Differential effects of gonadectomy on the thymocyte phenotypic profile in male and female rats

Leposavić, Gordana; Karapetrović, Branka; Obradović, S.; Danković, B.Vidić; Kosec, Duško

doi:10.1016/0091-3057(95)02165-5

Cited by 50 publications

(34 citation statements)

References 43 publications

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“…The latter was evident from the dramatic drop in: (i) the number of CD4+CD8+ DP thymocytes, which is related to thymopoietic efficacy [21], and (ii) RTE counts in blood from aged compared to young rats. Orchidectomy, as expected from the previous studies in rodents and humans [9,32,33,34], increased the count of T PBLs in young rats, augmenting thymopoiesis and thymic T-cell export. However, as in control rats, the count of T PBLs in ORX rats declined with aging.…”

Section: Discussionsupporting

confidence: 63%

“…Given that the pubertal surge of sex steroids coincides with the first morphological and functional signs of the involution process, until fairly recently, gonadal steroids were considered the major contributing factors to thymic involution [6,7]. In the same line were data indicating increased thymic size in rodents following surgical ablation of testicular hormones [8,9], as well as in male mice showing inherited androgen receptor (AR) insensitivity [10]. However, subsequent reassessment of the role of androgens in thymic involution in mice [11] and rats [12] showed that the beneficial effects of androgen ablation on thymic size and cellularity are of limited duration.…”

Section: Introductionsupporting

confidence: 49%

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Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way

Arsenović-Ranin¹,

Kosec

Pilipović

et al. 2014

Neuroimmunomodulation

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Objective: Considering a causal role of androgens in thymic involution, age-related remodeling of peripheral T-cell compartments in the absence of testicular hormones was evaluated. Methods: Rats were orchidectomized (ORX) at the age of 1 month, and T-peripheral blood lymphocytes (PBLs) and splenocytes from young (75-day-old) and aged (24-month-old) rats were examined for differentiation/activation and immunoregulatory marker expression. Results: In ORX rats, following the initial rise, the counts of CD4+ and CD8+ PBLs diminished with aging. This reflected the decline in thymic export as shown by recent thymic emigrant (RTE) enumeration. Orchidectomy increased the count of both of the major T-splenocyte subsets in young rats, and they (differently from controls) remained stable with aging. The CD4+:CD8+ T-splenocyte ratio in ORX rats shifted towards CD4+ cells compared to age-matched controls. Although in the major T-cell subsets in the blood and spleen from aged ORX rats the numbers of RTEs were comparable to the corresponding values in age-matched controls, the numbers of mature naïve and memory/activated cells substantially differed. Compared with age-matched controls, in aged ORX rats the numbers of CD4+ mature naïve PBLs and splenocytes were reduced, whereas those of CD4+ memory/activated cells (predictive of early mortality) were increased. Additionally, in spleens from aged ORX rats, despite unaltered thymic export, CD4+CD25+FoxP3+ and natural killer T cell counts were greater than in age-matched controls. Conclusion: (i) Age-related decline in thymopoietic efficacy is not dependent on androgen presence, and (ii) androgens are involved in the maintenance of peripheral T-cell (particularly CD4+ cell) homeostasis during aging.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionsupporting

confidence: 49%

Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way

Arsenović-Ranin¹,

Kosec

Pilipović

et al. 2014

Neuroimmunomodulation

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“…Multiple studies have demonstrated that androgen withdrawal increases thymic size and thymocyte numbers in male mice. [9][10][11][12][13] These studies suggested that this enlargement represents enhanced thymic activity as evidenced by subsequent increases in naive T cells in peripheral organs. 12,14 Furthermore, transplant studies in mice and man have shown enhanced thymic recovery and increased peripheral recent thymic emigrants (RTE) after androgen withdrawal, consistent with overall augmented thymopoiesis.…”

