Principal Investigator
Goldyne Savad Institute of Gene Therapy
Phone: 972-2-677-8784
Fax: 972-2-643-0982
Email: peled@hadassah.org.il
Academic Rank
Senior Lecturer
Affiliation
Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Education
1984 B.Sc. (cum laude) Hebrew University, Dept. of Plant Protection, Faculty of Agriculture, Rehovot, Israel
1987 M.Sc. (cum laude) Tel Aviv University School of Medicine, Dept. of Histology and Cell Biology. Thesis: "Inhibition of growth and induction of differentiation by butyric acid in mouse and human melanoma cell lines"
1994 Ph.D. The Weizmann Institute of Science, Dept. of Cell Biology. Thesis: "Molecular and Cellular Analysis of Stroma dependent hemopoiesis:
Research interests
Chemokines, chemokine receptors, tumor metastasis, inflammation, natural killer cells.
Selected recent publications
Darash-Yahana M, Gillespie JW, Hewitt SM, Chen YY, Maeda S, Stein I, Singh SP, Bedolla RB, Peled A, Troyer DA, Pikarsky E, Karin M, Farber JM. 2009. The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers. PLoS One 4(8):e6695.
Rudich N, Zamir G, Pappo O, Shlomai Z, Faroja M, Weiss ID, Wald H, Galun E, Peled A, Wald O. 2009. Focal liver necrosis appears early after partial hepatectomy and is dependent on T cells and antigen delivery from the gut. Liver Int 29(8):1273-84.
Beider K, Abraham M, Begin M, Wald H, Weiss ID, Wald O, Pikarsky E, Abramovitch R, Zeira E, Galun E, Nagler A, Peled A. 2009. Interaction between CXCR4 and CCL20 pathways regulates tumor growth. PLoS ONE 4(4):e5125.
Abraham M, Beider K, Wald H, Weiss ID, Zipori D, Galun E, Nagler A, Eizenberg O, Peled A. 2009. The CXCR4 antagonist 4F-benzoyl-TN14003 stimulates the recovery of the bone marrow after transplantation. Leukemia
Burger JA, Peled A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. 2009. Leukemia 23:43-52.
Beider K, Abraham M, Peled A. Chemokines and chemokine receptors in stem cell circulation. 2008. Front Biosci 13:6820-33. Review.
Lapidot A, Peled A, Berchanski A, Pal B, Kollet O, Lapidot T, Borkow G. 2008. NeoR6 inhibits HIV-1-CXCR4 interaction without affecting CXCL12 chemotaxis activity. Biochim Biophys Acta 1780(6):914-20.
Abraham M, Biyder K, Begin M, Wald H, Weiss ID, Galun E, Nagler A, Peled A. 2007. Enhanced Unique Pattern of Hematopoietic Cell Mobilization Induced by the CXCR4 Antagonist 4F-benzoyl-TN14003. Stem Cells 25(9):2158-66.
Wald O, Weiss ID, Galun E, Peled A. 2007. Chemokines in hepatitis C virus infection: Pathogenesis, prognosis and therapeutics. Cytokine 39(1):50-62.
Abraham M, Biyder K, Begin M, Wald H, Weiss ID, Galun E, Nagler A, Peled A. 2007. Enhanced Unique Pattern of Hematopoietic Cell Mobilization Induced by the CXCR4 Antagonist 4F-benzoyl-TN14003. Stem Cells 25(9):2158-2166.
Hidalgo-Grass C, Mishalian I, Dan-Goor M, Belotserkovsky I, Eran Y, Nizet V, Peled A, Hanski E. 2006. A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues. EMBO J 25(19):4628-37.
Wald O, Izhar U, Amir G, Avniel S, Bar-Shavit Y, Wald H, Weiss ID, Galun E, Peled A. 2006. CD4+CXCR4highCD69+ T Cells Accumulate in Lung Adenocarcinoma. J Immunol 177(10):6983-90.
