IL-7 and the adult human thymus: In vitro and in vivo studies of a potential immunotherapeutic.

摘要

Despite its diminished cellular output, the aging adult human thymus retains substantial function, and may be able to contribute to immune reconstitution in people who have lost their normal complement of T cells due to chemotherapy or HIV infection. We describe here the development of an in vitro adult thymic organ culture system (ATOC), and the use of this system to demonstrate that the adult human thymic microenvironment is capable of maintaining the viability of thymocytes in the absence of serum or growth factors.; With the aim of discovering a means of increasing thymic function in adults who have lost their T cell complement, we used our in vitro organ culture system to establish the ability of adult human thymic cells and tissues to respond to the thymic cytokine IL-7, and to characterize both the responding cells and the nature of the response. We have also assessed the ability of T cells developing in the presence of excess levels of IL-7 to respond to stimulation, and have added a molecular component to our cellular studies through the use of DNA microarray analysis to address both the mechanism of IL-7's action in the thymus and the nature of the genetic expression differences that exist between adult and fetal thymi.; In vivo administration of IL-7 to SCID hu-mice showed that IL-7 changes the phenotypic expression profile and cell cycle status of human thymocytes as well as resulting in small increases in human cells in the peripheral blood of the mice, suggesting that this cytokine may indeed have the desired effect of increasing peripheral T cell levels either through increased thymic output, or through increased peripheral expansion of naive cells.; We have further examined this cytokine in vivo as a therapeutic tool to stimulate the emergence of latent HIV-1 from quiescent cells.{09}Using the SCID-hu model of HIV-1 latency recently developed in our group (1), we show that IL-7 stimulates the emergence of latent virus more powerfully than any other single cytokine tested, and yet has minimal effects on human peripheral cell phenotype.