Skip to main content

Advertisement

SpringerLink
Log in

Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques

  • Published:
AGE Aims and scope Submit manuscript

Abstract

Aging is associated with a general dysregulation in immune function, commonly referred to as “immune senescence”. Several studies have shown that female sex steroids can modulate the immune response. However, the impact of menopause-associated loss of estrogen and progestins on immune senescence remains poorly understood. To help answer this question, we examined the effect of ovariectomy on T-cell homeostasis and function in adult and aged female rhesus macaques. Our data show that in adult female rhesus macaques, ovariectomy increased the frequency of naïve CD4 T cells. In contrast, ovariectomized (ovx) aged female rhesus macaques had increased frequency of terminally differentiated CD4 effector memory T cells and inflammatory cytokine-secreting memory T cells. Moreover, ovariectomy reduced the immune response (T-cell cytokine and IgG production) following vaccination with modified vaccinia ankara in both adult and aged female rhesus macaques compared to ovary-intact age-matched controls. Interestingly, hormone therapy (estradiol alone or in conjunction with progesterone) partially improved the T-cell response to vaccination in aged ovariectomized female rhesus macaques. These data suggest that the loss of ovarian steroids, notably estradiol and progesterone, may contribute to reduced immune function in post-menopausal women and that hormone therapy may improve immune response to vaccination in this growing segment of the population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Ansar Ahmed S, Talal N (1989) Sex hormones and autoimmune rheumatic disorders. Scand J Rheumatol 18:69–76

    Article  PubMed  CAS  Google Scholar 

  • Ansar Ahmed S, Penhale WJ, Talal N (1985) Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol 121:531–551

    PubMed  CAS  Google Scholar 

  • Cernetich A, Garver LS, Jedlicka AE, Klein PW, Kumar N, Scott AL, Klein SL (2006) Involvement of gonadal steroids and gamma interferon in sex differences in response to blood-stage malaria infection. Infect Immun 74:3190–3203

    Article  PubMed  CAS  Google Scholar 

  • De Martinis M, Franceschi C, Monti D, Ginaldi L (2005) Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 579:2035–2039

    Article  PubMed  Google Scholar 

  • Deguchi K, Kamada M, Irahara M, Maegawa M, Yamamoto S, Ohmoto Y, Murata K, Yasui T, Yamano S, Aono T (2001) Postmenopausal changes in production of type 1 and type 2 cytokines and the effects of hormone replacement therapy. Menopause 8:266–273

    Article  PubMed  CAS  Google Scholar 

  • Downs JL, Urbanski HF (2006) Neuroendocrine changes in the aging reproductive axis of female rhesus macaques (Macaca mulatta). Biol Reprod 75:539–546

    Article  PubMed  CAS  Google Scholar 

  • Evans MJ, MacLaughlin S, Marvin RD, Abdou NI (1997) Estrogen decreases in vitro apoptosis of peripheral blood mononuclear cells from women with normal menstrual cycles and decreases TNF-alpha production in SLE but not in normal cultures. Clin Immunol Immunopathol 82:258–262

    Article  PubMed  CAS  Google Scholar 

  • Giglio T, Imro MA, Filaci G, Scudeletti M, Puppo F, De Cecco L, Indiveri F, Costantini S (1994) Immune cell circulating subsets are affected by gonadal function. Life Sci 54:1305–1312

    Article  PubMed  CAS  Google Scholar 

  • Gillgrass AE, Ashkar AA, Rosenthal KL, Kaushic C (2003) Prolonged exposure to progesterone prevents induction of protective mucosal responses following intravaginal immunization with attenuated herpes simplex virus type 2. J Virol 77:9845–9851

    Article  PubMed  CAS  Google Scholar 

  • Gillgrass AE, Fernandez SA, Rosenthal KL, Kaushic C (2005) Estradiol regulates susceptibility following primary exposure to genital herpes simplex virus type 2, while progesterone induces inflammation. J Virol 79:3107–3116

    Article  PubMed  CAS  Google Scholar 

  • Ginaldi L, Di Benedetto MC, De Martinis M (2005) Osteoporosis, inflammation and ageing. Immun Ageing 2:14

    Article  PubMed  Google Scholar 

  • Hammarlund E, Lewis MW, Hansen SG, Strelow LI, Nelson JA, Sexton GJ, Hanifin JM, Slifka MK (2003) Duration of antiviral immunity after smallpox vaccination. Nat Med 9:1131–1137

    Article  PubMed  CAS  Google Scholar 

  • Hammarlund E, Lewis MW, Carter SV, Amanna I, Hansen SG, Strelow LI, Wong SW, Yoshihara P, Hanifin JM, Slifka MK (2005) Multiple diagnostic techniques identify previously vaccinated individuals with protective immunity against monkeypox. Nat Med 11:1005–1011