Eldor R, Yeffet A, Baum K, Doviner V, Amar D, Ben-Neriah Y, Christofori G, Peled A, Carel JC, Boitard C, Klein T, Serup P, Eizirik DL, Melloul D. 2006. Conditional and specific NF-{kappa}B blockade protects pancreatic beta cells from diabetogenic agents. Proc Natl Acad Sci USA 28;103(13):5072-7.
Wald O, Weiss ID, Wald H, Shoham H, Bar-Shavit Y, Beider K, Galun E, Weiss L, Flaishon L, Shachar I, Nagler A, Lu B, Gerard C, Gao JL, Mishani E, Farber J, Peled A. 2006. IFN-{gamma} Acts on T Cells to Induce NK Cell Mobilization and Accumulation in Target Organs. J Immunol 176(8):4716-29.
Avniel S, Arik Z, Maly A, Sagie A, Basst HB, Yahana MD, Weiss ID, Pal B, Wald O, Ad-El D, Fujii N, Arenzana-Seisdedos F, Jung S, Galun E, Gur E, Peled A. 2006. Involvement of the CXCL12/CXCR4 pathway in the recovery of skin following burns. J Invest Dermatol 126(2):468-76.
Dagan-Berger M, Feniger-Barish R, Avniel S, Wald H, Galun E, Grabovsky V, Alon R, Nagler A, Ben-Baruch A, Peled A. 2006. Role of CXCR3 carboxyl-terminus and third intracellular loop in receptor-mediated migration, adhesion, and internalization in response to CXCL11. Blood 107(10):3821-31.
Ahlenstiel G, Iwan A, Nattermann J, Bueren K, Rockstroh JK, Brackmann HH, Kupfer B, Landt O, Peled A, Sauerbruch T, Spengler U, Woitas RP. 2005. Distribution and effects of polymorphic RANTES gene alleles in HIV/HCV coinfection -- a prospective cross-sectional study. World J Gastroenterol. Dec 28;11(48):7631-8.
Petit I, Goichberg P, Spiegel A, Peled A, Brodie C, Seger R, Nagler A, Alon R, Lapidot T. 2005. Atypical PKC-zeta regulates SDF-1-mediated migration and development of human CD34+ progenitor cells. J Clin Invest 115:168-176.
Avniel S, Arik Z, Maly A, Sagie A, Basst HB, Yahana MD, Weis ID, Pal B, Wald O, Ad-El D, Fujii N, Arenzana-Seisdedos F, Jung S, Galun E, Gur E, Peled A. 2005. Involvement of the CXCL12/CXCR4 pathway in the recovery of skin following burns. J Invest Dermatol. 2006 Feb;126(2):468-76.
Byk T, Kahn J, Kollet O, Petit I, Samira S, Shivtiel S, Ben-Hur H, Peled A, Piacibello W, Lapidot T. Cycling G1 CD34+/CD38+ cells potentiate the motility and engraftment of quiescent G0 CD34+/CD38-/low severe combined immunodeficiency repopulating cells. 2005. Stem Cells Apr;23(4):561-74.
Wald O, Pappo O, Ari ZB, Azzaria E, Weiss ID, Gafnovitch I, Wald H, Spengler U, Galun E, and Peled A. 2004. The CCR5Delta32 allele is associated with reduced liver inflammation in hepatitis C virus infection. Eur J Immunogenet 31:249-52.
Spiegel A, Kollet O, Peled A, Abel L, Nagler A, Bielorai B, Vormoor J, Fujii N, Rechavi G, and Lapidot T. 2004. Unique SDF-1 induced activation of human precursor-B ALL cells due to altered CXCR4 signaling and expression. Blood 15;103(8):2900-7.
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. 2004. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ progenitors to the bone marrow. Blood 15;103(8):2981-9.
