Thymic Transplantation to Determine Mechanisms of Thymic Involution: Insulin-Like Growth Factor 1 Receptor and Forkhead Box Protein N1 in the Thymus Play a Role in Maintaining the Juvenile Thymus
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boton, MA.
Meeting: 2015 American Transplant Congress
Abstract number: A263
Keywords: Age factors, Miniature pigs, Thymus transplantation, Tolerance
Session Information
Session Name: Poster Session A: Preclinical Immunosuppression and Tolerance
Session Type: Poster Session
Date: Saturday, May 2, 2015
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Exhibit Hall E
Thymic involution has long been associated with age-related changes of the immune system, although the cause remains unclear. We have extensively studied the role of the thymus in the induction of transplantation tolerance. Our unique in vivo vascularized thymic lobe (VTL) transplantation model has enabled us to characterize the process of thymic involution and rejuvenation at the cellular level through selective transfer of thymus and bone marrow components between young and old inbred animals. We have previously demonstrated that aged thymi induce tolerance less effectively than juvenile thymi, but that this can be reversed through rejuvenation in a juvenile host. Here, we examined the factors involved in thymic involution in order to develop strategies to induce tolerance in the adult population,
METHODS and RESULTS: We have examined serum testosterone and IGF1 levels in 60 naïve MHC miniature swine (age range: 1-32 months). Serum testosterone levels in male pigs increased with age while conversely serum IGF1 levels decreased. Consistent with this observation, IGF1 receptor (IGF1R) expression was high in young naïve thymic medulla but decreased in aged thymus. Aged VTL grafts that underwent rejuvenation in MHC matched juvenile animals showed markedly increased expression of IGF1R to a level comparable to that observed in naïve juvenile thymi. Notably, cytokeratin negative/IGF1R positive cells were seen in the rejuvenated thymus. Finally, we assessed the role of the transcription factor Foxn1 in thymic involution/rejuvenation. There were larger numbers of Foxn1+ cells in juvenile thymus and this number declined with age. Strikingly, rejuvenated aged thymi showed an increase in Foxn1 expression. In contrast, when the juvenile thymic grafts were transplanted into adult recipients, the resulting involuted thymi had reduced numbers of Foxn1+ cells.
CONCLUSIONS: Taken together, these data indicate that higher levels of serum IGF1 as well as cells expressing IGF1R and Foxn1 in the thymus are necessary to maintain the juvenile thymus. These data may help us to develop a novel strategy for rejuvenating aged thymi in order to induce transplant tolerance.
To cite this abstract in AMA style:
Yamada K, Tasaki M, Sekijima M, Kawai A, Villani V, Tanabe T, Hanekamp I, Shimizu A, Sachs D. Thymic Transplantation to Determine Mechanisms of Thymic Involution: Insulin-Like Growth Factor 1 Receptor and Forkhead Box Protein N1 in the Thymus Play a Role in Maintaining the Juvenile Thymus [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/thymic-transplantation-to-determine-mechanisms-of-thymic-involution-insulin-like-growth-factor-1-receptor-and-forkhead-box-protein-n1-in-the-thymus-play-a-role-in-maintaining-the-juvenile-thymus/. Accessed May 17, 2025.« Back to 2015 American Transplant Congress