MTADV 5-MER peptide (5-MP) suppresses chronic inflammations   and unveils a new potential target –  Serum Amyloid A (SAA)

The peptide  (MTADV) targets SAA, that fuels inflammations, and thereby suppresses SAA potency   to stimulate the production of pro- inflammatory cytokines

Ma’ayan Shaked¹ , Haim Ovadia² , Keren-Or Amar¹, Lora Eshkar –Sebban¹ Shmuel Cohen¹ , Michal Melamed¹ , Jin Ryoun Kim ³ , Hanna Rosenmann⁴ ,Mary Cowman⁵, Ehud Cohen⁶ and David Naor¹

¹The Lautenberg Center of  Immunology and Cancer Research ,Faculty of Medicine, Hebrew University of Jerusalem, Israel; ²Department of Neurology, Hadassah-Hebrew University  Medical Center , Jerusalem ,Israel; ³Othmer-Jacobs Department of Chemical and Biological Engineering, Polytechnic Institute of New York University,  Brooklyn, USA; ⁴Department of Neurology,The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center; ⁵Tandon School of Engineering, New York University, New York, NY, USA,  ⁶Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel–Canada, Hebrew University, School of Medicine, Jerusalem, Israel;

Research Summary

A human anti-inflammatory   5-MER peptide (5-MP) MTADV (methionine-threonine-alanine-aspartic acid-valine) was derived from a sequence of a pro-inflammatory CD44 variant.  This human peptide displays an efficient anti-inflammatory effect and ameliorates pathology   in Collagen-Induced Arthritis (CIA), Inflammatory Bowel Diseases (IBD) and Experimental Autoimmune Encephalomyelitis (EAE), mouse models of Rheumatoid Arthritis (RA), Crohn’s Disease/Ulcerative Colitis  and Multiple Sclerosis (MS), respectively.  In addition, 5-MP substantially reduces   the number of   inflammatory Ectopic Lymphoid Structures (ELS)  that provide shelter and foster  Hepatic Cell Carcinoma (HCC) . In the CIA model, 5-MP was daily IP/SC injected after the onset of disease. In the EAE model the  peptide was  daily orally delivered. However, using similar protocols, the 5-MP did not inhibit normal immune responses. Mass spectrometric analysis following   protein pull down of  RA synovial   cell extract   with biotinylated peptide , revealed   that  the peptide is  bound to  SAA in vitro . Additionally, in vivo studies support the suggestion that SAA is a target of the 5-MP.  MTADV (but not scrambled TMVAD)   significantly inhibited the release of pro-inflammatory cytokines IL-6 , IL-1β and TNFά  from SAA-activated human cells .mRNA Bioinformatics and qRT-PCR analyses revealed upregulation of anti-inflammatory and anti-neurodegeneration  genes  after injection of 5-MP. The peptide disrupted SAA   molecular assembly  , which is associated   with its in vitro and in vivo  inflammation suppressive effects. Part of these  findings  were published in Peer Review journals and enjoyed the Hebrew university 2021 Kaye Prize for scientific innovation. They exhibit the anti-inflammation activity  of 5-MP and its potential to ameliorate SAA-associated  inflammatory, neurodegenerative and cancer diseases.

1. Therapeutic effects of 5-MER peptide in inflammatory diseases
2. Therapeutic effects of 5-MER peptide in neurodegenerative diseases
3. The therapeutic effects of 5-MER peptide in SAA-associated cancer diseases

4. The pro-inflammatory  activity of  Serum Amyloid A (SAA)

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2. Ickowicz, A. Shulov and D. Naor. The effect of Vipera  Palestina venom on the thymus and lymph nodes.  Harefuah   70:265-266, 1966.

3. Ickowicz, A. Shulov and D. Naor. The effect of Vipera  Palestina venom on the thymus, lymph nodes and kidneys. Toxicon   3:305-306, 1966.       

4. Naor and D. Sulitzeanu. Binding of radioiodinated bovine serum albumin to mouse spleen cells.  Nature 214:687-688, 1967.

5. Naor and D. Sulitzeanu. Binding of radioiodinated bovine serum albumin to lymphoid cells specifically primed or immunized mice in vitro.  Life Sciences.  7:(2),377-382, 1969.

6. Naor and D. Sulitzeanu. Affinity of radioiodinated bovine serum albumin for lymphoid cells. Binding of I125BSA to lymphoid cells of immune mice.  Israel J. Med. Sci. 5:217-229, 1969.

7. Sulitzeanu and D. Naor. The affinity of radioiodinated BSA for lymphoid cells.  Binding of 125I-BSA to lymphoid cells of normal mice.  Int. Arch. Allergy Appl. Immunol. 35:564-578, 1969.

8. Naor, Z. Bentwich and G. Cividalli. Inability of peripheral lymphoid cells of agammaglobulinaemic patients to bind  radioiodinated albumins.  J. Exp. Biol. Med. Sci. 47:(6)   759-761, 1969.       

9. Naor and D. Sulitzeanu. Binding of 125I-BSA to lymphoid   cells of tolerant mice.  Int. Arch. Allergy Appl. Immunol. 36:112-113, 1969.

10. Naor. Antigen uptake by lymphoid cells of normal, immune and   tolerant mice.  Ph.D. thesis, 1968.

11. Naor and D. Sulitzeanu. The affinity of radioiodinated   bovine serum albumin for lymphoid cells.  II.  Further experiments with cells of normal animals.  Israel J. Med. Sci. 6:519-522, 1970.

