Martin S. Kluger, Ph.D.

Research Scientist, Department of Dermatology, Interdepartmental Program in Vascular Biology and Transplantation

Director, Endothelial Cell Culture Core, Yale Skin Disease Research Center

Director, Yale University School of Medicine Dermatology Scientific Lecture Series

Research Interests

1. The biology of vascular leak in cancer and inflammation: how endothelial cell permeability is regulated by junctional molecules and by the actin cytoskeleton.
2. How vascular endothelial cells use adhesion molecules and chemokines present on their surface for recruiting circulating T cells from blood.
3. Specializations of cultured blood vessel- and lymphatic vessel-derived endothelial cells.

Research Program

Endothelium loses permselectivity upon encountering tumor-derived factors or inflammatory cytokines such as VEGF or TNF. Loss of permselectivity, vascular leak, leads to tissue swelling (edema, a normal consequence of inflammation). But vascular leak is harmful (as in bacterial sepsis), is a limiting toxicity of anti-tumor cytokine therapy, and can promote tumor growth by creating an abnormal tissue environment. Adhesion molecule expression on the endothelial cell (EC) surface contributes to chronic inflammatory and malignant disease. On this subject we found that expression of intercellular adhesion molecule-1 (ICAM-1) contributes to actin cytoskeleton reorganization and to structural alterations at endothelial junctions, changes that are associated with vascular leak. We observed leakiness in human dermal microvascular EC (HDMEC) transductants expressing high levels of ICAM-1; they allowed transmonolayer passage of blood macromolecules, showing fragmented and interdigitized junctional immunostaining for the intercellular scaffolding molecule zona occludens-1 (ZO-1; Figure 1; chosen for the cover of the Annual Report of the Yale School of Medicine Interdepartmental Program in Vascular Biology and Transplantation in 2006). We have received new funding for examining vascular hyperpermeability in melanoma. In this project, we are developing in vivo and in vitro models for identifying the cellular and molecular mechanisms of tumor vessel hyperpermeability. Adhesion molecules and chemokines expressed on the EC surface are necessary for T cell recruitment from blood into normal and diseased tissues. In this second research area, we have demonstrated that, in the absence of cytokine-driven endothelial activation, adhesion molecule and chemokine surface expression is sufficient for transendothelial migration of human CD4+ effector memory T cells. Phenotypic differences among cultured EC derived from lymphatic and blood-carrying microvessels may correlate with different functional roles in vivo. A third area of research interest being pursued through the Cell Culture Core of the Yale Skin Disease Research Center is comparing the barrier properties and signaling pathways of microvascular EC derived from these different types of vessels.

Education:	B.A., Yale University, magna cum laude M.S., University of Connecticut Ph.D., University of Connecticut
Training:	Postdoctoral Training, Dermatology and Immunobiology, Yale University School of Medicine

