Treatment-related complications pose a major limitation to long-term success in the field of transplantation. Therefore, the induction of specific transplantation tolerance, which would eliminate the need for chronic immunosuppression, remains a major goal of modern transplantation immunology. 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. The presence of donor- derived elements in such mixed chimeras induces specific tolerance, while host-type antigen presenting cells maintain normal immunocompetence. The major goal of this proposal is to utilize a clinically applicable, non- lethal preparative regimen to permit establishment of mixed chimerism and transplantation tolerance in a preclinical, non-human primate model. Specifically, we will: l) establish the efficacy of the mixed chimerism approach as a means of inducing transplantation tolerance in cynomolgus monkeys: 2) investigate the mechanism of tolerance in this model, including studies of the role of fractionated bone marrow cell populations and of the vascularized allograft in the induction of tolerance; and 3) assess the effects of variables in the preparative regimen in order to make this protocol applicable to cadaver-donor transplantation in humans. Our preliminary data indicate that a preparative regimen comparable to that which was used previously in mice, but using fractionated sublethal radiation, is capable of producing multilineage lymphohematopoietic chimerism and long-term tolerance to renal allografts between fully MHC mismatched cynomolgus monkeys. Although the number of animals treated so far with this regimen is small, mixed chimerism and tolerance appear to have been induced in all recipients. If confirmed and extended, with appropriate modifications of the timing of the preparative regimen, these results could have important clinical applications in the field of transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037692-03
Application #
2376407
Study Section
Special Emphasis Panel (SRC (23))
Project Start
1995-03-15
Project End
2000-02-29
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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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
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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

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