Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy

Coleman, Miranda A., Bridge, Jennifer A., Lane, Steven W., Dixon, Chantelle M., Hill, Geoffrey R., Wells, James W., Thomas, Ranjeny and Steptoe, Raymond J. (2013) Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy. Blood, 121 6: 1049-1058. doi:10.1182/blood-2012-06-434100


Author Coleman, Miranda A.
Bridge, Jennifer A.
Lane, Steven W.
Dixon, Chantelle M.
Hill, Geoffrey R.
Wells, James W.
Thomas, Ranjeny
Steptoe, Raymond J.
Title Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2013-02-07
Year available 2012
Sub-type Article (original research)
DOI 10.1182/blood-2012-06-434100
Open Access Status
Volume 121
Issue 6
Start page 1049
End page 1058
Total pages 10
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Collection year 2013
Language eng
Abstract Bone marrow (BM) or hematopoietic stem cell (HSC) transplantation is used as curative therapy for hematological malignancies. Incorporation of gene-therapy to drive tolerogenic expression of antigens is a promising strategy to overcome the limited long-term efficacy of autologous HSC transplantation for autoimmune diseases. HSC engraftment and tolerance induction is readily achieved after myeloablative or immune-depleting conditioning regardless of the cellular compartment in which antigen is expressed. It is unclear whether the efficiency of engraftment and tolerance induction is influenced by targeting antigen to specific cellular compartments. This is particularly important when using clinically-feasible low-intensity conditioning aimed at preserving infectious immunity in individuals where immunological memory exists to the autoantigen to be expressed. Here we demonstrate that, under immune-preserving conditions, confining expression of a transgenically-expressed antigen to dendritic cells permits stable, longterm engraftment of genetically-modified BM even when recipients are immune to the expressed antigen. In contrast, broader expression within the hematopoietic compartment leads to graft rejection and therapeutic failure due to antigen expression in HSC. These findings are relevant to the clinical application of genetically-engineered HSC and provide evidence that careful selection of promoters for HSC-mediated gene therapy is important, particularly where tolerance is sought under immune-preserving conditions.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online before print: 11 December 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
UQ Diamantina Institute Publications
 
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Created: Sat, 02 Feb 2013, 14:28:59 EST by Dr James Wells on behalf of UQ Diamantina Institute