Publications

• Clark, P, Manes TD, Pober JS, Kluger MS (2006) Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and junctional alterations. J Invest Dermatol in press.
• Ranjbaran H, Wang Y, Manes TD, Yakimov, AO, Akhtar, S, Kluger, MS, Pober, JS, Tellides, G (2006) Heparin Displaces Interferon-{gamma}-Inducible Chemokines (IP-10, I-TAC, and Mig) Sequestered in the Vasculature and Inhibits the Transendothelial Migration and Arterial Recruitment of T Cells. Circulation 114; 114(12):1293-300.
• Manes, T, Pober, JS and Kluger, MS (2006) IP-10 Stimulates Rapid Transendothelial Migration of Human Effector but not Central Memory CD4+ T Cells: Requirements for Shear Stress and Adhesion Molecules. Transplantation. 82: S9-S14.
• Li JH, Kluger MS, Madge LA, Zheng L, Bothwell AL, and Pober JS (2002) Interferon-gamma augments CD95(APO-1/Fas) and pro-caspase-8 expression and sensitizes human vascular endothelial cells to CD95-mediated apoptosis. Am J Pathol. 2002; 161:1485-1495.
• Kluger, MS, Shiao, SL, Bothwell, ALM, and Pober, JS (2002) Cutting Edge: Internalization of transduced E-selectin by cultured human endothelial cells: comparison of dermal microvascular and umbilical vein cells and identification of a phosphoserine-type di-leucine motif. J Immunol. 168:2091-2095.
• Gaeta, ML, Johnson, DR, Kluger, MS and Pober, JS (2000) The death domain of tumor necrosis factor receptor 1 is necessary but not sufficient for Golgi retention of the receptor and mediates receptor desensitization. Lab Invest. 80:1185-1194.
• Schechner, JS, Nath, AK, Zheng, L, Kluger, MS, Hughes, CC, Sierra-Honigmann, MR, Lorber, MI, Tellides, G, Kashgarian, M, Bothwell, AL and Pober, JS (2000) In vivo formation of complex microvessels lined by human endothelial cells in an immunodeficient mouse. Proc Natl Acad Sci U S A. 97:9191-9196.
• Zheng, L, Dengler, TJ, Kluger, MS, Madge, LA, Schechner, JS, Maher, SE, Pober, JS, and Bothwell, AL (2000) Cytoprotection of human umbilical vein endothelial cells against apoptosis and CTL-mediated lysis provided by caspase-resistant bcl-2 without alterations in growth or activation responses. J Immunol. 164:4665-4671.
• Kluger, MS, Johnson, DR and Pober, JS (1997) Mechanism of sustained E-selectin expression in cultured human dermal microvascular endothelial cells. J Immunol.158:887-896.

Invited Reviews

• Pober, J.S., Kluger, M.S. and J.S. Schechner. 2001. T cell homing to skin and endothelial cell presentation of antigen. In Cutaneous T Cell Lymphoma: Basic and Clinically Relevant Biology (Ed. Richard Edelson and Vincent T. DeVita ) Annals of the New York Academy of Sciences. 941:12-25.
• Kluger, M.S. 2004. Vascular Endothelial Cell Adhesion and Signaling during Leukocyte Recruitment. In Advances in Dermatology, (Ed., Sam Hwang) Vol. 20, pp. 163-201, N.Y., Elsevier. PDF version available

Recent Presentations

• September 11, 2006 – Invited Speaker, Cambridge-Yale Cardiovascular Research Programme, Trinity Hall, Cambridge University, UK. “A Novel Role for ICAM-1 in Vascular Leak”
• April 19, 2006 – 7th NHLBI Proteomics Investigators Meeting, Stanford University, Palo Alto, CA. “Targeting Endothelial Cell Proteins with Cell Permeable Peptides”
• November, 2005 –Section of Cutaneous Oncology, Yale University School of Medicine. “Vascular Leak and T cell Recruitment: Connections to Cancer.”
• October, 2005 - Interdepartmental Vascular Biology and Transplantation Seminar Series, Yale School of Medicine, Yale University School of Medicine, New Haven, CT. “ICAM-1 in Vascular Leak and IP-10 in T cell Recruitment: Molecular Keys to the Endothelial Gate”
• August, 2005 – Fourth Annual Yale-Cambridge Joint Cardiovascular Research Meeting, Yale University School of Medicine, New Haven, CT. “Control of Vascular Leak by a TNF-activated Factor.”
• February, 2005 – Yale Dermatology Scientific Lecture Series, Department of Dermatology, Yale University School of Medicine, New Haven, CT. “Vascular Endothelial Cell Adhesions and Signaling during Leukocyte Recruitment.”
• May, 2004 – Society for Investigative Dermatology, Angiogenesis and Vascular Biology Section, Providence, RI. "ICAM-1 as a basis for vascular leak induced by cytokine-mediated endothelial cell activation."

Patents

• “Selective modulation of Tumor Necrosis Factor Receptors in Therapy”, International PCT Application No., PCT/GB2006/001313 filed 11 April 2006.

 

Contact

Campus Address
Yale School of Medicine
333 Cedar Street 501 LCI
New Haven, CT 06520-8059

Clinical Office
Yale Dermatology Associates, P.C.
2 Church Street South, Suite 305
New Haven, CT 06519

Phone
(203) 737-2870

Email
martin.kluger@yale.edu