Immunologic mismatch may no longer be a barrier between living kidney donors and recipients, thanks to work being done by Suzanne T. Ildstad, MD, director of the Institute for Cellular Therapeutics at the University of Louisville in Louisville, Kentucky, and colleagues.
The group has overseen complete immunosuppression withdrawal at the one-year mark in a handful of kidney-transplant recipients after employing a pretransplant strategy for building donor-specific tolerance (Transplantation 2013;95:169-176). (Dr. Ildstad is also the founding scientist of biotechnology company Regenerex, LLC, which is involved in this research.) Dr. Ildstad described the process to Renal & Urology News.
How is donor-specific tolerance achieved?
Dr. Ildstad: Normally, transplanted organs are seen as “foreign” by the host immune system, and high levels of immunosuppression are needed to prevent rejection of the transplant. Tolerance is when the host immune system no longer recognizes the transplant as “foreign” but instead sees it as “self” and no longer attempts to reject it.
In our approach, peripheral blood mononuclear cells are mobilized by granulocyte colony-stimulating factor [GCSF; a glycoprotein that stimulates bone marrow to produce and release blood cells, including stem cells]. That is, the recipient undergoes treatment with growth factors that cause the stem cells to be released into the blood, where they can be collected in a manner similar to that for blood donation.
Once collected from the donor, the GCSF-mobilized blood cells are processed to remove “bad” GVHD [graft-versus-host disease]-causing cells but to retain stem cells and facilitating cells. The product is frozen and shipped back to the site for transplantation.
The recipient is then “conditioned” [with low-intensity chemotherapy and radiotherapy] to accept the facilitating cell-based hematopoietic stem cell product to promote tolerance one day after the living-donor kidney transplant is performed.
In your review article for Clinical & Cellular Immunology (2012;S9; available here), you and your coauthors stated that donor-specific tolerance has been referred to as the Holy Grail of organ transplantation. Why is this?
Dr. Ildstad: Currently, renal transplant recipients must take approximately 25 pills per day to prevent graft rejection and to control the complications associated with the use of immunosuppression (hypertension, diabetes, infections). Moreover, the same immunosuppressive agents that are critical to preventing rejection directly damage the kidneys.
As a result, the induction of tolerance with elimination of the need for these agents has remained the Holy Grail of organ transplantation.