Feeding the fire: the role of defective bone marrow function in exacerbating thymic involution

Dudakov, Jarrod A; Khong, Danika; Boyd, Richard; Chidgey, Ann Patricia

doi:10.1016/j.it.2010.02.002

Cited by 29 publications

(20 citation statements)

References 111 publications

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“…Other protocols investigating restoration of thymic function rightly suggest that permanent reversal of immune senescence may also require attention to the age-related decline in bone marrow output (40). Whether there is an age at which this feature would again result in failure of immune tolerance remains an important consideration under investigation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation

et al. 2011

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The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (Tregs); thymectomy or Treg depletion abrogated tolerance restoration. The aging of the immune system (“immune senescence”) is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation

et al. 2011

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“…These changes are associated with a dysregulated thymic architecture characterized by poorly defined cortical and medullary regions [4,5] . Age-related bone marrow alterations are also well reported and lead to a decline in number and quality of T precursor cells being produced and migrating to the thymus [4,8,16] , which could exacerbate intrinsic thymus defects (as reviewed in Dudakov et al [21] ).…”

Section: Thymic Agingmentioning

confidence: 99%

“…Androgen receptors are expressed throughout the thymus on both hematopoietic and stro- Increased numbers of ETPs [21] Increased B cell export [21] Improves haematopoietic recovery [18] Faster donor reconstitution of the bone marrow following HSC transplantation and/or high-dose chemotherapy [18,33] Thymus Reduction in thymic stromal cell number [6,66] Loss of microenvironment organization [6,66] Degeneration of functional areas [6,66] Increased numbers of double-negative, double-positive, and single-positive thymocytes [80] Increased number of thymic stromal cells [66] Reorganization of the thymic microenvironment [6,8,13,18,33,66,81] Improved thymopoiesis following high-dose chemotherapy and/or HSC transplantation [6,8,13,18,33,66,81] Spleen Increase in memory lymphocytes circulating in periphery [70] May aid in the maturation of lym phocytes, mast cells, thymocytes and splenocytes [80,83] Possible activation of splenocytes and NK cells [80,83] Increased number of naïve lymphocytes in the periphery [21] Improvement in proliferative capacity of these cells [6,8,13,18,33,66,81] Improved immunosurveillance and responsiveness throughout the body …”

Section: Sex Steroids and Their Receptors: Impact On Immune Function mentioning

confidence: 99%

Thymic Involution: Where Endocrinology Meets Immunology

Calder

Hince

Dudakov

et al. 2011

Neuroimmunomodulation

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The decline in immune function with aging represents a major clinical challenge in many disease conditions. It is manifest in many parameters but is essentially linked to the adaptive immune responses. The prediction would be that abnormalities in both T and B lymphocytes underlie the loss of cellular and humoral capacity, respectively. Somewhat surprisingly, this is not reflected in numerical losses but more in alterations at the population and single cell levels. There is a major reduction in naïve T cells with a proportional increase in memory cells, and also a generally reduced function of these cells. While bone marrow function reduces with age, the most obvious reason for the T cell defects is the severe atrophy of the thymus. This is closely aligned with puberty, thereby implicating a major aetiological role for sex steroids in both thymus and immune system deterioration with age. Accordingly surgical or chemical castration (utilizing luteinizing hormone-releasing hormone) blocks sex steroids resulting in profound rejuvenation of the immune system.

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“…Hematopoietic stem cells (HSCs) are characterized by their ability to generate all blood cell lineages while maintaining self-renewal. These properties are modified substantially when the host of these cells is exposed to either psychological or physical stressors (Dudakov et al, 2010), so that cells from the bone marrow and the vascular marginal pool are rapidly mobilized to the circulation (Rafii et al, 1995). Consequently, cytokines and chemokines capable of activating cells to immediately respond to various stimuli regulate the production and longevity and determine the number of circulating blood cells (Cavazzana-Calvo et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Stressing hematopoiesis and immunity: an acetylcholinesterase window into nervous and immune system interactions

Gilboa-Geffen¹,

Hartmann²,

Soreq³

2012

Front. Mol. Neurosci.

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Hematopoietic stem cells (HSCs) differentiate and generate all blood cell lineages while maintaining self-renewal ability throughout life. Systemic responses to stressful insults, either psychological or physical exert both stimulating and down-regulating effects on these dynamic members of the immune system. Stress-facilitated division and re-oriented differentiation of progenitor cells modifies hematopoietic cell type composition, while enhancing cytokine production and promoting inflammation. Inversely, stress-induced increases in the neurotransmitter acetylcholine (ACh) act to mitigate inflammatory response and regain homeostasis. This signaling process is terminated when ACh is hydrolyzed by acetylcholinesterase (AChE). Alternative splicing, which is stress-modified, changes the composition of AChE variants, modifying their terminal sequences, susceptibility for microRNA suppression, and sub-cellular localizations. Intriguingly, the effects of stress and AChE variants on hematopoietic development and inflammation in health and disease are both subject to small molecule as well as oligonucleotide-mediated manipulations in vitro and in vivo. The therapeutic agents can thus be targeted to the enzyme protein, its encoding mRNA transcripts, or the regulator microRNA-132, opening new venues for therapeutic interference with multiple nervous and immune system diseases.

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Feeding the fire: the role of defective bone marrow function in exacerbating thymic involution

Cited by 29 publications

References 111 publications

Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation

Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation

Thymic Involution: Where Endocrinology Meets Immunology

Stressing hematopoiesis and immunity: an acetylcholinesterase window into nervous and immune system interactions

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