Ilhem Messaoudi, Ph.D.

Biography
Dr. Ilhem Messaoudi received her B.Sc in Biochemistry from Lafayette College, Easton Pennsylvania in 1996.  She obtained her doctorate degree in immunology from Cornell University and Memorial Sloan Kettering Cancer Center in 2001. During her graduate tenure, she studied factors that influence the efficacy of the CD8 T cell response to viral infection. Dr. Messaoudi carried out her post-doctoral training in Dr. Janko Nikolich-Zugich’s laboratory at Oregon Health and Science University, Oregon National Primate Research Center where she focused on the characterization of changes in the phenotype and function of T cells with age in both mice and non-human primates. She is currently an assistant scientist at the Vaccine and Gene Therapy Institute, OHSU.

Research Overview
The emphasis of my laboratory is to further our understanding of mechanisms underlying age-related T cell immune deficiencies using nonhuman primate animal models. Aging is accompanied by an increase in susceptibility and severity of infectious diseases due to general decline in immunity. Since the proportion of aged individuals is rapidly increasing,  understanding the defects in the immune systems of this vulnerable population will undoubtedly help us design interventions to improve immunity and increase the efficacy of vaccinations that could alleviate disease complications. More specifically work in my laboratory is focused on two areas:
1) Elucidating immunological deficiencies that underlie varicella zoster virus (VZV) reactivation
2) Understanding the interplay between ovarian steroids and immunity in aged women as they undergo menopause
My laboratory is also part of a multidisciplinary project investigating the impact of high fat diet on organ systems. We believe that obesity accelerates immune senescence and increases susceptibility to infection.

VZV reactivation and herpes zoster:
VZV reactivation is a serious epidemiological problem for the elderly and immune compromised individuals. Although hardly life-threatening, VZV reactivation, which results in herpes zoster (HZ, more commonly known as shingles), causes severe pain and impacts the quality of life. The immunological basis for VZV reactivation is extremely poorly understood due to the lack of a suitable animal model. We have conducted preliminary studies at the Oregon National Primate Research Center that strongly suggest that infection of rhesus macaques (RM) with simian varicella virus (SVV) is an appropriate animal model to study VZV latency. The project has multiple facets aimed at identifying the role of different lymphocyte subsets in controlling the primary viral infection and maintaining viral latency. Furthermore, we are identifying immuno-dominant viral proteins that can be used to design non-replicating prophylactic subunit vaccines to boost anti VZV immunity in the elderly and immuno-compromised patients.

Ovarian senescence and its impact on immunity:
Aging is also accompanied by ovarian senescence in women (menopause), which exacerbates several age-related morbidities such as osteoporosis, cardiovascular disease and loss of cognitive abilities. Interestingly, osteoporosis has been linked to dys-regulation of cytokine secretion by T cells that influence bone metabolism, thereby establishing a complex interaction between immune senescence and menopause. However, the effects of aging cannot be dissected from those of ovarian senescence in human clinical studies since ovarian and immune senescence occur simultaneously. To address this ambiguity, we are studying the effect of surgical menopause in pre-menopausal females on T cell response to vaccination using a nonhuman primate animal model. Similar to humans, female RM have a 28-day menstrual cycle, undergo menopause, and are well suited for studying immune senescence. Furthermore, we are testing the impact of different hormone replacement regimens (HRT) on immune fitness.

The impact of obesity and insulin resistance on immune response to vaccination:
My laboratory is also engaged in a collaborative study to investigate the mechanisms by which obesity diminishes immunity. In the last decade, obesity has become one of the most serious public health crises in the United States for both children and adults. Adult obesity greatly increases the risk of cardiovascular disease, diabetes and cancer.  All of these diseases are accompanied by increased inflammatory cytokines. This heightened inflammatory state is now referred to as obesitis.  Abnormalities in immune function are likely to be associated with, or even the cause of, obesity related diseases such as poor wound healing, poor responses to vaccination, and cancer. However, the interplay between metabolism and immunity is poorly understood. Given our experience using nonhuman primates to evaluate the effect of caloric restriction on immunity, we are well positioned to carry out studies investigating the impact of adulthood obesity on lymphocyte homeostasis and function.

Selected References
Molano A., Erdjument-Bromage H., Fremont D. H., Messaoudi I., Tempst P., and Nikolic-Zugic J. (1998).  Peptide Selection by an MHC H-2Kb Class I Molecule Devoid of the Central Anchor (“C”) Pocket.  Journal of Immunology 160: 2815-2823.

