The induction of specific transplantation tolerance, which might eliminate both the need for long-term immunosuppressive medications and the persistent problem of chronic rejection, remains a major goal of clinical organ transplantation. Previous studies from our laboratory have demonstrated that the establishment of mixed lymphohematopoietic chimerism provides an effective means for the induction of long-term transplantation tolerance across major histocompatibility barriers in mice. Based on these murine studies, we successfully developed a non- myeloablative preparative regimen that permits the induction of mixed chimerism and renal allograft tolerance following bone marrow transplantation in MHC-mismatched cynomolgus monkeys, without GVHD. However, to apply this regimen to a clinical setting, several modifications will be necessary. Therefore, the major goals of this proposal are to achieve consistent tolerance, to reduce further the morbidity of the preparative regimen, and to extend its clinical application. Specifically, we will: 1) evaluate the addition of costimulatory blockade (with anti-CD40 ligand monoclonal antibody and/or CTLA4-Ig); 2) Attempt to minimize or remove the radiation requirements of the preparative regimen by either utilizing high-dose mobilized peripheral blood stem cell (PBSC) transplantation or the use of cyclophosphamide; and 3) modify the preparative regimen to improve its clinical applicability to cadaver-donor transplantation and to recipients of living donor transplants with good renal function, but who are currently not tolerating standard immunosuppression. In addition, we will investigate and compare the underlying mechanism of tolerance induced by each of these non-myeloablative regimens, with particular emphasis on distinguishing central from peripheral mechanisms. These analyses should provide valuable information for extending this approach to clinical allotransplantation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kraemer, Kristy A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Thaiss, Cornelius C; Oura, Tetsu; Sasaki, Hajime et al. (2018) Importance of Hematopoietic Mixed Chimerism for Induction of Renal Allograft Tolerance in Nonhuman Primates. Transplantation :
Oura, Tetsu; Ko, Dicken S C; Boskovic, Svjetlan et al. (2016) Kidney Versus Islet Allograft Survival After Induction of Mixed Chimerism With Combined Donor Bone Marrow Transplantation. Cell Transplant 25:1331-41
Kawai, Tatsuo; Sachs, David H; Sykes, Megan et al. (2013) HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 368:1850-2
Yamada, Y; Boskovic, S; Aoyama, A et al. (2012) Overcoming memory T-cell responses for induction of delayed tolerance in nonhuman primates. Am J Transplant 12:330-40
Yamada, Yohei; Aoyama, Akihiro; Tocco, Georges et al. (2012) Differential effects of denileukin diftitox IL-2 immunotoxin on NK and regulatory T cells in nonhuman primates. J Immunol 188:6063-70
Aoyama, A; Klarin, D; Yamada, Y et al. (2012) Low-dose IL-2 for In vivo expansion of CD4+ and CD8+ regulatory T cells in nonhuman primates. Am J Transplant 12:2532-7
Nadazdin, Ognjenka; Abrahamian, Gregory; Boskovic, Svjetlan et al. (2011) Stem cell mobilization and collection for induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys. J Surg Res 168:294-300
Murakami, Toru; Cosimi, A Benedict; Kawai, Tatsuo (2009) Mixed chimerism to induce tolerance: lessons learned from nonhuman primates. Transplant Rev (Orlando) 23:19-24
Traum, Avram Z; Kawai, Tatsuo; Vacanti, Joseph P et al. (2008) The need for tolerance in pediatric organ transplantation. Pediatrics 121:1258-60
Kawai, Tatsuo; Cosimi, A Benedict; Spitzer, Thomas R et al. (2008) HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 358:353-61

Showing the most recent 10 out of 27 publications