12. Naor, R.I. Mishell and L. Wofsy. Specific inhibition of an anti-hapten immune response by chemical modification of cells.  Immunol. 105:1322-1326, 1970.         

13. Wofsy, P. Truffa-Bachi and Naor. Chemical approaches to  the cell receptor problem.  Annals. N.Y. Acad. Sci. 190:432-442,   1971.

14. Naor, C. Henry and H. Fudenberg. An in vitro immune response to penicillin.  J. Immunol. 107:302-305, 1971.

15. Naor and R. Mishell. In vitro immunity to TNP and penicillin.  Specific inhibition with hapten-conjugated isologous red cells.  J. Immunol. 108:246-252, 1972.

16. Naor, S. Morecki and E. Kedar. Differential induction and suppression of direct and indirect PFC responses to TNP conjugated to heterologous erythrocytes.  Adv. Exp. Med. Biol. 29:225-232, 1972.

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18. Naor, S. Morecki and G.F. Mitchell. Differential induction of anti-trinitrophenyl plaque forming cell responses to lightly and heavily conjugated trinitrophenylated heterologous and autologous erythrocytes in mice.  Eur. J. Immunol. 4:311-314,   1974.

19. Zolla, D. Naor and P. Tanapatchaiyapong. Cellular basis of of immunodepression in mice with plasmacytomas.  J. Immunol. 112:2068-2076, 1974.

20. Sulitzeanu, S. Morecki and D. Naor. Specific interaction of antigen with cells studied by means of rosette formation.  Israel  J. Med. Sci. 10:1397-1404, 1974.

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24. Naor, R. Berman-Goldman, M. Kahan, H. Goldfisher, R. Laskov, E. Simon and R. Tchakirov. Induction of hapten recognizng helper function by heavily trinitrophenylated sheep erythrocytes erythrocytes.  Adv. Exp. Med. Biol.  66:253-260, 1975.

25. Kahan, R. Berman-Goldman, R. Saltoun and D. Naor. Studies on the immune response to fixed antigens.  Preferential induction  of helper function with heavily trinitrophenylated sheep erythrocytes and glutaraldehyde treated sheep erythrocytes.  J. Immunol. 117:16-22, 1976.

26. Galili, D. Naor, B. Asjo and G. Klein. Induction of immune responsiveness in genetically low-responsive tumor host combination by chemical modification of the immunogen.  Eur. J.     Immunol. 6:473-476, 1976.

27. Naor and N. Galili. Immune response to chemically modified antigens.  Review article.  Prog. Allergy  22:107-146, 1977.      

28. Kedar, E. Unger,N. Galili, G. Klein, B. Asjo, B. Bonavida and D. Naor. Immunogenicity of tumor cells modified by trinitrobenzene sulfonic acid (TNBS).  In:  Membranes and neoplasia.  New approaches and strategies.  V.T. Marchesi (ed), pp. 109-121, Alan R. Liss, New York, 1976.

29. Naor, B. Bonavida, R.A. Robinson, I.N. Shibata, D.E. Percy, D. Chia and E.V. Barnett. Immune response of New Zealand (NZB and NZB/W) mice to trinitrophenylated mouse red cells. Eur. J. Immunol. 6:783-789, 1976.

30. Naor, B. Bonavida and R.L. Walford. Autoimmunity and aging:  The age-related response of a long-lived strain to trinitrophenylated syngeneic mouse red blood cells.  J. Immunol. 117:2204-2208, 1976.

31. Naor and C. O`Toole. Cryopreservation of immunological memory and other lymphoid cell functions.  J. Immunol. Methods  16:361-370, 1977.

32. Naor and M. Kahan. Studies on the immune response to fixed antigens.  II.  Optimal conditions for inducing and eliciting  helper function by fixed antigens and the mechanism responsible for this effect.  Israel J. Med. Sci. 13:561-576, 1977.

33. Naor. Immune surveillance against autoimmunity.  Review paper.  In: Dynamic aspects of host-parasite relationship. V.3.  A. Zukerman (ed.), pp. 9-31,  Keter, Jerusalem, 1979.

34. F. Ashman and D. Naor. Defective receptor capping and   regeneration in the antigen binding cells of tolerant mice.  In:  Immune system: genetics and regulation.  E.E. Sercarz, L. Herzenberg and C.F. Fox (eds.), pp. 707-711,  Academic Press, New York, 1977.

35. Naor. Delayed type hypersensitivity.  Encyclopedia   Hebraica. V. 30 pp. 501-504, 1978.

36. Naor. Suppressor cells:  Permitters and promoters of   malignancy?  Invited review.  Adv. Cancer Res. 29:45-125, 1979.

37. Leshem and D. Naor. Cellular assay for measuring anti-erythrocyte antibody responses.  J. Immunol. Methods  20:263-275,1978.     

38. Galili, B. Devens, D. Naor, S. Becker and E. Klein. Immune responses to weakly immunogenic virally induced tumors.  I. Overcoming low responsiveness by priming mice with a syngeneic in vitro tumor line or allogeneic cross-reactive tumor.  Eur. J. Immunol. 8:17-22, 1978.

39. Devens, N. Galili, O. Deutsch, D. Naor and E. Klein. Immune responses to weakly immunogenic virally induced tumors.  II.  Suppressive effects of the in vivo carried tumor YAC.  Eur. J.      Immunol.  8:573-578, 1978.