Lilic M., Kulig K., Messaoudi I., Remus K., Jankovic M., Nikolic-Zugic J., and Vukmanovic S. (1999).  CD8+ T cell cytolytic activity independent of mitogen-activated protein kinase/ extracellular regulatory kinase signaling (MAP kinase/ ERK).  European Journal of Immunology 29 (12):3971-3977.

Messaoudi I., LeMaoult J., and Nikolic-Zugic J. (1999).  The mode of ligand recognition by two peptide:MHC class I specific monoclonal antibodies.  Journal of Immunology 163: 6348-6391.

Dyall R., Messaoudi I., Janetzki S., and Nikolic-Zugic J. (2000).  MHC polymorphism can enrich the T-cell repertoire of the species by shifts in intrathymic selection.  Journal of Immunology  161:1695-1698.

LeMaoult J., Messaoudi I., Manavalan JS., Potvin H., Nikolich-Zugich D., Dyall R., Szabo P., Wecksler ME., and Nikolic-Zugic J. (2000). Age-related dysregulation in CD8 T cell homeostasis: kinetics of a diversity loss. Journal of Immunology 165:2367-2373.

Messaoudi I., LeMaoult J., Metzner BM., Miley MJ., Fremont DH., and Nikolich-Zugich J. (2001). Functional evidence that conserved TCR CDRa3 loop docking governs the cross-recognition of closely related peptide:class I complexes. A mechanism of TCR cross-reactivity. Journal of Immunology 167:836-843.

Messaoudi I., Guevara-Patino J., LeMaoult J., Dyall R., and Nikilocih-Zugich J. (2002).  Direct link between mhc polymorphism, T cell avidity and diversity in immune defense.  Science 298:1797-1800.

Jankovic V., Messaoudi I., and Nikolich-Zugich J. (2003). Age-related changes in T cell response to polyconal stimuation in Rhesus Macaques. Blood: 102(9):3244-51.

Nikolich-Zugich J., Slifka M., and Messaoudi I. (2004) The many important facets of T-cell repertoire diversity. Nature Immunology Reviews 4(2):123-32.

Nikolich-Zugich J, Fremont D.H., Miley M.J, and Messaoudi I. (2004) The role of mhc polymorphism in anti-microbial resistance. Microbes and Infection 6(5):501-12.

Messaoudi I., LeMaoult J., Guevara-Patino J.A., Metzner B.M., Nikolich-Zugich J. (2004). Age-Related CD8 T-Cell Clonal Expansions (TCE) Constrict CD8 T-Cell Repertoire and Have the Potential to Impair Immune Defense. J. Exp. Med. 200(10):1347-58.

Miley M, Messaoudi I., Metzner B.M., Wu Y., Nikolich-Zugich J., Fremont D.H. (2004) Structural basis for the restoration of TCR recognition of an MHC allelic variant by peptide secondary anchor substitution J. Exp. Med. 200(11): 1445-54.

McAllister S.C., Hansen S.G., Messaoudi I., Nikolich-Zugich J., and Moses A.V. (2005) Increased efficiency of phorbol ester-induced lytic reactivation of Kaposi’s Sarcoma-associated herpesvirus during S-phase. J. Virol. 74(4): 2626-30.

Nikolich-Zugich J, Messaoudi I. (2005) Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp. Gerontol. 40(11):884-93
Messaoudi I., Warner J., Nikolich-Zugich D., Fischer M., and Nikolich-Zugich J. (2006) Molecular, cellular and antigen requirements for development of age-associated T cell clonal expansions in vivo. J. Immunol 176(1): 301-8.

Braaten DC, McClellan JS, Messaoudi I, Tibbetts SA, McClellan KB, Nikolich-Zugich J, Virgin HW. (2006) Effective control of chronic gamma-herpesvirus infection by unconventional MHC Class Ia-independent CD8 T cells. PLoS Pathog. 2(5):e37.

Messaoudi I., Warner J., and Nikolich-Zugich J. (2006) Age-Related CD8 T Cell Clonal Expansions Express Elevated Levels of CD122 and CD127 and Display Defects in Perceiving Homeostatic Signals. J. Immunol. 177:2784-92.

Messaoudi I., Warner J., Fischer M., Park B., Hill B., Mattison J., Lane M. A., Roth G. S., Ingram D. K., Picker L. J.,  Douek D. C.,  Mori M., and Nikolich-Zugich J. (2006). Delay of T cell senescence by caloric restriction in aged long-lived non-human primates. Proc Natl Acad Sci U S A. 103(51):19448-53.