Wald O, Pappo O, Safadi R, Dagan-Berger M, Beider K, Wald H, Franitza S, Weiss I, Avniel S, Boaz P, Hanna J, Zamir G, Eid A, Mandelboim O, Spengler U, Galun E and Peled A. 2004. Involvement of the CXCL12/CXCR4 Pathway in Advanced Hepatitis C and B Virus-Associated Liver Disease. Eur J Immunol 34(4):1164-74.
Franitza S, Grabovsky V, Wald O, Weiss I, Beider K, Dagan-Berger M, Darash-Yahana M, Nagler A, Brocke S, Galun E, Alon R, Peled A. 2004. Differential usage of VLA-4 and CXCR4 by CD3+CD56+ NK T and CD56+CD16+ NK cells regulates their interaction with endothelial cells. Eur J Immunol 34:1333-1341.
Darash-Yahana M, Pikarsky E, Karplus R, Boaz P, Zeira E, Abramovitch R, Galun E, and Peled A. 2004. Role of high expression levels of CXCR4 in tumor growth, vascularization and metastatis. FASEB J 18:1240-1242.
Samira S, Ferrand C, Peled A, Nagler A, Ben-Hur H, Tovbin Y, Taylor N, Globerson A and Lapidot T. 2004. Tumor necrosis factor promotes human T-cell development in nonobese diabetic/severe combined immunodeficient mice. Stem Cells 22:1085-1100.
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, Lapidot T. 2004. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow. Blood 103:2981-2989.
Beider K, Nagler A, Wald O, Franitza S, Dagan-Berger M, Wald H, Giladi H, Brocke S, Hanna J, Mandelboim O, Darash-Yahana M, Galun E, Peled A. 2003. Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice. Blood 102:1951-1958.
Hanna J., Wald O, Goldman-Whol D, Prus D, Markel G, Gazit R, Katz G, Haimov-Kochman R, Fujii N,, Yagel S, Peled A, Mandelboim O. 2003. CXCL12 expression by invasive trophoblasts induces the specific migration of CD16-human natural killer cells. Blood 102:1569-1577.
Peled A, Hardan I, Trakhtenbrot L, Gur E, Magid M, Darash-Yahana M, Cohen N, Grabovsky, V, Franitza S, Kollet O, Lider O, Alon R, Rechavi G, and Lapidot T. 2002. Immature leukemic CD34+CXCR4+ Cells from CML patients have reduced integrin-dependent migration and adhesion in response to the chemokine SDF-1. Stem Cells 20:259-266.
Kollet O, Petit I, Kahn J, Samira S, Dar A, Peled A, Deutsch V, Gunetti M, Piacibello W, Nagler A, and Lapidot T. 2002. Human CD34+CXCR4- sorted cells harbor intracellular CXCR4, which can functionally be expressed and provide NOD/SCID repopulation. Blood 100:2778-86.
Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T. 2002. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 3:687-94.
Patents
1. Gutierrez-Ramos J.C.,, Peled A “Methods for diagnosing and treatment of diseases associated with abnormal levels of myeloid cells utilizing Eotaxin and antagonists and agonists thereof.” 1998, Harvard Medical School, the Center for Blood Research. U.S. Provisional Application No. 60/056, 734.
2. Lapidot T, Peled A “Hematopoietic cell composition for use in transplantation,” 1999. The Weizmann Institute of Science, Rehovot, Israel.
3. Wald O, Galun E, Peled A: Pharmaceutical compositions comprising CCR5 antagonists. 2003.
4. Wald O, Galun E, Weiss I, Peled A: Use of IFN- and IL-18 pathway to induce the mobilization of NK cells during viral infection, tumor metastasis, and donor lymphocyte infusion. 2004.