40. Leshem and D. Naor. Studies on the immune response to fixed antigens.  III.  Induction of helper function for antibody  dependent cellular cytotoxicity responses.  J. Immunol. 121:401-408, 1978.

41. Klein, S. Becker, N. Galili, B. Devens and D. Naor. Cell mediated cytotoxic reactions against oncorna virus induced lymphomas in mice.  In:  Proceedings of Erwin Riesch Symposium on Cytotoxic Cell-Interaction and Immunostimulation. 1979.

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45. Leshem and D. Naor. Studies on the immune response to fixed antigens.  IV.  Recall of immunologic memory with fixed antigens.  Israel J. Med. Sci. 16:25-32, 1980.

46. Devens, D. Naor and E. Kedar. Immune response to weakly immunogenic virally induced tumors.  IV.  Dissociated recognition of H-2 and tumor-associated antigens.  Transplantation  28:389-395, 1979.

47. Naor. Unresponsiveness to modified self antigens.  A   censorship mechanism controlling autoimmunity.  Invited review.  Immunological Reviews  50:187-226, 1980.

48. Devens, N. Galili, D. Naor and E. Klein. Opposing tumorogenic and immunogenic properties of the in vitro and the in vivo sublines of Moloney induced tumor.  In: Cell Biology and Immunology of Leukocyte Function.  M.R. Quastel (ed.) pp. 707-714.  Academic Press, New York, 1979.

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50. Deutsch, B. Devens and D. Naor. Immune responses to weakly immunogenic murine-leukemia-virus-induced tumors.  VIII.  Characterization of suppressor cells.  Isr. J. Med. Sci.     16:538-544, 1980.

51. Devens and D. Naor. Immune responses to weakly immunogenic virally induced tumors.  VI.  Comparison of the immune response of the hybrid to the immune responses of the parents reveals “hybrid responsiveness” effect.  J. Immunol. 125:988-994. 1980.

52. Y. Klein, S. Frenkel, A. Ahituv and D. Naor. Immunogenicity  of subcellular fractions and molecular species of MuLV-induced tumors.  I.  Screening of immunogenic components by isopycnic ultracentrifugation and polyacrylamide electrophoresis of a tumor homogenate.  J. Immunol. Methods  38:325-341, 1980.

53. Y. Klein, B. Devens, O. Deutsch, A. Ahituv, S. Frenkel, B.J. Kobrin and D. Naor.  Isolation of immunogenic and suppressogenic determinants of nonimmunogenic YAC tumor and the change in its immunogenic repertoire after in vitro cultivation. Transplant. Proc. 8:790-797, 1981.

54. J. Kobrin, D. Naor and B.Y. Klein. Immunogenicity of subcellular fractions and molecular species of MuLV-induced tumors. II.  Stimulation of syngeneic anti-tumor cell-mediated immune responses by subcellular fractions and molecular species of the   Rauscher-virus-induced RBL5 tumor.  J. Immunol. 125:1874-1882, 1981.

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56. Devens, O. Deutsch, Y. Avraham and D. Naor. Immune responses to weakly immunogenic virally induced tumors.  IX.  Mice injected with the in vitro variants of YAC tumor (YAC-1) resist lethal doses of the tumorgenic YAC cells.  Immunobiology 159:432-443, 1981.

57. Naor, B.Y. Klein and R. Sharon. T cells and cancer.Proceedings of the XIth Triennial World Congress of Pathology.  Advances in Pathology  1:293-298, 1982.

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63. Tarcic, R. Sharon, E. Rosenmann and D. Naor. Auto-delayed type hypersensitivity (DTH) induced in immunodeficient mice with syngeneic modified self antigens.  II.  Suppressor T cells control the autoimmune response.  Scand. J. Immunol. 19:111-121, 1984.

64. Naor. Coexistence of immunogenic and suppresssogenic   epitopes in tumor cells and various types of macromolecules.  Invited editorial review.  Cancer Immunol. Immunother. 16:1-10, 1983.

65. Adler, J.A. Stein, E. Kedar, D. Naor and D.W. Weiss. Intralesional injection of IL-2 expanded autologous lymphocytes in melanoma and breast cancer patients.  A pilot study.  J. Biol. Resp. Modifiers.  3:491-500, 1984.

66. Klein and D. Naor. Self reactive delayed type hyper-sensitivity (DTH) induced in mice by syngeneic lymphoblasts.  Immunobiology.  169:45-59, 1985.

67. Tarcic, R. Baler and D. Naor. Auto-delayed-type hypersensitivity (DTH) induced in immunodeficient mice with modified self antigens.  III.  Suppressive T cell factor (SF) controls the autoreactivity against self antigens.  Scand. J. Immunol.    20:389-401, 1984.

68. Tarcic, B.Y. Klein and D. Naor. Auto-delayed-type hypersensitivity (DTH) induced in immunodeficient mice with modified self antigens.  IV.  Characterization of the suppressive T cell factor (SF) that controls the autoreactivity against self antigens.  Scand. J. Immunol.  20:403-411, 1984.

69. Naor and J.S. Duke-Cohan. Suppressor cells and malignancy,  I.  Suppressor macrophages and suppressor T cells in experimental animals.  Invited review.  Advances in Immunity and Cancer Therapy, Vol. 2. pp 1-129 P.K.Ray (ed.) Springer-Verlag, New York, 1986.

