 
         ·       Characterizing  the  affected  cells;  T & NK cells. What  is the T & NK cell molecular milieu  activated  by MDSCs that leads
                  to CD247 downregulation and impaired T and NK cell functions.
 
         ·       Establishing  treatment  using MDSCs and/or  Treg for murine autoimmune models as Collagen Induced Arthritis (CIA) and
                 diabetes Type I, resembling similar human diseases.
 
         ·       Establishing   immunotherapeutic   treatments   of  cancer-bearing   hosts  using   a  combination   of   CD247   expression
                 measurements, anti-inflammatory drugs and immunotherapy.

 

The discovery of a novel biomarker for the evaluation of the immune status under chronic diseases-clinical implications.

Based on our studies, we developed a diagnostic kit for evaluating and monitoring the status of the immune system prior to and following immunotherapy/drug treatment in chronic diseases. Patients living with chronic diseases, such as diabetes, arteriosclerosis, IBD, rheumatoid arthritis, infections and cancer often suffer from complications that could be foretold by changes in the function of the immune system, such as chronic inflammation and associated immunosuppression. In addition, many respond poorly to a chosen immunotherapy, thus further aggravating their condition. Currently, prognosis of immunotherapy success rates or complication appearance in these patients is done retrospectively, since there are no available prognostic/diagnostic tools to predict the harmful immune status and to follow up effects of given treatments. We identified a novel biomarker, CD247, for distinguishing between acute and chronic inflammation, detecting the immune status in patients suffering from diseases characterized by chronic inflammation, and monitoring the efficacy of a given therapy.
 
Based on this discovery, we developed a prognostic/diagnostic kit, utilizing a simple assay analyzing a whole blood sample for monitoring the immune status prior to and following treatment. This kit will enable an intelligent selection of the timing and drug/immunotherapeutic treatment (personalized treatment), improving the efficacy of a given immunotherapy to patients with chronic diseases. Better diagnosis and prognosis of the immune status should dramatically increase quality of life and decrease the high expenses needed for treating complications characterizing late stages of chronic disease. The advantages of the novel kit were established both by results in animal models, and in preliminary trials with diabetic patients. We are currently:
 
        ·       Optimizing the kit and analyses.
     
        ·      Applying  the  use  of  this  kit   in  the  evaluation   of  the  immune   status  during:  cancer   development,  transplantation,
               autoimmune diseases and aging and  offering therapeutic  regiments to overcome  complication  appearance and increase 
               success rates of given therapies.
 
TCR structure and signaling function under normal and pathological conditions.
Normal conditions:The TCR plays a dual role in antigen recognition and signal transduction leading to T cell activation. The number of TCRs expressed on the cell surface, their structural integrity and intracellular route are all critical factors that regulate survival and function of both resting and activated T cells. Following activation, most T cell receptors (TCRs) transmit activating signals and are internalized and degraded, though some long-lived T cell-antigen presenting cell (APC) conjugates are maintained by an unknown mechanism. We had previously showed that T cells express at least two TCR forms, non-cytoskeleton (non-cska), and cytoskeleton (cska) associated, linked to actin via the zeta chain. We recently showed that following prolonged activation the receptors stably expressed on the cell surface are the cska-TCRs, suggesting a role for cska-TCRs in T cell-APC polar interaction. We identified two motifs within the zeta chain mediating its binding to F-actin and inducing actin bundling. T cells expressing zeta chain mutated in these motifs, are devoid of cska-TCRs, and are unable to mediate activation-dependent immunological synapse (IS) establishment and cytokine production. Moreover, APCs display abnormal activation patterns following interaction with the mutated T-cells. These results suggest that cska-TCRs expressed in resting and activating T cells play a key role in the formation/maintenance of the immunological synapse and in T cell activation. We are currently focusing on: 
 
        ·       Generating transgenic mice expressing the mutated zeta chain.
 
        ·       Analyzing the effect of absence of cska-TCRs on T cell development and function.
 
        ·       Assess the effect of mutated zeta chain on the function of NK activating receptors depending on zeta chain function.
 
 
Pathological conditions: As mentioned above, the MDSCs generated in the course of chronic inflammation are responsible for bystander impairment of in vitro and in vivo TCR-mediated function and zeta chain lysosomal degradation. Under these conditions, the remaining TCR subunits are assembled and expressed on the cell surface, albeit with diminished function. Moreover, we identified the zeta chain intracytoplasmic region serving a target for its degradation under chronic inflammatory conditions. However, the mechanistic bases for zeta down-regulation and impaired TCR-mediated function induced during chronic inflammation are still unknown. We are currently focusing on:
 
        ·       Investigating the T cell molecular mechanisms responsible for targeting the zeta chain to degradation.
 
