SCID-HU MICE AS A MODEL TO STUDY TOLERANCE AFTER FETAL STEM-CELL TRANSPLANTATION

SCID-hu mice were constructed with human fetal liver and human fetal thymus, obtained from the same or from different donors. Hematopoietic cells originating from the fetal liver migrate to the fetal thymus and give rise to medullary and cortico-medullary macrophages and dendritic cells. Thymic epithelial cells remain of thymic donor origin. The fetal liver donor derived stem cells differentiate in this environment into double positive and finally single. positive CD4 or CD8 expressing T cells. The TCR V-beta repertoire generated at the double positive stage is identical to that generated in the thymus of the donor. Thymic selection induces changes in V-beta usage comparable to those previously reported for normal human thymus. Single-positive, functionally mature, and mainly TCR-alpha-beta+ T cells reach the peripheral blood compartment of the SCID-hu mice. These T cells are able of specific proliferative and cytotoxic alloresponses. No autoreactivity is observed. Single positive T cells which differentiated in the thymus of SCID-hu mice transplanted with liver and thymus of two different donors are tolerant to the HLA antigens of both donors. By limiting dilution analysis, it could be demonstrated that tolerance to the fetal liver donor is due to clonal deletion whereas tolerance to the fetal thymus donor is not. These data show that human T cell development is progressing normally in these mice and gives rise to a mature, functional and polyclonal T cell repertoire which is comparable to that observed in normal individuals. In addition, we demonstrated that human thymic hematopoietic cells induce tolerance to the antigens expressed on their membrane by clonal deletion, whereas thymic epithelial cells mediate tolerance by non-deletional mechanisms, probably involving clonal anergy.