70. Y. Klein, S. Frenkel and D. Naor. Isolated soluble fractions from the murine B16 melanoma induce primary in vitro syngeneic antitumor responses.  Cancer Immunol. Immunother.  18:195-202, 1984.

71. Sharon and D. Naor. The isolation of immunogenic molecular entities from immunogenic and non-immunogenic tumor homogenates by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).  Cancer Immunol. Immunother.  18:203-208, 1984.

72. S. Duke-Cohan, H. Weinberg, R. Sharon and D. Naor. Immunological function in Osteoporosis. Clin. Immunol. Immunopathol. 35:125-129, 1985.

73. Naor, B.Y. Klein, N. Tarcic and J.S. Duke-Cohan. Immunosuppression in human malignancy. Humana Press, New Jersey, 1988.

74. Hutchings, D. Naor and A. Cooke. Effects of low doses of cyclophosphamide and low doses of irradiation on the regulation of induced erythrocyte autoantibodies in mice.  Immunology. 54:97-104, 1985.

75. Naor and A. Langer. Analysis of the cyclosporin (CSA)  mechanism in immunological autoreactive model of delayed type hypersensitivity.  Transplant. Proc.  17:2706-2708, 1985.

76. Naor, N. Tarcic and R. Baler. Control of in vivo immunological autoreactivities with suppressive T cell factor (TF) derived from hybridoma cell line.  Transplant. Proc. 17:2617-2621, 1985.

77. Langer, E. Rosenmann and D. Naor. The effect of cyclosporin on murine autoreactive delayed type hypersensitivity induced with syngeneic lymphoblasts. Immunopharmacology.  10:147-155, 1985.

78. Naor, N. Tarcic, I. Klein, and A. Langer. Immunological autoreactivity to lymphoblast antigens and its suppression by cyclosporin (CsA) or suppressor T cell factors (TsFs). UCLA Symposia on Molecular and Cellular Biology, New Series, Volume 41. Immune Regulation by Characterized Polypeptides.  G. Goldstein, J.F. Bach, H. Wigzell (eds.), Alan R. Liss, Inc., New   York, pp. 165-179, 1987.

79. S. Duke-Cohan, I. Leichter, N. Husseini, R. Sharon, J.Stessman, D. Naor and H. Weinberg. Immune function in   Osteoporosis:  A central role for peripheral blood monocytes in immune suppression and Osteopaenia.  Proc. of the 7th International Workshop on Calcified Tissue. Ein Gedi, Israel, 1986. Current Advances in Skeletogenesis. 3:304-310, 1986 .

80. Tarcic and D. Naor. The genetic control of syngeneic delayed type hypersensitivity (syn-DTH).  Immunogenetics.  24:31-134, 1986.

81. Naor. Suppressor cells and human malignancy.  Clin. Immun. Newsletter.  8: 65-69, 1987.

82. E. Kelley, D. Naor, N. Tarcic, C.N. Gaulton, and T.B. Strom. Anti-Interleukein 2 receptor antibody suppresses delayed-type hypersensitivity to foreign and syngeneic antigens.  J. Immunol. 137:2122-2124, 1986.

83. S. Duke-Cohan, R. Hirt, A. Dahan, and D. Naor. On the immune reaction to autologous human lymphoblasts: Evidence for the stimulation by activating factors rather than induction by autoantigens.  Clin. Immunol. Immunopathol. 43:229-242, 1987.

84. Klein, B.Y. Klein, and D. Naor. Self-reactive delayed type hypersensitivity induced in mice by syngeneic lymphoblasts. II. Isolation of two distinct lymphoblast antigens, one of which reacts (or cross-reacts) with anti-H-2Dd monoclonal antibody.  Scand. J. Immunol. 27: 209-222, 1988.

85. Klein, and D. Naor. Self-reactive delayed type hypersensitivity induced in mice by syngeneic lymphoblasts. III.  Immunological characterization of the small and large antigens of the blast cells.  Scand. J. Immunol. 27:385-392, 1988.

86. Sharon, H. Giloh, and D. Naor. Experimental autoimmune anemia induced with haptenated syngeneic mouse red blood cells and low dose X-irradiation.  Clin. Immunol. Immunopathol. 47: 310-322, 1988.

87. Naor, N. Tarcic, P. De Berardinis, M. Kahan, and M. Feldmann. Autoreactivity against class I or class II antigens — immunological downregulation mechanism? Bull. Inst. Pasteur, 87:3-17, 1989.

88. S. Duke-Cohan, R. Hirt, M. Rottem, A. Ben-Zvi, A. Rubinow, and D. Naor. Use of an autologous reaction in vitro to assess contributions of T and B lymphocytes to immune hyperreactivity of atopics.  Clin. Exp. Allergy 19, 163-168, 1989.

89. Naor, G. Essery, M. Kahan, and M. Feldmann. T-cell clone anti-clone interactions effects on suppressor and helper activities.  J. Autoimmun. 2 (Supp.), 3-14, 1989.

90. Sharon and D. Naor. Experimental model of autoimmune   hemolytic anemia induced in mice with Levodopa.  Clin. Immunol. Immunopathol., 52, 160-172, 1989.

91. Klein and D. Naor. Autoinflammatory response to   self-antigens of lymphoblasts.  Isr. J. Med. Sci. 24:373-375, 1988.