        ·       Characterizing the composition and fate of abnormal TCRs under chronic inflammatory conditions.
 

These studies will shed light on the basic mechanisms that control receptor expression, transport and function, as well as contribute to the development of immunotherapeutic strategies for immunosuppression associated with chronic inflammatory diseases.  

 
 
Publications  
 
Baniyash, M., Netanel, T., and Witz, I.P. (1981) Differences in cell density associated witt differences in lung-colonizing ability of B16 melanoma cells.  Cancer Res. 41: 433-437.
 
Baniyash, M., Smorodinsky, N.I., Yaakubovicz, M., and Witz, I.P. (l982) Serologically-detectable MHC and tumor associated antigens on B16 melanoma variants and humoral immunity in mice bearing these tumors.  J. Immunol. 129: 1318-1323.
 
Ballin, A., Aldjem, M., Baniyash, M., Boichis, H., Barzilay, Z., Gal, R., and Witz, I.P. (1983) The effect of Lithium Chloride in tumor appearance and survival of melanoma bearing mice.  Br. J. Cancer 48: 83-87.
 
Baniyash, M., and Eshhar, Z. (1984) Monoclonal antibodies to murine IgE inhibit IgE binding to rat basophilic leukemia cells.  Eur.J.Immunol. 14: 799-807.
 
Baniyash, M., Eshhar, Z., and Rivnay, B. (1986) Interrelation between antigenic sites on IgE recognized by monoclonal anti-IgE antibodies and the mast cell receptor.  J. Immunol. 136: 588-593.
 
Baniyash, M., Alkalay, I., and Eshhar, Z. (1987) Monoclonal antibodies specific to the alpha chain of mast cells Fc-epsilon receptor.  J.Immunol. 138: 2999-3004.
 
Baniyash, M., and Eshhar, Z. (1987) Anti-anti-IgE idiotypic antibodies mimic IgE in its binding to the Fc-epsilon receptor. Eur. J. Immunol. 17: 1337-1341.
 
Baniyash, M., Eshhar, Z., and Khery, M. (1988) Anti-IgE monoclonal antibodies directed at the Fc-epsilon-receptor binding site.  Mol. Immunol. 25: 705-711.
 
Weissman, A.M., Baniyash, M., Hou, D., Samelson, L.E., and Klausner, R.D. (1988) Disulfide linkage of the zeta and eta chains of the T cell antigen receptor.  Science 239: 1018-1021.
 
Baniyash, M., Garcia-Morales, P., Bonifacino, J.S., Samelson, L.E., and Klausner, R.D. (1988) Disulfide linkage of the zeta and eta chains of the T cell receptor:  Possible identification of two structural classes of receptors.   J. Biol. Chem. 263: 9874-9878.
 
Baniyash, M., Garcia-Morales, P., Luong, E., Samelson, L.E., and Klausner, R.D.  (1988) The T cell antigen receptor zeta chain is tyrosine phosphorylated upon activation.  J. Biol. Chem. 263:18225-18230.
 
Sharon, M., Gnarra, J.R., Baniyash, M., and Leonard, W.J. (l988) Possible association between IL2 receptors and class I HLA molecules on T cells.  J. Immunol. 141: 3512-3515.
 
Klausner, R.D., Weissman, A.M., Baniyash, M., Bonifacino, J.S. and Samelson, L.E. (l989) The role of the zeta chain in expression, structure and function of the T cell receptor.  Adv. Exp. Med. Biol. 254: 21-24.
 
Baniyash, M., Hsu, V.W., Seldin, M.F., and Klausner, R.D.  The isolation and characterization of the murine T cell antigen receptor zeta chain gene. (1989) J. Biol. Chem., 264: 13252-13257.
 
Hsu, V.W., Klausner, R.D., Fine, J.S., Kruisbeek, A.M., and Baniyash, M. (1992) Changes in the methylation pattern of the TCR zeta chain gene correlate with its expression in T cells and developing thymocytes. The New Biologist, 4: 166-171.
 
Caplan, S., Zeliger, S., Wang, L., and Baniyash, M. (1995) Cell surface expressed T cell antigen receptor zeta chain is associated with the cytoskeleton.  PNAS, 92: 4768-4772.
 
