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Jordan S. Orange, MD, PhD

Expertise

CLINICAL:

Genetic immunodeficiency disorders
Natural Killer cell deficiencies

ITMAT:

Dr. Orange is interested in determining the role of natural killer cells in human host defense through the study of inborn genetic errors that affect natural killer cell function. The laboratory has identified a specific functional defect in NK cells of patients with the Wiskott-Aldrich syndrome and has recently opened a phase-I clinical trial based upon these findings (www.wastherapy.com).

OTHER:

Natural killer (NK) cells are lymphocytes critical to host defense that play important roles in surveillance of tumor cells as well as in control of viral infections. They do not undergo genetic recombination to attain specificity and therefore are part of the innate immune system. NK cells mediate cytotoxicity by extruding secretory lysosomes in a directed manner after a favorable balance between the ligation of activating and inhibiting receptors has been achieved. The foundations of NK cell activities and regulation therefore lie at the interface between NK cells and cells with which they are interacting. Molecules accumulate in this region and result in a dynamic structure called the NK cell immunologic synapse (NKIS).

My laboratory is investigating the formation, function and regulation of the NKIS. We have focused upon the cytoskeleton as a critical juncture for these processes due to an interest in a human disease that impairs cytoskeletal function called the Wiskott-Aldrich syndrome. Using cells from patients with this disorder, as well as various cytoskeletal inhibitors, we have shown that the activating NKIS is actin-dependent. This is in contrast to the inhibitory NKIS, which is actin-independent. We have also identified sequential steps required for creation of the activating NKIS and have demonstrated that actin reorganization precedes and is required for microtubular function at the synapse. The microtubules are then needed to translocate lytic granules to the center of the NKIS called the central supramolecular activation cluster (cSMAC). Most recently our work has focused upon cytoskeletal events critical in forming the activating NKIS and we have been evaluating actin complex-associated proteins for their role in granule localization to the cSMAC. We are additionally studying how molecular rearrangement at the NKIS results in activation-induced transcriptional regulation and how this ultimately affects cytotoxic function. NK cells are a most useful model for these studies because they have an easily defined function and a more gradual activation process attributed to the interplay of activating and inhibitory receptors.

RESEARCH:

Research Interests
Directed secretion at the cytolytic immunological synapse
Role of NF-kB activation in cytolytic function

Key words: Natural killer cells, immunological synapse, cytotoxicity,
secretory lysosomes.

Description of Research
Natural killer (NK) cells are lymphocytes critical to host defense that play important roles in surveillance of tumor cells as well as in control of viral infections. They do not undergo genetic recombination to attain specificity and therefore are part of the innate immune system. NK cells mediate cytotoxicity by extruding secretory lysosomes in a directed manner after a favorable balance between the ligation of activating and inhibiting receptors has been achieved. The foundations of NK cell activities and regulation therefore lie at the interface between NK cells and cells with which they are interacting. Molecules accumulate in this region and result in a dynamic structure called the NK cell immunologic synapse (NKIS).

My laboratory is investigating the formation, function and regulation of the NKIS. We have focused upon the cytoskeleton as a critical juncture for these processes due to an interest in a human disease that impairs cytoskeletal function called the Wiskott-Aldrich syndrome. Using cells from patients with this disorder, as well as various cytoskeletal inhibitors, we have shown that the activating NKIS is actin-dependent. This is in contrast to the inhibitory NKIS, which is actin-independent. We have also identified sequential steps required for creation of the activating NKIS and have demonstrated that actin reorganization precedes and is required for microtubular function at the synapse. The microtubules are then needed to translocate lytic granules to the center of the NKIS called the central supramolecular activation cluster (cSMAC). Most recently our work has focused upon cytoskeletal events critical in forming the activating NKIS and we have been evaluating actin complex-associated proteins for their role in granule localization to the cSMAC. We are additionally studying how molecular rearrangement at the NKIS results in activation-induced transcriptional regulation and how this ultimately affects cytotoxic function. NK cells are a most useful model for these studies because they have an easily defined function and a more gradual activation process attributed to the interplay of activating and inhibitory receptors.

Rotation Projects for 2006-2007
1. Mechanism by which NF-kB essential modulator function and NF-kB activation enable cytolytic function
2. Biochemical and spatial evaluation of functional linkages between the actin cytoskeleton and the microtubular network in formation of the cytolytic immunological synapse.
3. Requirements for and behavior of secretory lysosome traffic to the cytolytic immunological synapse

Lab personnel:
Linda Monaco Shawver - Research Technician Level III
Raquel P. Deering - Research Technician Level II
Christine Destephan - Research Technician Level I
Pinaki P. Banerjee - Postdoctoral Fellow
Rahul Pandey - Postdoctoral Fellow
Eric Hanson - Postdoctoral Fellow

Appointments

Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine (2003 – present)

Education

M.D., Brown University (1997)

Ph.D., Pathobiology, Brown University (1996)

A.B., Biology, Brown University (1990)

Selected Publications

Orange, J.S.. Natural killer cell deficiency syndromes.. UpToDate. Vol 12.1. In Press.

Orange JS, Brodeur SR, Jain A, Ballas ZK, Schneider LC, Bonilla FA, Geha RS. The spectrum of clinical phenotype and immunodeficiency due to NFkB essential modifier (NEMO) mutation. J. Allergy Clin. Immunol.. Vol 111. 2003:S190.

Levy, O., Orange, J.S., Hibberd, P., Steinberg, S., LaRussa, P., Weinberg, A., Wilson, B.S., Shaulov, A., Fleischer, G., Geha, R.S., Bonilla, F.A., Exley, M.. Disseminated Varicella infection due to vaccine (Oka) strain Varicella zoster virus in a patient with a novel deficiency in natural killer T cells.. J. Infect. Dis.. Vol 188. 2003 OCT:948-953.

Orange, J.S., Harris, K.E., Andzelm, M.M., Valter, M.M., Geha, R.S., and Strominger, J.L.. The activating natural killer cell immunologic synapse is formed in distinct stages. Proc. Natl. Acad. Sci. Vol 100. 2003 NOV:14151-14156.

Orange, J.S. and R.S. Geha.. Finding NEMO: genetic disorders of NF-kB activation.. J. Clin Invest.. Vol 112. 2003:983-985.

Orange, J.S. and Strominger, J.L.. Natural killer cells from a structure at their interface with susceptible target cells.. Harvard University Department of Cell and Molecular Biology external web page. 2003.

Orange JS, Brodeur SR, Jain A, Bonilla FA, Schneider LC, Kretschmer R, Nurko S, Rasmussen WL, Koehler JR, Gellis SE, Fergusson BM, Strominger JL, Zonnana J, Ramesh N, Ballas ZK, Geha RS. Deficiency of natural cytotoxicity in patients with IKKy/NEMO mutations. J. Clin. Invest.. Vol 109. 2002 JUN:1501-1509.

Orange JS, Ramesh N, Remold-O'Donnell E, Sarahara Y, Koopman L, Bryne M, Bonilla FA, Rosen FS, Geha RS, Strominger JL. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin in NK cell activating immunologic synapses. Proc. Nat. Acad. Sci. USA. Vol 99. 2002 AUG:1351-1356.