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

Immune senescence causes resistance to transplantation tolerance that can be functionally restored by targeting sex steroid production. A Fountain of Youth for the Immune System Raging hormones are often blamed for the sometimes erratic behavior of teenagers; yet, hormonal fluctuations aren’t saddled with the stigma they deserve for altering biological behaviors in older adults. An example of such a phenomenon is the senescent immune system, which responds poorly to new stimuli. This failure may stem in part from the shrinking of the thymus that begins by puberty (thymic involution). However, in contrast to what one might intuit, this age-related muting of the immune response does not improve tolerance induction and reduce rejection after cell or organ transplantation. Instead, an active immune system is required to promote tolerance to novel antigens. Zhao et al. now show that modifying hormone concentrations can restore the induction of transplant tolerance in aged mice. The authors found that after the age of 12 months, mice became resistant to tolerance induction for cardiac transplants. However, surgical castration led to long-term graft acceptance and restoration of thymic cellularity. They then confirmed their findings with a procedure more likely to elicit patient assent—Lupron Depot injections, which temporarily disrupt gonadal function and are used clinically in prostate cancer care. This hormone-dependent transplant tolerance required the thymic production of regulatory T cells. Although it’s hard to extrapolate a mouse’s age to a human’s, these results suggest that hormone modification may improve transplant acceptance in older patients by restoring youthful exuberance to the immune system. 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.