92. Tarcic, C. S. David and D. Naor. Auto-delayed-type   hypersensitivity induced in immunodeficient mice with modifed self-antigens.  V. Cellular autoreactivity directed against self-H-2Dd subregion mediates the inflammatory responses.Immunology, 67:184-190, 1989.    

93. Lugasi, S. Hajos, J. R. Murphy, T. B. Strom, J. Nichols, C. Penarroja and D. Naor. Murine spontaneous T cell leukemia constitutively expressing IL-2 receptor-a model for human T cell malignancies expressing IL-2 receptor.  Int. J. Cancer, 45:163-167, 1990.

94. S. Duke-Cohan, A. Rubinow, R. Hirt and D. Naor. The reaction against autologous lymphoblasts as an indicator of lymphocyte hyperreactivity in rheumatoid arthritis.  Clin. Immunol.  Immunopathol., 54:298-308, 1990.

95. Alvarez, C. Mongini, C.I. Waldner, T.B. Fenandez, D. Naor and S.E. Hajos.  The inter-relationships between spontaneous murine T cell leukemia LB and the immune system:  LB is a nonimmunogenic tumor in its syngeneic host.  J. Exp. Clin. Cancer Res. 8, 181-191, 1989.

96. Naor, G. Essery, N. Tarcic, M. Kahan and M. Feldmann. Interactions between autologous T cell clones.  Cell Immunol.  128:490-502, 1990.

97. Naor, G. Essery, N. Tarcic, M. Kahan, J.R. Lamb and M. Feldmann.  Specific interactions between a human CD4+ clone and autologous CD4+ bifunctional immunoregulatory clones.  Immunol. Rev. 116, 63-83, 1990.

98. A. Zahalka and D. Naor. Inflammatory Response induced with an isolated syngeneic activation antigen shared by normal lymphoblasts and YAC lymphoma cells.  Clin. Immunol. Immunopathol.  59:72-88, 199l.

99. Naor, D. Essery, G. Tarcic, N. Kahan, M. and Feldmann, M.  Regulatory interactions among autologous T cell clones human bifunctional T cell clones regulate the activity of an autologous T cell clone.  N. Y. Academy of Sciences.  636, 135-146, 199l.

100. Naor, D. Short analytical review. A different outlook at the phenotype-function relationships of T cell Subpopulations.  Fundamental and clinical implications.  Clin Immunol.  62, 127-132, 1991.

101. Pillemer, G., Lugasi-Evgi, H., Scharovsky, G., and Naor, D. Insulin dependence of murine lymphoid T cell leukemia.  J. Cancer. 50, 80-85, l992.

102. Sharon, R. and Naor, D. Experimental model of autoimmune  hemolytic anemia induced in mice with levodopa by intraperitoneal injection or oral feeding.  J. Immunopharmac.  14, 1241-1247, 1992.

103. Naor, D. Bifunctional T cell clones challenge the traditional compartmentalization concept of the immune system. Immunol. Ther. Exp. 40, 67-70, 1992.

104. Sharon, R., Pillemer, G., Ish-Shalom, D., Kalman, R., Ziv, E., Berry, M.E. and Naor, D. Insulin dependence of murine T-cell lymphoma II. Insulin deficient diabetic mice develop resistance to the lymphoma growth.  J. Cancer., 53, 843-849, 1993.

105. Sharon, R. Polliack, A., Rahamim, E., Kahane, A. and Naor, D. Autoimmune hemolytic anemia induced with levadopa or  -methyldopa animal model and clinical implications. Advances in Allergy and Immunology.  2, 65-78, 1993.

106. Zahalka, M.A. Okon, E. and Naor, D. Blocking lymphoma   invasiveness with monoclonal antibody directed against the ß chain of the leukocyte adhesion molecule (CD18).  Immunol. 150, 4466-4477, 1993.

107. Zahalka, M.A. and Naor, D. ß2-Integrin dependent aggregate formation between LB T cell lymphoma and spleen cells:  assessment of correlation with spleen invasiveness.  International Immunol.  6, 917-924, 1994.     

108. Ish-Shalom, D., Tzivion, G., Cristoffersen, C.T., Urso, B., De Meyts, P. and Naor, D.,  Mitogenic potential of insulin and lymphoma cells lacking IGF-I receptor.  N.Y. Acad. Sci. 776, 409-415.
109. Stock, R. and Naor, D. Induction of an autoimmune response against syngeneic lymphoma cells by immunogenic 64-kDa protein isolated from normal balst cells of BALB/c mice.  Cancer Immunol. Immunother. 40, 48-56, 1995.
110. Zahalka, M.A., Okon, E., Gosslar, U., Holzmann, B. and Naor, D. Lymph node (but not spleen) invasion by murine lymphoma is both CD44 and Hyaluronate-dependent.  Immunol.  154, 5345-5355, 1995.

111. Naor, D., Vogt Sionov, R., and Ish-Shalom, D. CD44: Structure, function and its association with the malignant process.  Cancer Res.,  71, 241-319, 1997

112. Naor, D.   Encyclopedia of Immunology.  Academic Press, London. 487-491, 1998.

113. Gosslar, U., Jonas, P., Luz, A., Lifka, A., Naor, D., Hamann, A., and Holzmann, B. Predominant role of (4-integrins for distinct steps of lymphoma metastasis.  Natl. Acad. Sci. USA vol. 93, 4821-4826, 1996.