    PubMed  CAS  Google Scholar 

  • Holland AM, van den Brink MR (2009) Rejuvenation of the aging T cell compartment. Curr Opin Immunol 21:454–459

    Article  PubMed  CAS  Google Scholar 

  • Hughes GC, Thomas S, Li C, Kaja M-K, Clark EA (2008) Cutting edge: progesterone regulates IFN-{alpha} production by plasmacytoid dendritic cells. J Immunol 180:2029–2033

    PubMed  CAS  Google Scholar 

  • Jankovic V, Messaoudi I, Nikolich-Zugich J (2003) Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): differential behavior of CD4 and CD8 subsets. Blood 102:3244–3251

    Article  PubMed  CAS  Google Scholar 

  • Kamada M, Irahara M, Maegawa M, Yasui T, Takeji T, Yamada M, Tezuka M, Kasai Y, Aono T (2000) Effect of hormone replacement therapy on post-menopausal changes of lymphocytes and T cell subsets. J Endocrinol Investig 23:376–382

    CAS  Google Scholar 

  • Kaushic C, Murdin AD, Underdown BJ, Wira CR (1998) Chlamydia trachomatis infection in the female reproductive tract of the rat: influence of progesterone on infectivity and immune response. Infect Immun 66:893–898

    PubMed  CAS  Google Scholar 

  • Keller ET, Zhang J, Yao Z, Qi Y (2001) The impact of chronic estrogen deprivation on immunologic parameters in the ovariectomized rhesus monkey (Macaca mulatta) model of menopause. J Reprod Immunol 50:41–55

    Article  PubMed  CAS  Google Scholar 

  • Klein PW, Easterbrook JD, Lalime EN, Klein SL (2008) Estrogen and progesterone affect responses to malaria infection in female C57BL/6 mice. Gend Med 5:423–433

    Article  PubMed  Google Scholar 

  • Kohama SG, Freesh F, Bethea CL (1992) Immunocytochemical colocalization of hypothalamic progestin receptors and tyrosine hydroxylase in steroid-treated monkeys. Endocrinology 131:509–517

    Article  PubMed  CAS  Google Scholar 

  • Kozlowski PA, Williams SB, Lynch RM, Flanigan TP, Patterson RR, Cu-Uvin S, Neutra MR (2002) Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: influence of the menstrual cycle. J Immunol 169:566–574

    PubMed  CAS  Google Scholar 

  • Kumru S, Godekmerdan A, Yilmaz B (2004) Immune effects of surgical menopause and estrogen replacement therapy in peri-menopausal women. J Reprod Immunol 63:31–38

    Article  PubMed  CAS  Google Scholar 

  • Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB, Estes DM (2005) Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol 175:5716–5723

    PubMed  CAS  Google Scholar 

  • Larbi A, Franceschi C, Mazzatti D, Solana R, Wikby A, Pawelec G (2008) Aging of the immune system as a prognostic factor for human longevity. Physiology 23:64–74

    Article  PubMed  CAS  Google Scholar 

  • Lynch HE, Goldberg GL, Chidgey A, Van den Brink MRM, Boyd R, Sempowski GD (2009) Thymic involution and immune reconstitution. Trends Immunol 30:366–373

    Article  PubMed  CAS  Google Scholar 

  • Manes NP, Estep RD, Mottaz HM, Moore RJ, Clauss TR, Monroe ME, Du X, Adkins JN, Wong SW, Smith RD (2008) Comparative proteomics of human monkeypox and vaccinia intracellular mature and extracellular enveloped virions. J Proteome Res 7:960–968

    Article  PubMed  CAS  Google Scholar 

  • Marx PA, Spira AI, Gettie A, Dailey PJ, Veazey RS, Lackner AA, Mahoney CJ, Miller CJ, Claypool LE, Ho DD, Alexander NJ (1996) Progesterone implants enhance SIV vaginal transmission and early virus load. Nat Med 2:1084–1089

    Article  PubMed  CAS  Google Scholar 

  • McElhaney JE, Effros RB (2009) Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 21:418–424

    Article  PubMed  CAS  Google Scholar 

  • Messaoudi I, Warner J, Fischer M, Park B, Hill B, Mattison J, Lane MA, Roth GS, Ingram DK, Picker LJ, Douek DC, Mori M, Nikolich-Zugich J (2006) Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc Natl Acad Sci U S A 103:19448–19453

    Article  PubMed  CAS  Google Scholar 

  • Messaoudi I, Barron A, Wellish M, Engelmann F, Legasse A, Planer S, Gilden D, Nikolich-Zugich J, Mahalingam R (2009) Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans. PLoS Pathog 5:e1000657

