Induction of chimerism in rhesus macaques through stem cell transplant and costimulation blockade-based immunosuppression.
A strategy for producing high-level hematopoietic chimerism after non-myeloablative conditioning has been established in the rhesus macaque. This strategy relies on hematopoietic stem cell transplantation after induction with a non-myeloablative dose of busulfan and blockade of the IL2-receptor in the setting of mTOR inhibition with sirolimus and combined CD28/CD154 costimulation blockade. Hematopoietic stem cells derived from bone marrow and leukopheresis products both were found to be successful in inducing high-level chimerism. Mean peripheral blood peak donor chimerism was 81% with a median chimerism duration of 145 days. Additional immune modulation strategies, such as pre-transplant CD8 depletion, donor-specific transfusion, recipient thymectomy or peritransplant deoxyspergualin treatment did not improve the level or durability of chimerism. Recipient immunologic assessment suggested that chimerism occurred amidst donor-specific down-regulation of alloreactive T cells, and the reappearance of vigorous T-mediated alloreactivity accompanied rejection of the transplants. Furthermore, viral reactivation constituted a significant transplant-related toxicity and may have negatively impacted the ability to achieve indefinite survival of transplanted stem cells. Nevertheless, this chimerism-induction regimen induced amongst the longest-lived stem cell chimerism reported to date for non-human primates and thus represents a platform upon which to evaluate emerging tolerance-induction strategies.
Kean
L S
LS
The Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA.
Adams
A B
AB
Strobert
E
E
Hendrix
R
R
Gangappa
S
S
Jones
T R
TR
Shirasugi
N
N
Rigby
M R
MR
Hamby
K
K
Jiang
J
J
Bello
H
H
Anderson
D
D
Cardona
K
K
Durham
M M
MM
Pearson
T C
TC
Larsen
C P
CP
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D002066:Busulfan / Q000494:pharmacology; D046528:Chimerism; D003586:Cytomegalovirus Infections / Q000150:complications; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007937:Leukapheresis / Q000379:methods; D008253:Macaca mulatta / Q000235:genetics / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D023001:Transplantation Tolerance
D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D002066:Busulfan; D020123:Sirolimus