Research group
Beider, Katia (Ph.D. student) Phone: 677-8783
Wald, Hanna, Ph.D. (Res. Associate) Phone: 677-8881
Wald, Ori (M.D./Ph.D. student) Phone: 677-8827/8784
Weiss, Ido (Ph.D. student) Phone: 677-8784
Clausen, Mery, B.A. (editor) Phone: 677-8881
Avraham, Michal, Ph.D., postdoc
Rudich, Noah, M.Sc. student
Sadeh, Neta, M.Sc. student
Collaborators
Prof. A. Nagler, Department of Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel
Prof. E. Galun, Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel.
Dr. E. Pikarsky, Departments of Pathology and Cytology, Jerusalem Hadassah University Hospital, Israel.
Prof. I. Shahar, Department of Pulmonary Diseases and Allergy Center, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Prof. J. Farber, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, MD.
RESEARCH SUMMARY
I. Background and Objectives-
In recent years, chemokines, a family of structurally related proteins that play an essential role in the recruitment and activation of cells from the immune system, have received increasing attention due to their critical role in the progression of immune disease states such as Asthma, Atherosclerosis, Graft Rejection, AIDS, and Multiple Sclerosis (MS). Many cancers express an extensive network of chemokines and chemokine receptors. These tumors are characterized by a disregulated production of chemokines and an abnormal chemokine receptor signaling and expression. Because of their varied activities, chemokines are potentially valuable targets for therapeutic intervention in a wide range of human diseases. In the past few years, we found that the chemokine receptor, CXCR4, and its ligand, CXCL12, play a crucial role in the trafficking of hematopoietic stem cells to the bone marrow (BM, ref). The involvement of the CXCR4/CXCL12 axis in this process makes this chemokine-receptor pair of particular interest in investigating their role in tumor growth and metastasis to the BM. During the past four years, our first objective was to study the role of the chemokine-receptor pair, CXCL12/CXCR4, in the development, maintenance and metastasis of tumors which are known to metastasize to the BM, such as prostate cancer, or tumors which originate from the BM such as chronic myeloid leukemia (CML). NK cells are the key effector cells mediating the graft-versus- leukemia (GVL) effect, which is used to control minimal residual disease (MRD) and for re-induction of remission in CML patients who relapse post-allo-stem cell transplantation. The molecular mechanisms that regulate the homing during transplantation and retention of NK cells to and within the tumor microenvironment are mostly not known. Furthermore, the role of chemokines in this process is not well understood. Thus, the second objective of our research was focused on understanding the mechanisms that regulate NK trafficking and targeting of these cells into tumors.
II. Summary of Findings and future goals:
-Role of high expression levels of CXCR4 in tumor growth, vascularization and metastasis
Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. Prostate neoplasms tend to metastasize to the bone marrow. Our study suggests a critical role for CXCR4 in the development of prostate tumors. However, in contrast to the current views on the role of CXCR4 as a chemotactic factor that induces tumor metastasis by cell migration, our in vitro and in vivo studies indicate that rather than acting merely as a homing receptor for circulating tumor cells, CXCR4 acts a positive regulator for tumor growth inducing cell proliferation, survival and neovascularization in the primary and distant metastatic tumor site. CML is a malignant myeloproliferative disorder caused by the (9,22)(q34.1; q11.21) translocation that generates the BCR/ABL fusion oncogene producing the philadelphia chromosome, designated Ph+. CML is characterized by the abnormal release of the expanded malignant stem cell clone from the BM into the circulation. Previous studies have shown that cell lines expressing CXCR4 and transfected with bcr/abl demonstrate reduced migration to CXCL12. Our study suggests that both migration as well as the CXCL12 mediated integrin-dependent polarization and adhesion of Ph+CD34+CXCR4+ cells is significantly reduced. In contrast to the defect in migration and adhesion, in CML cells, CXCR4 acts a positive regulator for tumor growth inducing both cell proliferation and survival. Our findings support a role for CXCR4 in cancer cells spreading within the BM tissue by enhancing proliferation, survival, and accelerating angiogenesis. What then are the precancerous molecular pathways regulated by CXCR4 in prostate cancer and CML? To further study these questions, we intend to identify genes whose expression is regulated by CXCR4 stimulation and are involved in the aggressive phenotype of prostate tumor cells. A comparison between the expression pattern of CXCL12 stimulated and non stimulated PC3LG-CXCR4 was performed by screening human DNA chip arrays using the Affymatrix genechip expression analysis system. Genes found to be differentially expressed in CXCL12-stimulated and -non stimulated cells will be further evaluated by PCR and ELISA assays and their expression pattern in prostate tumor samples will be evaluated by immunohistochemistry. The role of genes that are regulated by CXCR4 and are expressed in prostate tumors will be tested in in vivo experimental animal models for prostate cancer developed in our laboratories.
