Aging of the recipients but not of the bone marrow donors enhances autoimmunity in syngeneic radiation chimeras

Doria, Gino; Mancini, Camillo; Utsuyama, Masanori; Frasca, Daniela; Hirokawa, Katsuíku

doi:10.1016/s0047-6374(97)01871-x

Cited by 23 publications

(13 citation statements)

References 32 publications

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“…While an impact of aging on hemato-lymphoid progenitors is inevitable, the onset of thymic atrophy, which may be as early as birth, but certainly occurs no later than adolescence, seems to precede any known defects in the lymphoid component. A dominant effect of stromal vs. lymphoid cells in early thymic aging has also been suggested by numerous transplant models (Doria et al , 1997; Zhu et al , 2007; Mackall et al , 1998). To assess the relative contributions of lymphoid vs. stromal cells to aging and regrowth, we utilized a recently published approach (Griffith et al , 2009) for deriving global stromal gene expression signatures in situ, using microdissected tissue and purified lymphoid cells to probe cDNA microarrays (Affymetrix MOE-430_2).…”

Section: Resultsmentioning

confidence: 75%

Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth

et al. 2011

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Summary The thymus is the most rapidly aging tissue in the body, with progressive atrophy beginning as early as birth and not later than adolescence. Latent regenerative potential exists in the atrophic thymus, since certain stimuli can induce quantitative regrowth, but qualitative function of T lymphocytes produced by the regenerated organ has not been fully assessed. Using a genome-wide computational approach, we show that accelerated thymic aging is primarily a function of stromal cells, and that while overall cellularity of the thymus can be restored, many other aspects of thymic function cannot. Medullary islet complexity and tissue-restricted antigen expression decrease with age, representing potential mechanisms for age-related increases in autoimmune disease, but neither of these is restored by induced regrowth, suggesting that new T cells produced by the regrown thymus will probably include more autoreactive cells. Global analysis of stromal gene expression profiles implicates widespread changes in Wnt signaling as the most significant hallmark of degeneration, changes that once again persist even at peak regrowth. Consistent with the permanent nature of age-related molecular changes in stromal cells, induced thymic regrowth is not durable, with the regrown organ returning to an atrophic state within two weeks of reaching peak size. Our findings indicate that while quantitative regrowth of the thymus is achievable, the changes associated with aging persist, including potential negative implications for autoimmunity.

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Section: Resultsmentioning

confidence: 75%

Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth

et al. 2011

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“…Moreover, ETP from older mice were inefficient at seeding fetal thymic lobes and generating DP and SP thymocytes 79 . However, a number of studies transferring young bone marrow into aged lethally irradiated hosts have shown that thymic and splenic repopulation and mitogenic responses were consistently lower in the aged recipients 80 . Furthermore, young bone marrow injected into aged mice failed to restore histological abnormalities of the thymus 81 .…”

Section: The Thymus T‐cell Development and Ageingmentioning

confidence: 99%

Immunosenescence: emerging challenges for an ageing population

2007

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A functional immune system is considered vital for the host's continued survival against the daily onslaught of foreign organisms and pathogens. In humans, as well as in many other species, it is becoming recognized that the immune system declines with age, a term known as immunosenescence, which leads to a higher incidence of infections, neoplasia and autoimmune diseases. The impact of age-related changes in the immune system was clearly not an issue when the average human life span was approximately 40 years. However, over the past 150 years, advances in medical sciences and nutrition have resulted in a dramatic increase in life expectancy to an unprecedented 80 years. Currently, in the UK more than 18% of the population are 65 years or older, and this percentage is expected to rise to 25% by 2031; a trend predicted worldwide.2 Thus, in the absence of any major evolutionary pressure, an immune system that was designed to function for approximately 40 years now has to continue for an additional four decades. Therefore, it is unsurprising that the increased susceptibility to cancers and infections seen in older persons points to severe deficiencies in the immune system. The activity of haematopoietic stem cells in the agedA detailed overview addressing the impact of ageing on haematopoietic stem cell (HSC) function is beyond the scope of this article and more comprehensive reviews can be found elsewhere.3,4 Here we will discuss the more salient points and highlight recent findings. HSC possess the ability to differentiate into different blood-borne cells (Fig. 1), coupled with the capacity of self-renewal to prevent clonal exhaustion. Considering that all haematopoietic cells are derived from HSC, the age-dependent decline in immunity could be attributed to the functional activity of HSC in the aged. Earlier studies addressing the effect of ageing on HSC function were inconclusive. This SummaryIt is now becoming apparent that the immune system undergoes age-associated alterations, which accumulate to produce a progressive deterioration in the ability to respond to infections and to develop immunity after vaccination, both of which are associated with a higher mortality rate in the elderly. Immunosenescence, defined as the changes in the immune system associated with age, has been gathering interest in the scientific and health-care sectors alike. The rise in its recognition is both pertinent and timely given the increasing average age and the corresponding failure to increase healthy life expectancy. This review attempts to highlight the age-dependent defects in the innate and adaptive immune systems. While discussing the mechanisms that contribute to immunosenescence, with emphasis on the extrinsic factors, particular attention will be focused on thymic involution. Finally, we illuminate potential therapies that could be employed to help us live a longer, fuller and healthier life.

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“…Although the mechanisms responsible for thymic involution could theoretically localize at any of these levels, increasing experimental data indicate they are differentially involved in the process. Thus, the results from different studies reveal no age-related decline either in the numbers or functionality of T cell progenitors entering the thymus (Aspinall and Andrew, 2000b;Doria et al, 1997). Concerning extrinsic factors, it is well established that the thymus, as a part of the neuroendocrine axis, is under the influence of various hormones (for a review see Kelley et al, 1998); however, this control is somewhat limited, as no experimental hormonal treatment has been found capable of fully abolishing thymic regression (Hirokawa et al, 1994;Kincade et al, 1994).…”

Section: Involution and Growth Factorsmentioning

confidence: 99%

Involvement of growth factors in thymic involution

García‐Suárez

Pérez-Pérez

Germanà

et al. 2003

Microscopy Res & Technique

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The thymus undergoes an age-dependent degenerative process which is mainly characterized by a progressive loss of lymphoid tissue. Thymic involution is particularly important in relation to immunosenescence and its various associated diseases; this fact has prompted many studies aimed at understanding the causes and mechanisms of thymic degeneration which may, ultimately, lead to the possibility of manipulating it. In this sense, one of the aspects which has deserved most attention is the thymic microenvironment, and more precisely, the many growth factors to which the cells present in the organ are exposed. Thus, the levels of several of such factors have been reported to undergo age-dependent changes in the thymus, which may point at an influence on the regression of the organ. In this article we consider which growth factors and growth factor receptors occur in the vertebrate thymus. Then, focusing on those whose influences are better documented, i.e., neurotrophins, cytokines and IGFs, we discuss their potential role in the organ and the possibility of their being involved in thymic involution.

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Aging of the recipients but not of the bone marrow donors enhances autoimmunity in syngeneic radiation chimeras

Cited by 23 publications

References 32 publications

Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth

Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth

Immunosenescence: emerging challenges for an ageing population

Involvement of growth factors in thymic involution

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