114. Rocha, M., Kruger, A. Umansky, V., von Hoegen, P., Naor, D., and Schirrmacher, V. Dynamic expression changes in vivo of adhesion and costimulatory molecules determine load and pattern of lymphoma liver metastasis.  Cancer Res. 2, 811-820, 1996.

115. Naor, D., Vogt Sionov, R., Zahalka, M., Kantor, B., Rochman, M., Holzmann, B. and Ish-Shalom, D. Organ-specific requirements for cell adhesion molecules during lymphoma cell dissemination. Top. Microbiol. Immunol.  231, 143-166, 1998

116. Ish-Shalom, D., Christoffersen, C.T., Vorwerk, P., Sacerdoti-Sierra, N., Shymko, R.M., Naor, D. and De Meyts, P. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor.    40, S25-S31, 1997

117. Vogt Sionov, R. and Naor, D. Hyaluronan-independent lodgement of CD44+ lymphoma cells in lymphoid organs. J. Cancer. 71, 462-469, 1997.
118. Vogt Sionov, R. and Naor, D. Calcium-and calmodulin-dependent PMA-activation of CD44 adhesion molecule. Cell Adhesion and Communication. 6: 503-523, 1998.

119. Rochman, M., Moll, J., Herrlich, P., Wallach, S.B., Nedvetzki, S., Vogt Sionov, R., Golan, I., Ish-Shalom, D., and Naor, D. The CD44 receptor of lymphoma cells: structure-function relationships and mechanism of action. Cell Adhesion and Communication.  7, 331-347, 2000.

120. Nedvetzki, S., Walmsley, M., Alpert, E., Williams, R.O., Feldmann, M. and Naor, D. CD44 involvement in experiment collagen-induced arthritis (CIA). J. Autoimmunity.  13, 39-47, 1999.

121. Wallach, S B.., Friedmann, A., and Naor, D. The CD44 receptor of the mouse LB T cell lymphoma:  Analysis of the isoform repertoire and ligand binding properties by reverse-transcriptase polymerase chain reaction (RT-PCR) and anti-sense oligonucleotides.  Cancer Detection and Prevention. 24, 33-45, 2000.

122. Weiss, L., Slavin, S., Reich, S., Cohen, P., Shuster, S., Stern, R., Kaganovsky, E., Okon, E., Rubinstein, A.M., and Naor, D. Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with specific monoclonal antibody. Natl. Acad. Sci. USA.  97, 285-290, 2000.

123. Naor, D. CD44. Encyclopedia of Molecular Medicine. John Wiley & Sons.  Invited entry. 2000.
124. Naor, D., Nedvetzki, S., Golan, I. and Faitelson, Y. CD44 in Cancer.  Critical Reviews in Clinical Laboratory Sciences. 39, 527-579, 2002

125. Wallach-Dayan, S. B., Grabovsky, V., Moll, J., Sleeman, J., Herrlich, P., Alon, R. and Naor, D. CD44-dependent lymphoma cell dissemination: a cell surface CD44 variant, rather than standard CD44, supports in vitro lymphoma cell rolling on hyaluronic acid substrate and its in vivo accumulation in the peripheral lymph nodes.  Journal of Cell Science.  114, 3463-3477, 2001

126. Naor, D. and Nedvetzki, S. CD44 in Rheumatoid Arthritis.  Arthritis Research & Therapy. 5, 105-115, 2003.

127. Guy, R., Yefenof, E, Naor D., Dorogin, A. and Zilberman, Y. CD44 co-stimulates apoptosis in thymic lymphomas and T cell hybridomas.  Cell. Immunol. 216, 82-92, 2002.

128. Melnik, L., Rochman, M., Ronen, D., Zick, Y. Naor, D., and Golan, I. Identification of Novel CD44 Ligands May Provide New Targets for Therapy.  In:  Proceedings of the 2^nd International Conference on Tumor Microenvironment Progression, Therapy & Prevention, Isaac P. Witz (ed.),pp. 213-220, Monduzzi Editore, Bologna, Italy, 2002.

129. Urso, B., Ilondo, M. M., Holst, P.A., Christoffersen, C.T., Ouwnes., M.,

Giorgetti, S. Van, Obberghen,  E., Naor, D., Tornqvist, H., and De Meyts, P.  IRS-4 mediated  mitrogenic signalling by insulin and growth harmone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors.  Cellular Signalling. 5630, 1-10, 2002.

130. Nedvetzki, S., Golan, I., Assayag, N., Gonen, E., Caspi, D., Gladnikoff M.Yayon,A., and Naor, D. A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of FGF with its receptor.  J. Clin. Invest. 111, 1211-1220, 2003.

131. Avigdor, A., Goichberg, P., Shivtiel, S., Dar, A., Peled, A., Samira, S., Kollet, O., Hershkoviz, R., Alon, R., Hardan, I., Ben-Hur, H., Naor, D., Nagler, A., and Lapidot, T. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to the bone marrow. Blood. 103,2981-2989,2004.

132. Nedvetzki,S.,Gonen, E.,Assayag,N.,Reich, R,,Williams, R.O.,Thurmond,R.L.,Huang,J-F.,Neudecker,B.A.,F.,Wang,F-S.,Turley,E.A. and Naor,D. RHAMM,a receptor for hyaluronan-mediated motility compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy. PNAS 101,18081-18086,2004.

