Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

Abstract

One of the main consequences of thymus aging is the decrease in naïve T cell output. This condition accelerates at the onset of puberty, and presents as a major clinical complication for cancer patients who require cytoablative therapy. Specifically, the extensive use of chemotherapeutics, such as cyclophosphamide, in such treatments damage thymic structure and eliminate the existing naïve T cell repertoire. The resulting immunodeficiency can lead to increased incidence of opportunistic infections, tumor growth relapse and/or autoimmune diseases, particularly in older patients. Thus, strategies aimed at rejuvenating the aged thymus following chemotherapeutic damage are required. Previous studies have revealed that sex hormone deprivation in male mice is capable of regenerating the thymic microenvironment following chemotherapy treatment, however, further investigation is crucial to identify gender-based differences, and the molecular mechanisms involved during thymus regeneration. Through phenotypic analyzes, we identified gender-specific alterations in thymocytes and thymic epithelial cell (TEC) subsets from the onset of puberty. By middle-age, females presented with a higher number of thymocytes in comparison to males, yet a decrease in their Aire + medullary TEC/thymocyte ratio was observed. This reduction could be associated with an increased risk of autoimmune disease in middle-aged women. Given the concurrent increase in female Aire + cTEC/thymocyte ratio, we proposed that there may be an impediment in Aire + mTEC hi differentiation, and Aire + cTEC hi as its upstream precursor. The regenerative effects of LHRH receptor antagonist, degarelix, on TEC subsets was also less pronounced in middle-aged females compared to males, possibly due to slower progression of thymic involution in the former, which presented with greater TEC hi proportions. Furthermore, following cyclophosphamide treatment, degarelix enhanced thymocyte and mature TEC subset recovery, with faster recovery kinetics observed in females. These events were found to involve both reactivation and proliferation of thymic epithelial progenitor cells. Taken together, the findings from this study portray Hun et al. Gender Disparity in the Aging Thymus a relationship between gender disparity and thymus aging, and highlight the potential benefits of LHRH receptor antagonist treatment for thymic regeneration. Further research is required, however, to determine how gender may impact on the mechanisms underpinning these events.

“Age Related Differences in the Biology of Chronic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation”

“…Puberty is the result of activation of the hypothalamopituitary-gonadal axis and, as a consequence, of the increased production of androgens and estrogens usually starting between the age of 8 and 13 years in girls and 9 and 14 years in boys (9). Onset of puberty is associated with a decline in thymic function, and possibly splenic function as well (10,11). Yet, the exact differences that age and puberty have on the development of immune reconstitution post-HSCT, GvHD, and the induction of immune tolerance are still incompletely studied.…”

Thymic Engraftment by in vitro-Derived Progenitor T Cells in Young and Aged Mice

“…In contrast to the clear increase in the number of thymocytes after cytoablative treatment followed by SSI, the TEC compartment of the thymus appears to increase in cell size, but not necessarily due to TEC proliferation (85,92). Elegant immunofluorescence analyses of TECs demonstrated that morphological changes in TECs, and not de novo regeneration, were largely responsible for the expansion of the cortical region of the aged thymus after SSI treatment (92).…”

“…Accordingly, the most remarkable effect on thymus size and output was uncovered as a consequence of physical ( 84 ) or chemical castration in both sexes ( 51 , 85 ), revealing the potential for reversal of age-related thymic atrophy. These effects may be blocked by administration of sex hormones, demonstrating the direct effect of androgens on immunity, and specifically, on thymus involution.…”

“…Hence, SSI remains a viable option for treatment of the aged to generate de novo peripheral T cells. In this regard, when SSI treatment was given following the combination of chemical therapy and HSCT in preclinical models, thymocyte recovery was twice as efficient with SSI treatment ( 85 ).…”

Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

“…With aging, a thymic atrophy results in a decrease of functional naïve CD4+ and CD8 T cells [ 95 ]. This decline is more pronounced in males than in females [ 96 ] and is more noticeable for CD8 T cells with a peripheral oligo-clonal expansion of memory T cells, which in general provides a contracted T cell antigen receptor (TCR)-repertoire diversity inducing immunosenescence. In addition, aging causes CD4+ T cells to become longer-lived but functionally impaired with reduced proliferation and IL-2 production.…”