Suppressing the production of sex hormones could help prevent transplant rejection in elderly patients, researchers claim. They have shown that chemically or surgically castrating aging mice that were otherwise unable to benefit from the tolerance-inducing effects of the anti-CD45RB mAb led to thymic regeneration and long-term acceptance of cardiac allografts.
Treating aging mice with injections of the marketed GnRH agonist Lupron Depot (leuprolide) was as effective as surgical castration at restoring long-term tolerance to allografts, says the team from at Harvard Medical School, Sichuan Provincial People’s Hospital, and Sichuan Academy of Medical Sciences in China.
Writing in Science Translational Medicine, the authors say their results support the proposition that targeting sex steroid production with drugs already in clinical use could overcome the immunological barrier to tolerance associated with age-related immune system senescence. They describe their findings in a paper titled “Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation.”
The aging immune system loses its ability to respond to novel antigens, and T-cell production is compromised because of thymic involution, or shrinkage, Shaoping Deng, M.D., of Harvard and colleagues report. To investigate age-related detriments to these immune system functions further and evaluate potential approaches to reversing them, the authors studied tolerance to cardiac allografts induced by anti-CD45RB mAb therapy in mice.
They first confirmed that in about 50% of young, 2-month-old mice, a short course of anti-CD45RB resulted in long-term allograft survival. Conversely, age-matched mice that didn’t receive anti-CD45RB all demonstrated rapid graft rejection. Mice at age six and nine months were similarly susceptible to tolerance induction by anti-CD45RB. By one year of age, however, anti-CD45RB therapy was unable to stimulate allograft tolerance.
To look into whether rejuvenating thymic mass can restore tolerance-promoting capacity, the team investigated the ability of anti-CD45RB to induce tolerance to allogafts in aged male mice after surgical castration. They surprisingly found that gonadectomy restored anti-CD45RB-related tolerance sensitivity to levels similar to those of antibody-treated, uncastrated two month old mice.
The researchers then went on to investigate whether drug-based therapy could have the same beneficial effects. Comparing drug-induced with surgical castration methods was also useful because gonadectomy induces a state of hypergonadotropic hypogonadism, in which circulating gonadotropins increase after castration, whereas treatment with Lupron induces hypogonadotropic hypogonadism and causes circulating gonadotropin levels to drop.
Encouragingly, injecting 12–14 month old mice with Lupron restored anti-CD45RB-induced tolerance to levels similar to those observed in both young mice and surgically castrated older allograft recipients. Moreover, Lupron therapy appeared to further augment tolerance induction in young mice. Whereas up to 50% of young mice demonstrated long-term graft acceptance after anti-CD45RB therapy, injecting young animals with Lupron Depot as well as anti-CD45RB therapy led to successful tolerance induction in every case.
The researchers subsequently carried out an extensive analysis of thymus glands from young, aged, and chemically or surgically castrated aged mice. Visually, the organs from surgically castrated animals were bigger than those from age-matched controls and similar in weight to those of young mice.
Chemical castration also produced an increase in thymic mass, although not to quite the same degree as the surgical procedure. Microscopic evaluation showed normal architecture in a specimen from a 2-month-old mouse, the loss of cortical-medullary differentiation in aged mice, and the restoration of normal architecture in the specimen from a surgically castrated animal. The increase in thymic mass was accompanied by an increase in thymocyte number in both the surgically and the chemically castrated treatment groups.
Importantly, the absolute number of regulatory T cells was also much higher in both the surgically and chemically castrated animals than it was in their age-matched controls. There was, however, no associated increase in splenic regulatory T cells.
Because both drug-induced and surgically induced castration were equally effective at rejuvenating the tolerance axis, the authors conclude the mechanism involved is not mediated by gonadotropins but rather by effects on sex steroid levels. “The transplantation data suggest that sex steroids, through their action on the thymus, promote a state of immune rigidity in which tolerance (or reactivity) to novel antigens is limited,” they add.
Interestingly, estrogens have also been implicated in thymic involution, and a recent study found that ovariectomy leads to enhanced numbers of thymocytes, increased thymocyte function, and normalization of thymic subsets in a rat model. The authors thus further postulate that treatment with an aromatase inhibitor that globally suppresses the conversion of testosterone to estrogen may have a similar or enhanced immune rejuvenating function.
At the clinical level, Lupron is already being actively considered in clinical trials to modulate immunologic function in aged individuals receiving bone marrow transplantation, the authors point out. However, all of these trials are evaluating the capacity of endocrine modulation to enhance immunity.
What hasn’t yet been considered is whether hormonal modulation can improve transplant tolerance induction. “Verifying thymic function and applying new methods such as that described here to restore thymic function may hasten the attainment of immune tolerance in individuals across all ages,” they conclude.