Messika, E.J., Yefenof, E., Gallily, R., Avni, O., and Baniyash, M. (1995) Identification and characterization of a novel protein associated with macrophage CR3.  J. Immunol., 154: 6564-6570.
 
Wang, L., Bronstein, N., Hsu, V. and Baniyash, M. (1995) Transcriptional regulation of the murine TCR  gene. Int. Immunol., 7:1627-1635.
 
Caplan, S. and Baniyash, M.  (1995) Multisubunit receptor complexes in the immune system and their association with the cytoskeleton in search of functional significance.  Invited review for Immunologic Research, 14:98-118.
 
Caplan, S. and Baniyash, M. (1996) Normal T cells express two TCR populations, one of which is linked to the cytoskeleton via chain and displays a unique activation-dependent phosphorylation pattern. J. Biol. Chem., 271:20705-20712.
 
Palumbo, G. A., Yarom, N., Gazit, A., Sandalon, Z., Baniyash, M., Kleinberger-Doron, N., Levitzki, A., Ben-Yehuda, D. (1997) The Tyrphostin AG17 Induces Apoptosis and Inhibition of cdk2 Activity in a Lymphoma Cell Line That Overexpresses bcl-2. Cancer Res., 37, 2434-2439.
 
Bishara, A., Aker, A., Amar, A., Brautbar, C., Schlesinger, M., Rabinowitz, R., Slavin, S., and Baniyash, M. (1998) Enhanced lymphoid cell recovery of an immunodeficient child following bone marrow transplantation:  Correlation with the presence of costimulatory antibodies in the serum. Exp. Hematol., 26: 580-587.
 
Avni, O., Pur, Z., Yefenof ,E., and Baniyash, M. (1998) Complement receptor 3 (CR3) of macrophages is associated with galectin-1-like protein. J. Immunol., 160: 6151-6158.
 
Bronstein-Sitton, N., Wang, L., Cohen, L., and Baniyash, M. (1999) Expression of the TCR chain following activation is controlled at distinct checkpoints: implications for cell surface. J. Biol. Chem. 274: 23659-23665.
 
Caplan, S., and Baniyash, M. (2000) Searching for significance in TCR-cytoskeleton interactions.  Immunology Today 21:223-228.
 
Caplan, S., Almogi-Hazan, O., Ezernitchi, A., Manaster, E., Gazit, A., and Baniyash, M. (2001) The cytoskeleton-associated TCR chain is constitutively phosphorylated in the absence of an active p56(lck) form. Eur J Immunol. 31:580-589.
 
Villa, A., Sobacchi, C., Notarangelo, LD., Bozzi, F., Abinun, M., Abrahamsen, TG., Arkwright, PD., Baniyash, M., Brooks, EG., Conley, ME., Cortes, P., Duse, M., Fasth, A., Filipovich, AM., Infante, AJ., Jones, .A, Mazzolari, E., Muller, SM., Pasic, S., Rechavi, G., Sacco, MG., Santagata, S., Schroeder, ML., Seger, R., Strina, D., Ugazio, A., Valiaho, J., Vihinen, M., Vogler, LB., Ochs, H., Vezzoni, P., Friedrich, W., and Schwarz, K. (2001) V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood. 97:81-88.
 
Mostoslavsky, G., Fischel, R., Yachimovich, N., Yarkoni, Y., Rosenmann, E., Monestier, M., Baniyash, M., and Eilat, D. (2001) Lupus anti-DNA autoantibodies cross-react with a glomerular structural protein: a case for tissue injury by molecular mimicry. Eur J Immunol. 31:1221-7.
 
Bronstein-Sitton N., Cohen-Daniel L., Vaknin I., Ezernitchi AV., Leshem B., Halabi A., Houri-Hadad Y., Greenbaum E., Zakay-Rones Z.,  Shapira L., and Baniyash M. (2003). Sustained exposure to bacterial antigen induces IFNg-dependent T cell antigen receptor z down-regulation and impaired T cell function. Nat. Immunol. 4:957-964.
 
Gonen-Gross, T., Achdout, H., Gazit, R., Hanna, J., Mizrahi, S., Markal, G., Goldman-Wohl, D., Yagel, S., Horejsi, V., Levy, O., Baniyash, M., and Mandelboim, O. (2003). Complexes of HLA-G protein on the cell surface are important for the LIR-1 function. J. Immunol. 171:1343-5.
 
