Recruitment of semiallogeneic dendritic cells to the thymus during post-cyclosporine thymic regeneration.

Based on studies of the thymic microenvironment in the model of cyclosporine (CsA)-associated syngeneic graft-versus-host disease, we have hypothesized that immune tolerance develops after CsA is stopped, as the thymus regenerates and recruits new dendritic cells. CsA normally induces medullary involution with destruction of the medullary dendritic cells (DC) and epithelium. This principle could provide practical advantages for transplantation if it is used to recruit new DC into the thymic medulla. Here we administer LEW x BN F1 splenocytes to BN rats and treat them with a short course of CsA. After CsA is stopped, the F1 cells are rapidly recruited to the thymus, and by 10 days after CsA, they are localized at the corticomedullary junction, the natural location of thymic DC. In contrast, dexamethasone, which induces cortical involution, did not lead to thymic recruitment of F1 DC. Recruitment was better if the splenocytes were administered before CsA was stopped. Engraftment of the thymus was also achieved using bone marrow and temporary skin grafts as sources of DC. These observations provide the basis for a novel approach to inducing tolerance to alloantigens with minimal immune suppression and define the goals for further development.

Enhancement of thymic recovery after cyclosporine by recombinant human growth hormone and insulin-like growth factor I.

Correlation of thymic changes with the development of CsA-associated syngeneic graft-versus-host disease (sGVHD) suggested that the development of tolerance depends on the prompt regeneration of the thymus after stopping CsA. Accordingly, we have tested recombinant human growth hormone (rhGH) and recombinant human insulin-like growth factor I (rhIGF-1) to determine if they accelerate reconstitution of the rat thymus after CsA-induced involution. After 14 days of CsA, the thymus has marked medullary involution but normally recovers fully in 6 weeks. In this study, LEW rats were injected with vehicle, rhGH, or rhIGF-1 for 21 days after stopping CsA and were examined. The vehicle-treated rats showed partial recovery with respect to Hassall's corpuscles, class II antigen expression, medullary size, medullary dendritic cells (DC), and T cell maturation. The mature thymocytes were predominantly CD8+ T cells. Both rhGH and rhIGF-1 induced significant thymic enlargement compared with the vehicle-treated rats. They also both significantly enhanced regeneration with respect to Hassall's corpuscles. The mature thymocyte population had significantly greater CD4+ cells. In addition, rhIGF-1 induced a significant improvement in the medullary size and medullary DC. While the medullae of a normal thymus are in intimate contact with cortical class II antigen, after CsA the cortex adjacent to the medulla is primarily class II antigen negative. RhGH significantly increased the class II antigen in the deep cortex while rhIGF-1 demonstrated a trend toward greater expression in this region (P = 0.06). We conclude that rhGH and rhIGF-1 accelerate thymic regeneration post-CsA. Further studies are now indicated to establish the potential for these factors to enhance the development of antigen-specific tolerance.