Role of ovarian hormones in age-associated thymic involution revisited

Perišić, Milica; Arsenović-Ranin, Nevena; Pilipović, Ivan; Kosec, Duško; Pešić, Vesna; Radojević, Katarina; Leposavić, Gordana

doi:10.1016/j.imbio.2009.06.012

Cited by 18 publications

(15 citation statements)

References 69 publications

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“…Similar observations were made in rodents where studies showed that gonadectomy and the ablation of sex steroids in young male and female rodents increases the production of new naïve T cells by the thymus (Lynch et al 2009;Perisic et al 2010). Although the difference was not statistically significant, we noted a small decrease in inflammatory cytokine production by T cells from ovx adult female rhesus macaques, which is also consistent with the notion that ablation of sex steroids can rejuvenate the immune system in young animals (Holland and van den Brink 2009).…”

Section: Discussionsupporting

confidence: 91%

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

Engelmann

Barron

Urbanski

et al. 2010

AGE

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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 menopauseassociated 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 AGE (2011) 33:275-289

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Section: Discussionsupporting

confidence: 91%

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

Engelmann

Barron

Urbanski

et al. 2010

AGE

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“…related change results in a significant reduction in thymic size, overall thymocyte cell number, and the absolute number of single-positive CD4+ and CD8+ T cells that leave the thymus [61,62]. Castration has been demonstrated to restore thymic architecture, improve adaptive immunity in both sexes, alter lymphocyte cytokine profile, and in some cases, reverse the Th1/Th2 differences [49,60,[63][64][65][66]. We previously reported that castration did restore thymic architecture.…”

Section: Discussionmentioning

confidence: 99%

Elevated Levels of Interferon-γ Production By Memory T Cells Do Not Promote Transplant Tolerance Resistance in Aged Recipients.

et al. 2014

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Immunosenescence predisposes the elderly to infectious and autoimmune diseases and impairs the response to vaccination. We recently demonstrated that ageing also impedes development of transplantation tolerance. Unlike their young counterparts (8-12 weeks of age) aged male recipients (greater than 12 months of age) transplanted with a full MHC-mismatched heart are resistant to tolerance mediated by anti-CD45RB antibody. Surprisingly, either chemical or surgical castration restored tolerance induction to levels observed using young recipients. Based on the strong impact of endocrine modulation on transplant tolerance, we explored the impact of ageing and castration on the immune system. Here we report a significant increase in the percentage of T cells that produce interferon-γ (IFN-γ) in aged male versus young male animals and that the overall increase in IFN-γ production was due to an expansion of IFN-γ-producing memory T cells in aged animals. In contrast to IFN-γ production, we did not observe differences in IL-10 expression in young versus old male mice. We hypothesized that endocrine modulation would diminish the elevated levels of IFN-γ production in aged recipients, however, we observed no significant reduction in the percentage of IFN-γ+ T cells upon castration. Furthermore, we neutralized interferon-γ by antibody and did not observe an effect on graft survival. We conclude that while elevated levels of interferon-γ serves as a marker of tolerance resistance in aged mice, other as yet to be identified factors are responsible for its cause. Defining these factors may be relevant to design of tolerogenic strategies for aged recipients.

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“…containing ketamine (100 mg/mL, Ketamidor Õ , Richter Pharma AG, Austria), xylazine (20 mg/mL, Xylased Õ , Bioveta, Czech Republic) and saline in a 1:0.5:8.5 ratio were subjected to bilateral ovariectomy or sham-ovariectomy as previously described in details. 25 Completeness of ovariectomy was validated by histological examination of removed tissue and detailed inspection at post-mortem. Animals were euthanized by exposure to increasing doses of CO 2 followed by cardiac puncture exsanguinations.…”