133. Naor,D and Assayag N. The lesson to be learned from CD44 knockout mice.In Hyaluronan 2003. Proceedings(eds:Balazs,E.A.and Hascall V.C). Matrix Biology Institute 2004.

134. Tolg,C., Hamilton,S.R, Naor,D., McCarthy,J.B. and Turley,E.A. Analysis of convergent divergent signaling pathways regulated by Rhamm and CD44: Identification  of Actin Cytoskeleton proteins AS Rhamm binding partners. In Hyaluronan 2003. Proceedings(eds:Balazs,E.A.and Hascall V.C). Matrix Biology Institute,2004.

135. Naor,D., Nedvetzki,S., Assayag,N., Thurmond,R.L.,Huang J-F.and E.A.Turley. The mechanism of molecular redundancy in autoimmune inflamation in the context of CD44 deficiency. Ann.N.Y.Acad.Sci.1050,52-63,2005

136. Golan I, Nedvetzki S, Golan I, Eshkar-Sebban L, Levartovsky D, Elkayam O,Caspi D, Aamar S, Amital H, Rubinow A, Naor D. Expression of extra trinucleotide in CD44 variant of rheumatoid arthritis patients allows generation of disease-specific monoclonal antibody. J Autoimmun. 28: 99-113, 2007.

137. Garin T, Rubinstein A, Grigoriadis N, Nedvetzki S, Abramsky O, Mizrachi-Koll R, Hand C, Naor D, Karussis D. CD44 variant DNA vaccination with virtual lymph node ameliorates experimental autoimmune encephalomyelitis through the induction of apoptosis. J Neurol Sci. 258:17-26, 2007.

138. Lora Eshkar Sebban, Denise Ronen, David Levartovsky, Ori Elkayam, Dan Caspi , Suhail Aamar, Howard Amital, Alan Rubinow, Ira Golan, David Naor, Yehiel Zick and Itshak Golan. The Involvement of CD44 and its Novel Ligand Galectin-8 in Apoptotic Regulation of Autoimmune Inflammation. J Immunol. 179:1225-1235, 2007.

139. David Naor, Shlomo Nedvetzki, Marita Walmsley, Avner Yayon, Eva A. Turley, Ira Golan, Dan Caspi, Lora Eshkar Sebban, Yehiel Zick, Tali Garin, Dimitrios Karussis, Nathalie Assayag-Asherie, Itamar Raz, Lola Weiss, Shimon Slavin and Itshak Golan. CD44 involvement in autoimmune inflammations: The lesson to be learned from CD44-targeting by antibody or from knock out mice. Ann NY Acad Sci. 1110:233-47, 2007.

140. Naor D, Wallach-Dayan SB, Zahalka MA, Sionov RV.Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin Cancer Biol.18:260-267,2008.

141. Weiss L, Botero-Anug AM, Hand C, Slavin S, Naor D. CD44 gene vaccination for insulin-dependent diabetes mellitus in non-obese diabetic mice. Isr Med Assoc J.10:20-5,2008

142. . Gonen E, Nedvetzki S, Naor D, Shpigel NY.CD44 is highly expressed on milk neutrophils in bovine mastitis and plays a role in their adhesion to matrix and mammary epithelium. Vet Res. 2008 39:29,2008.
143. Shulamit Batya Wallach-Dayan, Ariel M. Rubinstein, Carla Hand, Raphael      Breuer  and David Naor DNA Vaccination with CD44 Variant Isoform Reduce  Mammary Tumor Local Growth and Lung Metastasis. Molecular Cancer Therapeutic (MCT). 7:1615-1623 , 2008.  
144. Vagima Y, Avigdor A, Goichberg P, Shivtiel S, Tesio M, Kalinkovich A, Golan K, Dar A, Kollet O, Petit I, Perl O, Rosenthal E, Resnick I, Hardan I, Gellman YN, Naor D, Nagler A, Lapidot T.MT1-MMP and RECK are involved in human CD34+ progenitor cell retention, egress, and mobilization. J Clin Invest. 119:492-503, 2009.

145. Kahaly GJ, Shimony O, Gellman YN, Lytton SD, Eshkar-Sebban L,Rosenblum N,

Refaeli E, Kassem S, Ilany J, and Naor D  Regulatory T-cell in Graves’ orbitopathy: Baseline findings and immunomodulation by anti-T lymphocyte globulin. J Clin Endocrinol Met (JCEM). 96: 422-429,2011.

146.    Turley EA,  and Naor D. RHAMM and CD44 peptides-analytic tools and potential drugs

2011. Front Biosci. 17:1775-1794, 2012.

147. Shimony O,Nagler A,Gellman YN, Refaeli E, Rosenblum N. Eshkar-Sebban L

 Yerushalmi R, Shimoni A, Lytton SD, Stanevsky A,Or R, Naor D. Anti-T lymphocyte

  globulin (ATG) induces generation of Regulatory T Cells, at least part of them express

  activated CD44. J Clin Immunol  32:173–188 , 2012

148.     Girbl T, Hinterseer E, Grössinger EM, Asslaber D, Oberascher K, Weiss L, Hauser-           

      Kronberger C, Neureiter D, Kerschbaum H, Naor D, Alon R, Greil R, Hartmann TN. 

      CD40-    mediated activation of chronic lymphocytic leukemia cells promotes their CD44-

      dependent adhesion to hyaluronan and restricts CCL21 induced motility. Cancer Res.  

