Improving sex steroid ablation-induced thymic recovery for clinical application

2017-01-16T00:04:43Z (GMT) by Hince, Melanie Natasha
It is a widely accepted dogma that the immune system deteriorates with advancing age. This is best exemplified functionally by the increased incidence of opportunistic infections and cancer with older age, and structurally by the physical involution of the thymus. The latter directly leads to a reduced naïve T cell output and a homeostatic expansion of the peripheral memory T cell pool. The impact is most prominent, however, following severe infections best exemplified by HIV and common immunodepletive therapies, such as chemotherapy and irradiation, where patients suffer extensive periods of immune insufficiency. In addition, while pre- pubertal patients are able to recovery pre-treatment CD4+ T cell numbers within around 6 months, this time can be extended to at least 2 years in adults. During this period, the risk of infections and disease relapse is significant and leads to high mortality and morbidity rates. This indicates that there is a major clinical requirement to improve thymic function and T cell output in these patients. While multiple factors can precipitate and exacerbate thymus atrophy, there is compelling evidence for a primary role of sex steroids: their removal through surgical gonadectomy reverses age-related involution and improves overall naïve T cell output following HSCT or chemotherapy. Clinically, chemical sex steroid ablation using LHRH-agonists are preferential to surgical gonadectomy and are the standard care for many diseases including some forms of prostate and breast cancer. In both preclinical mouse models and human clinical trials we have demonstrated the LHRH-agonist to reverse age-related thymic atrophy and improve immune reconstitution following allogeneic and autologous HSCT. Although relatively successful, the number and effectiveness of responders during our clinical trials were limited when compared to pre-clinical animal studies. Thus we investigated the clinical parameters that may affect the transfer of LHRH-A therapy from animal models to humans. While LHRH-A was successful in reversing age-related thymic atrophy in male mice, the degree of recovery was dependent on mouse genetic background and this demonstrates the need to customise the timing of LHRH-A therapy when combined with chemotherapy/irradiation in patients. Secondly, we compared LHRH-A induced thymic recovery in male and female mice. While LHRH-A has already been shown to greatly increase thymic recovery following cyclophosphamide and to reverse age- related atrophy in males, within females, LHRH-A is not as successful. We hypothesised that this was due to extragonadal estrogen, which is produced by the adrenal gland following ovariectomy and in postmenopausal women. In addition, LHRH-A induces an initial sex steroid flare and could be interfering with thymic recovery. Thus, we combined LHRH-A treatment with an estrogen receptor antagonist (ER-A) in an attempt to block total estrogen interactions, particularly within the thymus. Interestingly, combination treatment with LHRH-A and Tamoxifen (a common clinical ER-A) enhanced early thymic atrophy indicating a combination of the LHRH-A induced surge plus a potential pro-estrogenic effect of the ER-A. This has been seen previously within the thymus and indicates the need to find an ER-A that is exclusively an antagonist for the immune system, or a global blocker of estrogen production, for future studies. The possibility that Tamoxifen may inhibit thymus function and hence immune capacity in these patients needs to be explored. We also investigated whether a similar strategy of AR blockade would prevent the immunodepleting effects of the initial LHRH-A induced sex steroid flare and result in overall increased thymic hypertrophy in the male setting. We first formally demonstrated that an initial androgen flare induced thymic collapse then, with the combination of LHRH-A and an AR-antagonist (Cosudex), we showed that the immunosuppressive effect of an androgen flare is prevented and that thymic recovery is enhanced following chemotherapy treatment with cyclophosphamide. Together, the results in this thesis demonstrate that, while sex steroid ablation is a clinically viable therapy for the improvement of thymic regeneration, the combination of LHRH-agonist with AR-antagonist enhances the effectiveness, but usage of ER blockers in females needs substantial refinement in terms of inducing immune recovery in female patients.