Immuno-intervention for the induction of transplantation tolerance through mixed chimerism

Abstract

The induction of transplantation tolerance could liberate organ transplant recipients from the complications of life-long chronic immunosuppression. The original description of tolerance induction through mixed hematopoietic chimerism in mice utilized lethal whole body irradiation as the preparative regimen for achieving mixed chimerism. While such a regimen might be acceptable for treatment of patients with malignancies, which might also respond to the therapeutic effects of radiation, its toxicity would be unacceptable for patients in need only of an organ transplant. Graft-vs.-host disease, which is frequently a complication of mismatched bone marrow transplantation, would likewise be unacceptable for ordinary clinical transplantation. Therefore, as we have extended the use of this modality for tolerance induction from mice to large animal models, we have attempted to design preparative regimens that avoid both of these complications. In this article, we review our studies of mixed chimerism in mice, miniature swine and monkeys, as well as the results of our recent clinical studies that have extended this treatment modality to a series of kidney transplant patients who have been successfully weaned from all immunosuppression while maintaining stable renal function for up to 8 years.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Tolerance induction regimen in cynomolgus monkeys: A) The initial preparative and treatment regimens; B) Renal allograft survivals with initial regimen or with modified regimen (anti-CD154 with or without splenectomy)

Figure 2

Tolerance of kidneys in cynomolgus monkeys: A) Gross appearance of transplanted kidney at biopsy (normal); B) Microscopic appearance of same kidney, (normal histology); C) Frozen donor skin grafted onto thorax of recipient approximately one year after renal transplant is accepted (left), while third party skin, either fresh (top right) or frozen (bottom right) is rejected by day 15 after skin grafting.

Figure 3

Clinical tolerance induction regimen: Preparative and treatment regimen for HLA-matched sibling donors in first clinical trial for patients with ESRD and intractable multiple myeloma.