Janko Nikolich-Zugich M.D. Ph.D.

Biography
Janko Nikolich-Zugich received his M.D. from Belgrade University Medical School in 1984. He later received an M.Sc. and a Ph.D. in Immunology from the same University. Dr. Nikolich-Zugich worked from 1987 to 1990 as a Research Associate at the Scripps Clinic and Research Foundation. In 1990, he joined the Memorial Sloan-Kettering Cancer Center in New York as the Head of both the Flow Cytometry Core Facility and the Laboratory of T Cell Development. He served as an Assistant Professor (1990-1996) and an Associate Professor (1996-2001) at both the Cornell University Graduate School of Medical Sciences and the Division of Molecular Medicine in Cornell University School of Medicine. He was recipient of the Pew Biomedical Scholar Award and the Louise and Allston Boyer Young Scientist Award. Dr. Nikolich-Zugich is currently a Senior Scientist at the Vaccine and Gene Therapy Institute and holds joint appointments as a Professor in the Department of Molecular Microbiology and Immunology and a Senior Scientist at the Oregon National Primate Research Center. He is member of the NIH Cellular and Molecular Immunology-B Study Section and of multiple NIA and NIAID review panels, and is on the organizing or scientific committees for several international conferences and meetings.Dr. Nikolich-Zugich can be reached by e-mail at nikolich@ohsu.edu.

Research Overview 
My laboratory is interested in the biology of cytotoxic T lymphocytes (CTL) in health, infection and aging.  Much of the studies are performed in the context of the relationship between immunity and pathogens over the lifespan of the organism, with a specific emphasis upon the age-related defects in immunity and defects in homeostasis of the immune system.   Diagnosis of the most critical, primary defects in innate and adaptive immunity of the old age is being followed by studies to repair or modulate those defects by immune intervention as well as by tailored, rational vaccine design. Our studies are often pursued by vertical model integration - using broad and fundamental studies in rodents to crystallize questions to be asked and verified in non-human primates, leading to final and most relevant studies in humans. The main virus targets of these studies are herpesviruses (HSV and CMV) and flaviviruses (chiefly the West Nile virus - WNV). 
 
All of our studies fall under the two broad topics: (i) understanding which CTL properties are most critical for virus elimination; and (ii) elucidating how are CTL maintained for life and why their biology is disturbed with old age. These are described in more detail below

Cytotoxic T lymphocyte biology and antiviral activity


One main topic of research of my lab focuses is the selection, recognition, function, and homeostasis of cytotoxic T lymphocytes. We employ a combination of structural, molecular, transgenic, and functional approaches, using crystallographic modeling, TCR sequence and CDR3 length analysis, soluble and cell-bound TCR:peptide:MHC interactions, transgenesis and site-directed mutagenesis, and functional immunological assays. The emphasis of our approach is on following and manipulating the CTL response in vivo. This allows us to precisely dissect the CTL recognition, CTL repertoire and CTL activation in a setting where CTLs combat natural pathogens or cancer in the course of a lifespan of an organism.

The projects include:

Detailed information on cytotoxic T lymphocyte studies is available here.

Immune senescence and its correction

Our second major interest is to understand decline of the immune function with aging, which is believed to be one of the contributing causes to the morbidity and mortality in old age. We are studying the fundamental mechanisms behind this decline in a series of studies in rodents and primates. Maintenance of T-cell repertoire diversity, T-cell homeostasis and the emergence of age-related T-cell clonal expansions (TCE) are all being studied. Another fascinating problem is the interaction of the immune system with life-long chronic and persisting pathogens from the herpesvirus family, and the impact of this interaction upon the aging immune system. These studies should pave way for the immune reconstitution and vaccine engineering experiments that will ameliorate and treat the undesirable consequences of immune senescence.
The projects include:

Detailed information on immune senescence studies is available here.

Selected recent peer-reviewed publications:

Messaoudi, I., J. Warner, and J. Nikolich-Zugich. 2006.Age-related CD8+ T-cell clonal expansions (TCE) express elevated levels of CD122 and CD127 and display defects in perceiving homeostatic signals. J. Immunol. 177:2784.

Messaoudi, I., J. Warner, D. Nikolich-Žugich, M. Fischer and J. Nikolich-Žugich. 2006. Molecular, Cellular and Antigen Requirements for Development of Age-associated T-cell Clonal  Expansions (TCE) in vivo. J. Immunol. 176:301.

Lang, A. and J. Nikolich-Žugich. 2005. Development and migration of protective CD8+ T-cells into the nervous system following ocular HSV-1 infection. J. Immunol. 174:2919

Messaoudi, I., J. LeMaoult, J.A. Guevara Patino,  B. Metzner, J. Nikolich-Žugich. 2004. Age-related CD8+ T-cell clonal expansions (TCE) constrict T-cell repertoire and have the potential to impair immune defense J. Exp. Med. 200:1347

Miley, M.J., I. Messaoudi, B.M. Metzner, Y. Wu, J. Nikolich-Žugich and D.H Fremont. 2004. Structural basis for the restoration of TCR recognition of an MHC allelic variant by peptide secondary anchor substitution. J. Exp. Med. 200:1445.

Jankovi?, V., I. Messaoudi and J. Nikolich-Žugich. 2003. Phenotypic and functional T-cell aging in Rhesus Macaques (Macaca mulatta) : differential behavior of CD4 and CD8 subsets.  Blood 102:3244.

Messaoudi, I., J.A. Guevara Patino, R. Dyall, J. LeMaoult, and J. Nikolich-Zugich. 2002. Direct link between mhc polymorphism, T-cell avidity and diversity in immune defense. Science 298:1797. (Download PDF)

Jankovic, V., K. Remus, A. Molano, and J. Nikolich-Zugich. 2002 T cell recognition of an engineered MHC class I molecule : Implications for peptide-independent alloreactivity J. Immunol. 169:1887.

 
A complete list of references is also available.

Full publication list – just add these papers to the existing list:

Nikolich-Žugich, J.  and I. Messaoudi. 2005. Mice and flies and monkeys too: Caloric restriction rejuvenates the aging immune system of non-human primates. Exp. Gerontol. 40:884.

Messaoudi, I., J. Warner, D. Nikolich-Žugich, M. Fischer and J. Nikolich-Žugich. 2006. Molecular, Cellular and Antigen Requirements for Development of Age-associated T-cell Clonal  Expansions (TCE) in vivo. J. Immunol. 176:301.

Braaten, D.C.*, J.S. McClellan*, I. Messaoudi*, S.A. Tibbetts, K.B. McClellan, D.W. White, J. Nikolich-Zugich# and H.W. Virgin IV#. 2006.  Effective control of chronic gammaherpesvirus infection by unconventional MHC Class Ia-independent CD8 T cells. PLOS Pathog. 2:e37.   * and # denote joint first and senior authorship, respectively.

Messaoudi, I., J. Warner, and J. Nikolich-Zugich. 2006.Age-related CD8+ T-cell clonal expansions (TCE) express elevated levels of CD122 and CD127 and display defects in perceiving homeostatic signals. J. Immunol. 177:2784.

 

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