Thymus Degeneration and Regeneration

Duah, Maxwell; Li, Lingling; Shen, Jingyi; Qiu, Lan; Pan, Bin; Xu, Kailin

doi:10.3389/fimmu.2021.706244

Cited by 32 publications

(37 citation statements)

References 196 publications

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“…Our results recapitulate and extend earlier reports that the generation of functional T-cells by grafted thymus tissues decreases with the age of the graft and suggest that the extent to which T cells can mature is dependent on the degree of thymic involution [7]. However, generally aging also affects various stages of T cell development, from age-related alterations in T-cell progenitor cells and disruption in thymic microenvironment niche, to the changes in key signaling molecules that modulate thymopoiesis and the subsequent decline in T cell output and immune functions [29].…”

Section: Discussionmentioning

confidence: 99%

Thymic Rejuvenation by Adult Grafts in the Lymph Node

Rao

Gupta²,

Lagasse

2022

Preprint

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Immunologic aging is defined as a process in which the immune system undergoes tremendous decline in T cell numbers and function, thus affecting one’s ability to effectively mount an immune response. The degeneration of the thymus, the primary immune organ responsible for T cell development, is central to immunologic aging. Various studies have assessed thymic regeneration as an effective way to offset immune function decline. In this study, we determined the effect of mouse adult thymus transplants in the lymph node of athymic nude mice to rejuvenate thymus function. We transplanted thymuses of increasing ages and assessed engrafted ectopic thymuses by histology as well as for blood T cell numbers and function. We observed that transplanting aged thymuses, up to 8 months old, in the lymph node regenerated thymus function and corresponding T cell activation with some thymic rejuvenation when compared to the expected native thymus in control animals. However, transplanting 11- and 14-month old thymus in the lymph node had decreased-to-limited thymic function with no thymic rejuvenation detected. These observations provide important insights into the plasticity and regenerative capabilities of the thymus during age-associated involution.

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Section: Discussionmentioning

confidence: 99%

Thymic Rejuvenation by Adult Grafts in the Lymph Node

Rao

Gupta²,

Lagasse

2022

Preprint

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“…In fact, lymphopenic Rag2 Il2rg double KO mouse strain shows a markedly increased proportion of IL−7 + TECs compared to WT mice ( 91 ). IL-7R-deficient mice show defective thymic microenvironment, especially in corticomedullary structure, and reduced mTEC development ( 92 , 93 ). While this phenotype is most likely due to a failure of the crosstalk normally provided by IL-7-dependent thymocytes and other cells of the hematopoietic lineage, a possible direct impact of IL-7 on thymic stromal cells is currently unknown.…”

Section: Interleukin-7mentioning

confidence: 99%

Signaling Crosstalks Drive Generation and Regeneration of the Thymus

et al. 2022

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Optimal recovery of immune competence after periods of hematopoietic insults or stress is crucial to re-establish patient response to vaccines, pathogens and tumor antigens. This is particularly relevant for patients receiving high doses of chemotherapy or radiotherapy, who experience prolonged periods of lymphopenia, which can be associated with an increased risk of infections, malignant relapse, and adverse clinical outcome. While the thymus represents the primary organ responsible for the generation of a diverse pool of T cells, its function is profoundly impaired by a range of acute insults (including those caused by cytoreductive chemo/radiation therapy, infections and graft-versus-host disease) and by the chronic physiological deterioration associated with aging. Impaired thymic function increases the risk of infections and tumor antigen escape due to a restriction in T-cell receptor diversity and suboptimal immune response. Therapeutic approaches that can promote the renewal of the thymus have the potential to restore immune competence in patients. Previous work has documented the importance of the crosstalk between thymocytes and thymic epithelial cells in establishing correct architecture and function of thymic epithelium. This crosstalk is relevant not only during thymus organogenesis, but also to promote the recovery of its function after injuries. In this review, we will analyze the signals involved in the crosstalk between TECs and hematopoietic cells. We will focus in particular on how signals from T-cells can regulate TEC function and discuss the relevance of these pathways in restoring thymic function and T-cell immunity in experimental models, as well as in the clinical setting.

