Thursday, January 24, 2008

Rethinking transplants

The NEJM has a series of articles on transplantation without the maintenance of immunosupression.The idea is that along with the transplanted organ, say a kidney, you give some of the donor's hematopoietic stem cells. If the stem cell graft is successful it will result in a chimeric immune system which tolerates the transplanted organ despite being HLA mismatched. However, one wonders why the stem cell itself isn't rejected, since immunosupressive drugs are only given for a short period of time, so that the graft takes :

"Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA."

The cool thing is that this can spontaneously occur, such as this case of a young girl who received a liver transplant. Somehow either a liver stem cell or a resident cd34+ cell was a ble to colonise her bone marrow and turned her into a partial chimera, thus removing the need for lifelong immunosupression:

"Complete hematopoietic chimerism and tolerance of a liver allograft from a deceased male donor developed in a 9-year-old girl, with no evidence of graft-versus-host disease 17 months after transplantation. The tolerance was preceded by a period of severe hemolysis, reflecting partial chimerism that was refractory to standard therapies. The hemolysis resolved after the gradual withdrawal of all immunosuppressive therapy."