Section: Experimental Protocolmentioning

confidence: 99%

“…[22][23][24] Our findings indicating that one-month long deprivation of ovarian hormones initiated at the very end of rat reproductive age leads to reversal of thymic involution and re-shaping of peripheral T-cell compartment corroborate the notion that ovarian hormones contribute to the maintenance/progression of thymic involution, and consequently remodeling of the peripheral T-cell compartment. 25 Specifically, we showed that in 11-month-old AO rats ovariectomized (Ox) at the age of 10 months: (i) thymopoiesis is more efficient as shown by increased absolute and relative numbers of CD4 þ and CD8 þ recent thymic emigrants (RTEs) in peripheral blood and spleen, (ii) CD4þ:CD8 þ cell ratio in the periphery is altered, and (iii) number of CD4þCD25þFoxP3 þ cells in both thymus and peripheral blood is increased. 25 However, there are no data on the long-lasting effects of ovarian gland removal at that time point on the thymopoiesis and peripheral T-cell compartment.…”

Section: Introductionmentioning

confidence: 99%

“…25 Specifically, we showed that in 11-month-old AO rats ovariectomized (Ox) at the age of 10 months: (i) thymopoiesis is more efficient as shown by increased absolute and relative numbers of CD4 þ and CD8 þ recent thymic emigrants (RTEs) in peripheral blood and spleen, (ii) CD4þ:CD8 þ cell ratio in the periphery is altered, and (iii) number of CD4þCD25þFoxP3 þ cells in both thymus and peripheral blood is increased. 25 However, there are no data on the long-lasting effects of ovarian gland removal at that time point on the thymopoiesis and peripheral T-cell compartment. These data are needed to get the insight into the putative role of ovarian hormones in the age-related reshaping of peripheral T-cell compartment.…”

Section: Introductionmentioning

confidence: 99%

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Ovarian hormone level alterations during rat post-reproductive life-span influence CD8 + T-cell homeostasis

Arsenović-Ranin

Kosec

Nacka-Aleksić

et al. 2015

Exp Biol Med (Maywood)

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The study examined the putative role of ovarian hormones in shaping of rat peripheral T-cell compartment during postreproductive period. In 20-month-old rats ovariectomized (Ox) at the very end of reproductive period, thymic output, cellularity and composition of major TCRab þ peripheral blood lymphocyte and splenocyte subsets were analyzed. Ovariectomy led to the enlargement of CD8 þ peripheral blood lymphocyte and splenocyte subpopulations. This reflected: (i) a more efficient thymic generation of CD8 þ cells as indicated by increased number of CD4þCD8 þ double positive and the most mature CD4-CD8þTCRab high thymocytes and CD8 þ recent thymic emigrants (RTEs) in peripheral blood, but not in the spleen of Ox rats, and (ii) the expansion of CD8 þ memory/activated peripheral blood lymphocytes and splenocytes. The latter was consistent with a greater frequency of proliferating cells among freshly isolated memory/activated CD8 þ peripheral blood lymphocytes and splenocytes and increased proliferative response of CD8 þ splenocytes to stimulation with plate-bound anti-CD3 antibody. The former could be related to the rise in splenic IL-7 and IL-15 mRNA expression. Although ovariectomy affected the overall number of CD4 þ T cells in none of the examined compartments, it increased CD4þFoxP3 þ peripheral blood lymphocyte and splenocyte counts by enhancing their generation in periphery. Collectively, the results suggest that ovariectomy-induced long-lasting disturbances in ovarian hormone levels (mirrored in diminished progesterone serum level in 20-month-old rats) affects both thymic CD8 þ cell generation and peripheral homeostasis and leads to the expansion of CD4þFoxP3 þ cells in the periphery, thereby enhancing autoreactive cell control on account of immune system efficacy to combat infections and tumors.

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Role of ovarian hormones in age-associated thymic involution revisited

Cited by 18 publications

References 69 publications

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

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

Elevated Levels of Interferon-γ Production By Memory T Cells Do Not Promote Transplant Tolerance Resistance in Aged Recipients.

Ovarian hormone level alterations during rat post-reproductive life-span influence CD8 + T-cell homeostasis

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