Section: Introductionmentioning

confidence: 99%

CCL25 increases thymopoiesis after androgen withdrawal

Williams

Lucas

Bare

et al. 2008

Blood

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Although studies have demonstrated that androgen withdrawal increases thymic size, molecular mechanisms underlying this expansion remain largely unknown. We show that decreased androgen signaling leads to enhanced immigration of bone marrow T-cell precursors, as manifested by both an early increase of early thymic progenitors (ETP) and improved uptake of adoptively transferred quantified precursors into congenic castrated hosts. We provide evidence that the ETP niche is enhanced after androgen withdrawal by proliferation of UEA ؉ thymic epithelial cells (TEC) and increased TEC production of CCL25, a ligand critical for ETP entry. Moreover, the greatest increase in CCL25 production is by UEA ؉ TEC, linking function of this subset with the increase in ETP immigration. Furthermore, blockade of CCL25 abrogated the effects of castration by impairing ETP entry, retarding immature thymocyte development, limiting increase of thymic size, and impairing increase of thymopoiesis. Taken together, these findings describe a cohesive mechanism underlying increased thymic productivity after androgen withdrawal. (Blood. 2008;112: 3255-3263) IntroductionImpaired thymopoiesis contributes to the immune deficiency after lymphopenia or allogeneic hematopoietic stem cell transplantation (HSCT). 1,2 The thymus is the primary site of new naive T-cell generation and the site of central tolerance induction where potentially autoreactive T cells are deleted. 3 Without thymic renewal during recovery from lymphopenia, an oligoclonal repertoire of T cells persists, leading to impaired clearance of infectious diseases and tumors, and increased rates of auto-or alloimmunity (graft-versus-host disease). [4][5][6][7][8] Thus, an understanding of the mechanisms underlying renewed thymopoiesis may be of critical importance to correcting thymic deficits after HSCT, AIDS therapies, and chemotherapeutic treatment for cancer.Androgen withdrawal presents a potential therapy to renew thymic function. Multiple studies have demonstrated that androgen withdrawal increases thymic size and thymocyte numbers in male mice. [9][10][11][12][13] These studies suggested that this enlargement represents enhanced thymic activity as evidenced by subsequent increases in naive T cells in peripheral organs. 12,14 Furthermore, transplant studies in mice and man have shown enhanced thymic recovery and increased peripheral recent thymic emigrants (RTE) after androgen withdrawal, consistent with overall augmented thymopoiesis. 12,15,16 However, the mechanism by which androgen withdrawal induces thymic recovery remains incompletely understood. Because thymic epithelial cells (TEC) and thymocytes possess functional androgen receptors, studies have focused on these cells as mediators of thymic enlargement associated with androgen withdrawal. 17,18 Initial studies into the thymic effects of androgen revealed rapid thymocyte apoptosis associated with thymic involution after androgen administration. 19,20 Conversely, androgen withdrawal has been shown to enhance proliferation of t...

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“…Given that (1) the onset of age-associated thymic involution coincides with the rise in the levels of gonadal steroids at puberty [14] and (2) the rise in levels of these hormones in rodents of both sexes causes thymic atrophy similar to that observed during aging [21][22][23][24][25][26] , while in both sexes gonadectomies performed before and after puberty postpone/prevent thymic involution and produce reversal of age-associated thymus changes, respectively [23,[27][28][29][30][31][32][33][34] , the gonadal steroids have been implicated in initiation and/or progression of thymus involution. Understanding the putative role of gonadal steroids in thymic involution is impossible without deep insight into the extremely complex mechanisms of their action.…”

Section: Introductionmentioning

confidence: 99%

Age-Associated Remodeling of Thymopoiesis: Role for Gonadal Hormones and Catecholamines

Leposavić

Perišić

2008

Neuroimmunomodulation

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The present review summarizes recent data on age-related thymic changes termed thymic involution, and highlights the putative role of perturbances in extrathymical and, possibly, intrathymical production of gonadal steroids and catecholamines in this process. Thymic involution has been envisaged as an extremely complex process involving multifactorial mechanisms along the bone marrow-thymic axis that accounts for the major manifestations of immunosenescence. These mechanisms include basic cell aging processes (for example, cell replication and programmed cell death) and processes unique to the immune system (such as generation of the T cell receptor repertoire and control of potentially autoreactive cells). Given that the onset of age-associated thymic involution coincides with the rise in gonadal steroid levels at puberty, a causal link between these events has been suggested. It has been shown that: (1) peripubertal gonadectomy causes substantial decrease in the level of noradrenaline in adult male and female thymus and (2) catecholamines, acting via α- and β-adrenoceptor, produce suppressive effects on the thymic cellularity and production of both effector and regulatory T cells. Furthermore, the possibility that gonadal steroids contribute to thymic involution is discussed in this paper. In light of recent data indicating that effects of gonadal hormone deprivation on the thymic cellularity and function are long lasting but transitory, a putative role for the intrathymic sex steroid/catecholamine production in assuring the organ involution, under conditions of their limited supply by extrathymic sources, is also considered.

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Differential effects of gonadectomy on the thymocyte phenotypic profile in male and female rats

Cited by 50 publications

References 43 publications

Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way

Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way

CCL25 increases thymopoiesis after androgen withdrawal

Age-Associated Remodeling of Thymopoiesis: Role for Gonadal Hormones and Catecholamines

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