Supply-side economics finds the thymus

Dudakov, Jarrod A; Brink, Marcel R.M. van den

doi:10.1182/blood-2011-06-361337

Cited by 2 publications

(2 citation statements)

References 12 publications

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“…Given the fact that Cell development requires the input of hematopoietic progenitors, and the fact that the supply of those progenitors is severely limited after acute injury (126,127), one approach to promoting thymic function is to directly stimulate precursor populations; either in the BM or thymus.…”

Section: Strategies Of Boosting Thymic Function Ii: Targeting Hematopmentioning

confidence: 99%

When the Damage Is Done: Injury and Repair in Thymus Function

Kinsella

Dudakov

2020

Front. Immunol.

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Even though the thymus is exquisitely sensitive to acute insults like infection, shock, or common cancer therapies such as cytoreductive chemo-or radiation-therapy, it also has a remarkable capacity for repair. This phenomenon of endogenous thymic regeneration has been known for longer even than its primary function to generate T cells, however, the underlying mechanisms controlling the process have been largely unstudied. Although there is likely continual thymic involution and regeneration in response to stress and infection in otherwise healthy people, acute and profound thymic damage such as that caused by common cancer cytoreductive therapies or the conditioning regimes as part of hematopoietic cell transplantation (HCT), leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse. Furthermore, this capacity for regeneration declines with age as a function of thymic involution; which even at steady state leads to reduced capacity to respond to new pathogens, vaccines, and immunotherapy. Consequently, there is a real clinical need for strategies that can boost thymic function and enhance T cell immunity. One approach to the development of such therapies is to exploit the processes of endogenous thymic regeneration into novel pharmacologic strategies to boost T cell reconstitution in clinical settings of immune depletion such as HCT. In this review, we will highlight recent work that has revealed the mechanisms by which the thymus is capable of repairing itself and how this knowledge is being used to develop novel therapies to boost immune function.

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Section: Strategies Of Boosting Thymic Function Ii: Targeting Hematopmentioning

confidence: 99%

When the Damage Is Done: Injury and Repair in Thymus Function

Kinsella

Dudakov

2020

Front. Immunol.

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“…Less explored thymic regeneration strategies include chemokine and cytokine therapy, to improve homing of bone marrow lymphocyte progenitors and expansion of thymic T cell precursors in the thymus (91), as exemplified in Figure 3C. The mechanistic principles behind the elicitation of such strategies rely on the fact that chemotherapy has a detrimental effect on bone marrow hematopoiesis, and the restoration of lymphopoiesis is rather restricted following the termination of the cytotoxic result (185,186). A prominent example of such an approach includes pretreatment of bone marrow progenitors with CCL25 and CCL21 before autologous transplantation, to rescue their homing capacity in the thymus after exposure to the cytoreductive insult (187).…”

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

confidence: 99%

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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Supply-side economics finds the thymus

Cited by 2 publications

References 12 publications

When the Damage Is Done: Injury and Repair in Thymus Function

When the Damage Is Done: Injury and Repair in Thymus Function

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

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