In-Vivo Modulation of the Immune Response by Human Fetal Kidney • 1796

Recently a new approach enabling engraftment of human peripheral blood mononuclear cells (PBMC) in normal strains of mice and rats following split-dose lethal irradiation and radioprotection with SCID mouse bone marrow has been developed by our group (Blood,1994;83:2368, Transplantation,1995;60:740). Engrafted human B and T-cells were found to be functional by several criteria (Blood,1995;86:398, Blood,1996;88:721). We now report successful transplantation of human fetal kidney tissue, harvested from aborted fetuses at the age of 10, 12, 14, 16, and 22 weeks, under the kidney capsule of immunodeficient animals, SCID/Lewis and SCID/nude chimeric rats. The intrarenal human fetal renal implants displayed rapid growth (up to 5 times their initial size) and maintained numerous developing glomeruli and tubular structures with a distinct brush border up to 4 months posttransplant. Maturation of early nephrons in the younger grafts into maturing-stage human glomeruli in the older ones, and the ability of the older renal grafts to produce erythropoietin, were demonstrated. In our chimeric model, the rejection of human adult kidney tissue by allogeneic human PBMC, administered to the host's peritoneal cavity, is rapid and consistent. In contrast, in the human fetal implants we found either minimal human T-cell infiltration(involving small numbers of CD45RO+ or HLA-DR+ T-cells, and HLA-DR mRNA producing infiltrating cells) or abundunt non-rejecting T-cell infiltrates, characterized by reduced number of T cells of the CD45RO+ or HLA-DR+ subsets, both leading to less tissue destruction, as well as to continued growth of the human fetal tissue. The capacity of the human fetal grafts to avoid rejection by the human PBMC was found to be related to the reduced protein expression of tissue HLA-I and II, ICAM-I, and VCAM-I, compared to the adult grafts. Moreover, sequential RT-PCR analysis of the fetal and adult grafts following infusion of human PBMC, showed that transcript levels of IFN-γ and IL-2 were markedely reduced in the fetal grafts, while expression of IL-4 and IL-10 were similar in both the fetal and adult grafts (T-helper 2 bias). In addition, mRNA levels of the chemokines, RANTES, MIP1β, and the cytolytic effector molecule, Fas ligand, were found to be lower in the fetal tissue compared to the adult tissue. These findings indicate that the immune response of rejection is dependent on whether the target organ is of human fetal or adult kidney origin.