Chimerism after organ transplantation: is there any clinical significance?

Historically, attempts to clinically correlate microchimerism and cytotoxic T lymphocyte (CTL) dysfunction with allograft tolerance (via a "veto effect") have not been highly successful. We have re-examined this question by studying the case of JB, a maternal-renal allograft recipient who did not develop symptoms of acute or chronic rejection after ceasing immunotherapy of his own volition. A biopsy showed immunologic activity in the allograft that did not progress to full-scale rejection. A polymerase chain reaction (PCR) assay showed traces of donor-derived DNA in JB's peripheral blood leukocytes (PBL), which also were shown to display a "split tolerance" toward donor stimulators (MLC+/CTL-) in vitro. Subsequent experiments in our laboratory conclusively demonstrated that JB's suppressed CTL function was donor-specific and that small numbers of donor-derived cells in his PBL could cause the CTL suppression similar to the "veto effect" observed by other researchers. This confirmed the clinical link between microchimerism, CTL dysfunction, and allograft tolerance in a single patient. We propose a testable model for this unusual type of allograft tolerance. The model is based on donor-derived predendritic cell lineages that survive in the host and that exert a powerful "veto effect" by interfering with the normal development and function of donor-specific CD8+ T cells, perhaps even leading to their apoptosis. Additional experiments to test the details of our hypothetical model are under way.