    Article  PubMed  Google Scholar 

  • Pawelec G, Larbi A, Derhovanessian E (2009) Senescence of the human immune system. J Comp Pathol 142:S39–S44

    Article  PubMed  Google Scholar 

  • Perisic M, Arsenovic-Ranin N, Pilipovic I, Kosec D, Pesic V, Radojevic K, Leposavic G (2010) Role of ovarian hormones in age-associated thymic involution revisited. Immunobiology 215:275–293

    Article  PubMed  CAS  Google Scholar 

  • Phiel KL, Henderson RA, Adelman SJ, Elloso MM (2005) Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett 97:107–113

    Article  PubMed  CAS  Google Scholar 

  • Pinzan CF, Ruas LP, Casabona-Fortunato AS, Carvalho FC, Roque-Barreira MC (2010) Immunological basis for the gender differences in murine Paracoccidioides brasiliensis infection. PLoS ONE 5:e10757

    Article  PubMed  Google Scholar 

  • Pitcher CJ, Hagen SI, Walker JM, Lum R, Mitchell BL, Maino VC, Axthelm MK, Picker LJ (2002) Development and homeostasis of T cell memory in rhesus macaque. J Immunol 168:29–43

    PubMed  CAS  Google Scholar 

  • Porter VR, Greendale GA, Schocken M, Zhu X, Effros RB (2001) Immune effects of hormone replacement therapy in post-menopausal women. Exp Gerontol 36:311–326

    Article  PubMed  CAS  Google Scholar 

  • Saucedo R, Rico G, Basurto L, Ochoa R, Zarate A (2002) Transdermal estradiol in menopausal women depresses interleukin-6 without affecting other markers of immune response. Gynecol Obstet Investig 53:114–117

    Article  CAS  Google Scholar 

  • Smith SM, Baskin GB, Marx PA (2000) Estrogen protects against vaginal transmission of simian immunodeficiency virus. J Infect Dis 182:708–715

    Article  PubMed  CAS  Google Scholar 

  • Sonoda J, Laganiere J, Mehl IR, Barish GD, Chong LW, Li X, Scheffler IE, Mock DC, Bataille AR, Robert F, Lee CH, Giguere V, Evans RM (2007) Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense. Genes Dev 21:1909–1920

    Article  PubMed  CAS  Google Scholar 

  • Trunova N, Tsai L, Tung S, Schneider E, Harouse J, Gettie A, Simon V, Blanchard J, Cheng-Mayer C (2006) Progestin-based contraceptive suppresses cellular immune responses in SHIV-infected rhesus macaques. Virology 352:169–177

    Article  PubMed  CAS  Google Scholar 

  • Vural P, Akgul C, Canbaz M (2006a) Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women. Pharmacol Res 54:298–302

    Article  PubMed  CAS  Google Scholar 

  • Vural P, Canbaz M, Akgul C (2006b) Effects of menopause and postmenopausal tibolone treatment on plasma TNFalpha, IL-4, IL-10, IL-12 cytokine pattern and some bone turnover markers. Pharmacol Res 53:367–371

    Article  PubMed  CAS  Google Scholar 

  • Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B (2008) Vaccines: biology of immune responses to vaccines in elderly persons. Clin Infect Dis 46:1078–1084

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Laurie Renner, Allison Weiss, Alfred Legasse, Shane Tackitt, and Kyung Park for expert technical assistance.

This work was supported by National Institutes of Health grants AG-029612, RR-000163, pilot project grants from the Medical Research Foundation of Oregon and from the Center for Gender Based Medicine. Ilhem Messaoudi is supported by a fellowship from the Brookdale Foundation.

Author information

Authors and Affiliations

  1. Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR, 09006, USA

    Flora Engelmann, Alex Barron & Ilhem Messaoudi

  2. Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, 97239, USA

    Henryk Urbanski

  3. Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA

    Henryk Urbanski

  4. Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, 97006, USA

    Henryk Urbanski, Martha Neuringer, Steven G. Kohama & Ilhem Messaoudi

  5. Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR, 97006, USA

    Ilhem Messaoudi

  6. Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, 97006, USA

    Ilhem Messaoudi

  7. Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, OR, 97239, USA

    Byung Park

Authors
  1. Flora Engelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alex Barron
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henryk Urbanski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martha Neuringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven G. Kohama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Byung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ilhem Messaoudi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ilhem Messaoudi.

Additional information

Flora Engelmann and Alex Barron have contributed equally to this work.

About this article

Cite this article

Engelmann, F., Barron, A., Urbanski, H. et al. Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques. AGE 33, 275–289 (2011). https://doi.org/10.1007/s11357-010-9178-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-010-9178-0

Keywords

Search

Navigation