Methods of boosting thymic regeneration in patients suffering from a thymic injury by using rankl

Abstract

Age-related thymic involution is a major cause of immunosenescence, characterized by reduced T-cell production, resulting in increased susceptibility to cancers, infections, autoimmunity and reduced vaccine efficacy. RANK/RANKL axis in the thymus is altered during aging and endothelial cells (EC) depend on RANK for their cellularity and functional maturation. Decreased RANKL availability during aging results in a decline in cellularity and function of EC and thymic epithelial cells (TEC) leading to thymic involution. Whereas RANKL neutralization in young mice mimics thymic involution, RANKL cytokine treatment in aged mice restores thymic architecture, EC and TEC cellularity and functional properties. Consequently, RANKL improves T-cell progenitor homing to the thymus and boosts T-cell production. This cascade of events results in peripheral T-cell renewal and effective anti-tumor and vaccine responses. RANKL stimulates EC and TEC in human thymic organo-cultures and is the basis of a treatment that rejuvenates thymic function and improves T-cell immunity in the elderly.

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