      73(2):561-570, 2013

149. Benjamin Gesundheit MD PhD¹, Joshua Rosenzweig MD¹, David Naor PhD²,

      Armand Keating MD³, Bernard Lerer MD⁴, Dizah Zachor MD⁵, Vaclav Procházka MD

      PhD⁶, Michal Melamed PhD¹, Donald A. Kristt MD⁵, Abraham Steinberg MD⁸, Cory

      Shulman PhD⁹, Paul Hwang MD¹⁰, Gideon Koren MD¹¹, Asnat Walfish MD¹², Vijendra

      Singh PhD¹³, Basan Gowda S Kurkalli PhD¹⁴, Jacob R Passweg MD¹⁵, John Snowden

      MD¹⁶, Ryad Tamouza MD PhD¹⁷, Marion Leboyer MD PhD¹⁸, Dominique Farge-Bancel

      MD¹⁹, Paul Ashwood PhD²⁰ . Autoimmunity and Autism Spectrum Disorders. J

      Autoimmun. 2013 44:1-7, 2013

150. Gesundheit B, Ashwood P, Keating A, Naor D, Melamed M, Rosenzweig J

      Therapeutic properties of mesenchymal stem cells for autism spectrum disorders.  Med

      Hypotheses. 2015 Mar;84(3):169-77.

151. Nathalie Assayag-Asherie, Dror Sever, Marika Bogdani, Pamela Johnson, Talya

      Weiss, Ariel Ginzberg, Sharon Perles, Lola Weiss, Lora Eshkar Sebban, Eva A. Turley,

      Elimelech Okon, Itamar Raz, and David Naor. Can CD44   be a mediator of cell

      destruction   ?  the  challenge of type 1 diabetes . PLoS One. 2015; 10(12): e0143589

152. David Naor .Editorial: Interaction between hyaluronic acid and its receptors  

       (CD44,RHAMM) regulates the activity of inflammation and cancer .  Front. Immunol.

       7:39.doi: 10.3389/fimmu.2016.00039

153. Barzilay R, Ventorp F, Segal-Gavish H, Aharony I, Bieber A, Dar S, Vescan M,

       Globus R, Weizman A, Naor D, Lipton J, Janelidze S, Brundin L, Offen D.CD44

       Deficiency Is Associated with Increased Susceptibility to Stress-Induced Anxiety-like

       Behavior in Mice. J Mol Neurosci. 2016 Sep 13.

154. Pinner E, Gruper Y, Ben Zimra M, Kristt D, Laudon M, Naor D, Zisapel N CD44

       Splice Variants as Potential Players in Alzheimer’s Disease Pathology. J Alzheimers Dis.

       58(4):1137-1149. 2017

155. Beider K, Naor D, Voevoda V, Ostrovsky O, Bitner H, Rosenberg E, Varda-Bloom

    N, Canaani J, Danilesko I, Shimoni A, and Nagler A., Dissecting the mechanisms

       involved in anti-human T-lymphocyteimmunoglobulin (ATG)-induced tolerance in the

       setting of allogeneic stem cell transplantation – potential implications for Graft versus

       Host Disease. Oncotarget, 8(53):90748-90765, 2017

156. Toshiyuki Murai, Hiroto Kawashima and David Naor. Editorial: Cell-Cell and Cell-

       Matrix Adhesion in Immunobiology and Cancer. Front. Immunol. 10:3126. doi:

      10.3389/fimmu.2019.03126

157. D. Naor, M. Hemed-Shaked, M. Cowman, J Kim, J. Armengol, J. Alemany, D.Kanduc, A human-derived 5-mer peptide (MTADV), which restrictively alleviates the pro-inflammatory activity of serum amyloid a (SAA), substantially ameliorates IBD pathology: new potential drug (MTADV) and therapeutic target candidate (SAA) for IBD. Inflamm. Bowel Dis. 6:S3–4 (2020)

158. Maayan Hemed-Shaked , Mary K Cowman  , Jin Ryoun Kim  , Xiayun Huang  , Edward Chau, Haim Ovadia, Keren-Or Amar  , Lora Eshkar-Sebban  , Michal Melamed  , Libat Bar Lev  , Eli Kedar  , Jordi Armengol  , Jorge Alemany  , Shaul Beyth, Eli Okon, Darja Kanduc, Sharona Elgavish  , Shulamit B Wallach-Dayan  , Shmuel Jaffe Cohen  , David Naor     MTADV 5-MER peptide suppresses chronic inflammations as well as autoimmune pathologies and unveils a new potential target-Serum Amyloid A . J Autoimmun . 2021 Nov; 124:102713

159. David Naor, Mary Cowman, Jin Kim, Maayan Hemed-Shaked . MTADV 5-MER PEPTIDE SUPPRESSES IBD PATHOLOGY AND UNVEILS A NEW POTENTIAL TARGET-SERUM AMYLOID A. Gastroenterology Vol. 162, No. 3S.

• Prof Mary Cowman,     Tandon School of Engineering, New York University, New York, NY, United States
• Dr Jin Ryoun Kim,  Othmer-Jacobs Department of Chemical and Biological Engineering, Polytechnic Institute of New York University,  Brooklyn, USA
• Prof Hanna Rosenmann, Department of Neurology,The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center
• Prof Dimitrios Karusis, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
• Dr Ibrahim Kassis, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
• Prof Ehud Cohen, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel–Canada, Hebrew University, School of Medicine, Jerusalem, Israel