Facilitating cells: Translation of hematopoietic chimerism to achieve clinical tolerance

Abstract

For over 50 y the association between hematopoietic chimerism and tolerance has been recognized. This originated with the brilliant observation by Dr. Ray Owen that freemartin cattle twins that shared a common placental blood supply were red blood cell chimeras, which led to the discovery that hematopoietic chimerism resulted in actively acquired tolerance. This was first confirmed in neonatal mice by Medawar et al. and subsequently in adult rodents. Fifty years later this concept has been successfully translated to solid organ transplant recipients in the clinic. The field is new, but cell-based therapies are being used with increasing frequency to induce tolerance and immunomodulation. The future is bright. This review focuses on chimerism and tolerance: past, present and prospects for the future.

Keywords: chimerism; facilitating cells; freemartin cattle; stem cells; tolerance.

Figures

Figure 1.

The primary hurdles to applying chimerism to induce tolerance. (GVHD: graft versus host disease).

Figure 2.

Facilitating cells have multiple immunomodulatory and trophic effects on haematopoietic stem and progenitor cells to promote chimerism and tolerance.

Figure 3.

Algorithm for conditioning, kidney and FCRx transplant. Fludarabine is administered on days −4, −3, and −2 (30 mg/kg per dose) relative to the living donor kidney transplant (day 0). Dialysis is performed at least 6 hours after each dose before kidney transplant. Two doses of cyclophosphamide (Cy) (50 mg/kg) are given on days −3 and day +3. FCRx is administered on day +1.