Although bone marrow transplantation (BMT) would offer a cure to many patients with hemoglobinopathies, current preparative regimens for BMT are so toxic that few patients are offered this option until they have developed severe, and often irreversible complications of their disease. In addition, many patients do not have a suitable HLA-matched donor, and therefore do not have this therapeutic option. In this laboratory, we have previously demonstrated in mice that the induction of mixed chimerism provides a mode of hematopoietic reconstitution which involves much less toxic preparative regimens and may be applicable across MHC barriers. The overall objective of this research proposal is to extend our studies of mixed lymphohematopoietic chimerism to miniature swine in order to provide a large animal preclinical model to study the application of this modality to the cure of hemoglobinopathies. Specifically, we intend to: 1) Extend our non-myeloablative regimen for the induction of mixed chimerism, utilizing sublethal whole body irradiation, to miniature swine; 2) Determine the potential of very high doses (""""""""megadoses"""""""") of PBSC to achieve mixed chimerism and tolerance without irradiation; 3) Study parameters involved in determining the relative reconstitution of lymphoid, myeloid and erythroid precursors following the induction of mixed chimerism; and 4) Determine the mechanism(s) of mutual tolerance induction in host and donor T cell populations following the induction of mixed chimerism. Our preliminary data indicate feasibility of all of these aims, and suggest that the miniature swine model may permit us to design a clinically applicable protocol for the use of mixed chimerism in the treatment of hemoglobinopathies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063430-02
Application #
6183976
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M2))
Program Officer
Badman, David G
Project Start
1999-08-16
Project End
2003-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$384,750
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Mathes, David W; Solari, Mario G; Gazelle, Guy Scott et al. (2014) Stable mixed hematopoietic chimerism permits tolerance of vascularized composite allografts across a full major histocompatibility mismatch in swine. Transpl Int 27:1086-96
Mathes, David W; Solari, Mario G; Randolph, Mark A et al. (2005) Long-term acceptance of renal allografts following prenatal inoculation with adult bone marrow. Transplantation 80:1300-8
Wu, Anette; Yamada, Kazuhiko; Baron, Christophe et al. (2004) Detection of regulatory cells as an assay for allograft tolerance in miniature swine. J Heart Lung Transplant 23:210-7
Cho, Patricia S; Mueller, Nicolas J; Cameron, Andrew M et al. (2004) Risk factors for the development of post-transplant lymphoproliferative disorder in a large animal model. Am J Transplant 4:1274-82
Lima, Brian; Gleit, Zachary L; Cameron, Andrew M et al. (2003) Engraftment of quiescent progenitors and conversion to full chimerism after nonmyelosuppressive conditioning and hematopoietic cell transplantation in miniature swine. Biol Blood Marrow Transplant 9:571-82
Mathes, David W; Randolph, Mark A; Solari, Mario G et al. (2003) Split tolerance to a composite tissue allograft in a swine model. Transplantation 75:25-31
Mathes, David W; Randolph, Mark A; Bourget, Judy L et al. (2002) Recipient bone marrow engraftment in donor tissue after long-term tolerance to a composite tissue allograft. Transplantation 73:1880-5
Buhler, Leo H; Spitzer, Thomas R; Sykes, Megan et al. (2002) Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease. Transplantation 74:1405-9
Kunisaki, Shaun M; Haller, Gary W; Shimizu, Akira et al. (2002) Autologous graft-versus-host disease in a porcine bone marrow transplant model. Transplantation 74:465-71
Haller, Gary W; Lima, Brian; Kunisaki, Shaun M et al. (2002) MHC alloantigens elicit secondary, but not primary, indirect in vitro proliferative responses. J Immunol 169:3613-21

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