Hematopoietic chimerism and central tolerance created by peripheral-tolerance induction without myeloablative conditioning

Allogeneic hematopoietic chimerism leading to central tolerance has significant therapeutic potential. Realization of that potential has been impeded by the need for myeloablative conditioning of the host and development of graft-versus-host disease (GVHD). To surmount these impediments, we have ada...

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Bibliographic Details
Published in:The Journal of clinical investigation 2003-09, Vol.112 (5), p.795-808
Main Authors: Seung, Edward, Mordes, John P, Rossini, Aldo A, Greiner, Dale L
Format: Article
Language:English
Subjects:
Animals
Biomedical research
Blood Transfusion
Bone marrow
Bone Marrow Transplantation - immunology
CD40 Ligand - physiology
Cloning
Female
Graft versus host disease
Graft vs Host Disease - prevention & control
Hematopoiesis - immunology
Laboratory animals
Lymphocyte Depletion
Lymphocytes
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred CBA
Protocol
Receptors, Interleukin-2 - antagonists & inhibitors
Stem cell transplantation
T cell receptors
Transplantation Chimera - immunology
Transplantation Conditioning
Transplantation Tolerance - immunology
Transplantation, Homologous
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Summary:Allogeneic hematopoietic chimerism leading to central tolerance has significant therapeutic potential. Realization of that potential has been impeded by the need for myeloablative conditioning of the host and development of graft-versus-host disease (GVHD). To surmount these impediments, we have adapted a costimulation blockade-based protocol developed for solid organ transplantation for use in stem cell transplantation. The protocol combines donor-specific transfusion (DST) with anti-CD154 mAb. When applied to stem cell transplantation, administration of DST, anti-CD154 mAb, and allogeneic bone marrow leads to hematopoietic chimerism and central tolerance with no myeloablation and no GVHD. Tolerance in this system results from deletion of both peripheral host alloreactive CD8+ T cells and nascent intrathymic alloreactive CD8+ T cells. In the absence of large numbers of host alloreactive CD8+ T cells, the transfusion that precedes transplantation need not be of donor origin, suggesting that both allospecific and non-allospecific mechanisms regulate engraftment. Agents that interfere with peripheral transplantation tolerance impair establishment of chimerism. We conclude that robust allogeneic hematopoietic chimerism and central tolerance can be established in the absence of host myeloablative conditioning using a peripheral transplantation tolerance protocol.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci18599