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“…As proof-of-concept, there is now clear epidemiologic evidence that post-chemotherapy rheumatism and other autoimmune syndromes may develop not only shortly, but even months or years, after completion of cytoablative treatments in (childhood) cancer survivors (151,152). Mouse models of chemotherapyinduced thymic involution have determined that chemotherapy significantly obliterates the epithelial compartment of the thymus, most prominently the AIRE + MHC-II high mTEC subset, whose endogenous repair is a rather time-demanding process (91,126,(153)(154)(155)(156). An elegant study by Fletcher and colleagues (2009) has previously demonstrated that AIRE + mTEC need approximately 7-10 days to be fully restored after treatment with immunosuppressive drugs or chemotherapeutics.…”

Section: Chemotherapy-induced Second Primary Malignancy -Mechanistic ...mentioning

confidence: 99%

“…First, these studies collectively provide a proof-of-concept that damage/decline of various TEC components, including the most sensitive AIRE + mTEC subset, could potentially manifest as prolonged "disturbance" of tissue immune surveillance, characterized by profound deficiencies in T cell receptor repertoire, peripheral T cell pool, and the presence of autoreactive cytotoxic CD8 + T cells. All these consequences can hinder the ability of the immune system to prevent nascent neoplastic cells via a competent immune surveillance, and to maintain control of tumor cell growth during the equilibrium phase of the cancer immunoediting process (154). Second, the thymus reaches its maximum relative size around birth and its maximum absolute size at puberty.…”

Section: Chemotherapy-induced Second Primary Malignancy -Mechanistic ...mentioning

confidence: 99%

“…The thymus is extremely sensitive to a wide array of external factors and stressors, including, but not limited to, acute/chronic infections, certain medications, glucocorticoids, cytoreductive chemotherapies, and even certain physiological states, such as pregnancy. Although these individual factors exert distinct effects on the thymic environment, they can all cause, in principle, extensive deterioration and/or complete elimination of the cTEC and mTEC compartments, leading to impaired thymopoiesis and escape of autoreactive T cells to the periphery (88,91,154,155,160,161). In the case of cytoreductive treatments, the initial effect is dependent on the chemotherapy's mechanism of function, which is typically disruption of one or more steps associated with cell division, and as such the proliferating thymic epithelial cell pool is directly assaulted shortly after administration (88,91,161,162).…”

Section: Chemotherapy-induced Thymic Involution -Mechanistic Insights...mentioning

confidence: 99%

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A Proposed Link Between Acute Thymic Involution and Late Adverse Effects of Chemotherapy

Lagou

Anastasiadou²,

Karagiannis³

2022

Front. Immunol.

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Epidemiologic data suggest that cancer survivors tend to develop a protuberant number of adverse late effects, including second primary malignancies (SPM), as a result of cytotoxic chemotherapy. Besides the genotoxic potential of these drugs that directly inflict mutational burden on genomic DNA, the precise mechanisms contributing to SPM development are poorly understood. Cancer is nowadays perceived as a complex process that goes beyond the concept of genetic disease and includes tumor cell interactions with complex stromal and immune cell microenvironments. The cancer immunoediting theory offers an explanation for the development of nascent neoplastic cells. Briefly, the theory suggests that newly emerging tumor cells are mostly eliminated by an effective tissue immunosurveillance, but certain tumor variants may occasionally escape innate and adaptive mechanisms of immunological destruction, entering an equilibrium phase, where immunologic tumor cell death “equals” new tumor cell birth. Subsequent microenvironmental pressures and accumulation of helpful mutations in certain variants may lead to escape from the equilibrium phase, and eventually cause an overt neoplasm. Cancer immunoediting functions as a dedicated sentinel under the auspice of a highly competent immune system. This perspective offers the fresh insight that chemotherapy-induced thymic involution, which is characterized by the extensive obliteration of the sensitive thymic epithelial cell (TEC) compartment, can cause long-term defects in thymopoiesis and in establishment of diverse T cell receptor repertoires and peripheral T cell pools of cancer survivors. Such delayed recovery of T cell adaptive immunity may result in prolonged hijacking of the cancer immunoediting mechanisms, and lead to development of persistent and mortal infections, inflammatory disorders, organ-specific autoimmunity lesions, and SPMs. Acknowledging that chemotherapy-induced thymic involution is a potential risk factor for the emergence of SPM demarcates new avenues for the rationalized development of pharmacologic interventions to promote thymic regeneration in patients receiving cytoreductive chemotherapies.

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Thymus Degeneration and Regeneration

Cited by 32 publications

References 196 publications

Thymic Rejuvenation by Adult Grafts in the Lymph Node

Thymic Rejuvenation by Adult Grafts in the Lymph Node

Signaling Crosstalks Drive Generation and Regeneration of the Thymus

A Proposed Link Between Acute Thymic Involution and Late Adverse Effects of Chemotherapy

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