Tolerance and Immunity following in Utero Transplantation of Allogeneic Fetal Liver Cells: The Cytokine Shift

Abstract

Although in utero transplantation (IUT) has resulted in donor-specific tolerance to postnatal solid organ transplantation, the mechanisms of this tolerance remain poorly understood. Our recent findings demonstrate that under specific conditions prenatal injection of allogeneic cells may lead to allosensitization instead of tolerance. These laboratory observations were supported by clinical findings as well, and therefore suggested that, depending on the conditions of prenatal transplantation, tolerance or immunity may develop. The present study explored the role of CD4 cells, cytokines, and I-E superantigen in developing tolerance vs. immunity after in utero transplantation. Sixteen animals survived IUT (40–60% survival rate) and were free from any signs of graft-versus-host disease (GVHD). Mice were considered tolerant when their antidonor and antihost CTL responses were similar, sensitized when antidonor responses were significantly higher than antihost and anti-third-party responses, and nontolerant when antidonor responses in transplanted and control mice were similar. The TH1 → TH2 shift was associated with tolerance and TH2 → TH1 shift with allosensitization. Our results showed that tolerant BALB/c (H-2d, I-E+) → C57BL/6 (H-2b, I-E–) (2/7) mice showed higher IL-4 (p < 0.05) in antidonor MLR, and partial deletion of recipient I-E-reactive T cells (CD3Vβ11) (p < 0.045). On the other hand, nontolerant animals (5/7) demonstrated high production of IFN-γ (p < 0.05) without deletion of CD3Vβ11 T cells. In C57CBL/6 (H-2b, I-E–) → C3H (H-2k, I-E+) mice CD3Vβ11 T cells do not play any role in tolerance induction because they are deleted in the C3H background. Tolerant mice (4/9) showed an overproduction of IL-4 (p < 0.05) in antidonor MLR whereas allosensitized animals (5/9) demonstrated high level of IFN-γ (p < 0.05). Suppressor cells seem to play no role in tolerant C57BL/6 → C3H as demonstrated by suppressor assay. Hence, a shift from TH1 → TH2 or TH2 → TH1 cytokines may determine whether tolerance or immunity develops.