- Role of chemokines and their receptors in NK trafficking
Classical NK cells are non T cell lymphocytes lacking the expression of T-cell receptor (TCRs). NK cells are dependent upon the BM for development and are present as mature populations in blood and spleen. Upon stimulation, NK cells are recruited to sites of viral infection and tumor metastasis, are involved in the lysis of tumor cells and are critical for the control of viral infections. NK cells are also key effector cells mediating the graft-versus-leukemia (GVL) effect and are important for low intensity conditions (LIC) and non myeloablative allogeneic stem cell transplantation (NST). However, the mechanism(s) that regulates the trafficking of NK cells to the BM during transplantation is unknown. Our study suggests a critical role for CXCR4 in the homing and retention of human NK cells to and in the BM of NOD/SCID mice. To reach the BM, NK cells have to establish firm contacts with the endothelium and effectively cross the BM endothelial cell barrier under disruptive blood flow. The BM endothelium constitutively expresses selectins, the integrin ligands, VCAM-1 and ICAM-1, and the chemokine CXCL12. NK cells exhibited tethering and rolling interactions on both P and E selectins and expressed the integrins, VLA-4 and LFA-1. CXCL12, the ligand for CXCR4, rapidly stimulated the adhesion of NK cells and to VCAM-1 and ICAM-1. Furthermore, the arrest on VCAM-1 was dependent on high affinity VLA-4 and the homing of these cells to the BM of NOD/SCID was VLA-4-dependent. This study therefore suggests an important role for CXCR4 levels of expression and VLA-4 in regulating the interaction of NK cells with the BM endothelium. Treatment of NK cells with IL-2 inhibited their migration in response to CXCL12 and their homing and retention in the BM. In contrast to CXCR4, the expression levels of the chemokine receptor, CXCR3, and the migration of cells in response to its ligands CXCL9 and CXCL10, increased after IL-2 treatment. Thus, down-regulation of CXCR4 and up-regulation of CXCR3 following in vitro treatment of NK cells with IL-2 may direct the trafficking of cells to the site of inflammation rather than to hematopoietic organs and therefore may limit their alloreactive potential.
During inflammatory processes such as HCV and HBV, significant numbers of NK cells accumulate in the human liver relative to peripheral blood. Previous studies have shown that the chemokines receptors CCR1 and the CCR5 ligand, the chemokine CCL3, and the CXCR3 ligands, CXCL9 and CXCL10, play a crucial role in the recruitment of NK cells to the inflamed liver during murine cytomegalovirus (MCMV) infection. Our studies have shown that both CCR1 and CCR5 are involved in the trafficking of NK cells to the liver during ConA induced hepatitis. Furthermore, we found that liver inflammatory activity was significantly reduced in Jewish Israelis HCV patients carrying the CCR5D32 allele, a deletion mutation in the chemokine receptor CCR5. The CCR5D32 allele does not alter the susceptibility to HCV infection, however, decreased levels of CCR5 may affect viral clearance and liver damage. The role of chemokines and their receptors in leukocyte recirculation through the chronically inflamed liver is mostly unknown. Our observations suggest an important role for the CXCL12/CXCR4 pathway in the recruitment and retention of immune cells in the liver during chronic HCV and HBV infections.