Baniyash M. (2004). Down-regulation of the TCRz chain: curtailing an excessive inflammatory immune response. Invited review for Nat. Immunol. Rev. 4:675- 687.
 
Baniyash M. (2006). The inflammation-cancer linkage: A double-edged sword? Semin. Cancer Biol. 16:1-2. An editorial chapter as a guest editor of a volume in Seminars in Cancer Biology entitled “A double-edged sword?”
 
Baniyash M. (2006). Chronic inflammation, immunosuppression and cancer: New insights and outlook. Semin. Cancer Biol. 16:80-88.
 
Ezernitchi, AV., Vaknin, I., Cohen-Daniel, L., Levy, O., Manaster, E., Halabi, A., Pikarsky, E., Shapira, L., Baniyash, M. (2006). TCR zdown-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs. J Immunol. 177:4763-72.
 
Marhaba, R., Vitacolonna, M., Hildebrand, D., Baniyash, M., Freyschmidt-Paul, P., Zoller, M.    (2007). The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema. J Immunol. 179:5071-81.
 
Einstein, O., Fainstein, N., Vaknin, I., Mizrachi-Kol, R., Reihartz, E., Grigoriadis, N., Lavon, I., Baniyash, M., Lassmann, H., Ben-Hur, T. (2007). Neural   precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol. 61:209-18.
 
Vaknin, I., Blinder. L., Wang, L., Gazit, R., Shapira, E., Genina, O., Pines, M., Pikarsky, E., Baniyash, M. (2008). A common pathway mediated through Toll-like receptors leads to T- and natural killer-cell immunosuppression. Blood. 111:1437-47.
 
Fainstein, N., Vaknin, I., Einstein, O., Zisman, P., Ben Sasson, S.Z., Baniyash, M., Ben-Hur, T. (2008). Neural precursor cells inhibit multiple inflammatory signals. Mol Cell Neurosci. 39:335-41.
 
Silberman, I., Sionov, R.V., Zuckerman, V., Haupt, S., Goldberg, Z., Strasser, A., Ben-Sasson, Z.S., Baniyash, M., Koleske, A.J., Haupt, Y. (2008). T cell survival and function requires c-Abl tyrosine kinase. Cell Cycle. 7:3847-57.
 
Meyer, C., Sevko, A., Ramacher, M., Bazhin, AV., Falk, CS., Osen, W., Borrello, I., Kato, M., Schadendorf, D., Baniyash, M., Umansky, V. (2011) Proc Natl Acad Sci U S A. 108:17111-6.
 
Kanterman, J., Sade-Feldman, M., and Baniyash, M. New insights into chronic inflammation-induced immunosuppression. (2012) Seminars in cancer biology. 22:307-18 (Invited review).
 
Sevko, A., Sade-Feldman, M., Kanterman, J., Michels, T., Falk, CS., Umansky, L., Ramacher, M., Kato, M., Schadendorf, D., Baniyash, M., and Umansky, V. Cyclophosphamide Promotes Chronic Inflammation-Dependent Immunosuppression and Prevents Antitumor Response in Melanoma. (2012) J Invest Dermatol. [Epub ahead of print]
 
Sade-Feldman, M., Kanterman, J., Ish-Shalom, E., Elnekave, M., Horwitz, E., and Baniyash, M. TNF blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. (2013) Immunity, (Accepted for publication). 
 
 
Positions available
 
We are looking for talented PhD students and Post-doctorates to join the lab.
 
Staff currently in the lab
 
Prof. Michal Baniyash-Principle investigator
 
Dr. Lynn Wang-Research associate
 
Yair Kleiger-Post-doc
 
Eliran Ish Shalo-Post-doc
 
Ivan Mikula-Post-doc
 
Moshe Sade-Feldman-PhD student
 
Yulia Kanterman-PhD student
 
Yaron Meirow-PhD student
 
Tsuri Prets-MsC student
 
Former Students 
Ilan Vaknin-PhD
 
Efrat Manster-PhD
 
Analia Esernichi-MsC, PhD
 
Leonor Danielle Choen-MsC, PhD
 
Ofer Levy-PhD
 
Osnat Alnogi Hazan-PhD
 
Noemi Bronstein-PhD
 
Steve Caplan-PhD
 
Orli Avni-PhD
 
Shiri Puter-MsC
 
Inna Varfolomeev-MsC
 
Aya Eisenberg-MsC
 
Liora Blinder-MsC
 
Sigal Matza-MsC
 
Shlomit Zeliger-MsC 
 
 
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