|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1895-1905
Genetically Corrected Autologous Stem Cells Engraft, But Host Immune
Responses Limit Their Utility in Canine  -L-iduronidase Deficiency
Carolyn Lutzko,
Stephen Kruth,
Anthony C.G. Abrams-Ogg,
Kathy Lau,
Liheng Li,
Brian R. Clark,
Christine Ruedy,
Shaherose Nanji,
Robert Foster,
Donald Kohn,
Robert Shull, and
Ian D. Dubé
From the Department of Laboratory Medicine, Sunnybrook Health Science
Centre, and the Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, Ontario, Canada; the Department of
Clinical Studies, Ontario Veterinary College, University of Guelph,
Guelph, Ontario, Canada; the Oncology Research Program, Toronto
Hospital, Toronto, Ontario, Canada; Research Immunology and Bone Marrow
Transplantation, Childrens Hospital Los Angeles, Los Angeles, CA; and
the Department of Pathology, College of Veterinary Medicine, University
of Tennessee, Knoxville, TN.
Canine  -L-iduronidase (-ID) deficiency, a model of the human
storage disorder mucopolysaccharidosis type I (MPS I), is an ideal
system in which to evaluate the clinical benefit of genetically corrected hematopoietic stem cells. We performed adoptive transfer of
genetically corrected autologous hematopoietic cells in dogs with
-ID deficiency. Large volume marrow collections were performed on
five -ID-deficient dogs. Marrow mononuclear cells in long-term marrow cultures (LTMCs) were exposed on three occasions during 3 weeks
of culture to retroviral vectors bearing the normal canine -ID cDNA.
Transduced LTMC cells from deficient dogs expressed enzymatically
active -ID at 10 to 200 times the levels seen in normal dogs. An
average of 32% of LTMC-derived clonogenic hematopoietic cells were
provirus positive by polymerase chain reaction and about
half of these expressed -ID. Approximately 107
autologous gene-modified LTMC cells/kg were infused into
nonmyeloablated recipients. Proviral DNA was detected in up to 10% of
individual marrow-derived hematopoietic colonies and in 0.01% to 1%
of blood and marrow leukocytes at up to 2 to 3 years postinfusion.
Despite good evidence for engraftment of provirally marked cells,
neither -ID enzyme nor -ID transcripts were detected in any dog.
We evaluated immune responses against -ID and transduced cells. Humoral responses to -ID and serum components of the culture media
(fetal bovine and horse sera and bovine serum albumin) were identified
by enzyme-linked immunosorbent assay. Cellular immune responses to autologous -ID but not neor transduced
cells were demonstrated by lymphocyte proliferation assays. To abrogate
potential immune phenomena, four affected dogs received posttransplant
cyclosporine A. Whereas immune responses were dampened in these dogs,
-ID activity remained undetectable. In none of the dogs engrafted
with genetically corrected cells was there evidence for clinical
improvement. Our data suggest that, whereas the -ID cDNA may be
transferred and maintained in approximately 5% of hematopoietic
progenitors, the potential of this approach appears limited by the
levels of provirally derived enzyme that are expressed in vivo and by
the host's response to cultured and transduced hematopoietic cells
expressing foreign proteins.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. Traversari, S. Marktel, Z. Magnani, P. Mangia, V. Russo, F. Ciceri, C. Bonini, and C. Bordignon
The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies
Blood,
June 1, 2007;
109(11):
4708 - 4715.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Passini, J. Bu, J. A. Fidler, R. J. Ziegler, J. W. Foley, J. C. Dodge, W. W. Yang, J. Clarke, T. V. Taksir, D. A. Griffiths, et al.
Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse
PNAS,
May 29, 2007;
104(22):
9505 - 9510.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Berger, C. A. Blau, M.-L. Huang, J. D. Iuliucci, D. C. Dalgarno, J. Gaschet, S. Heimfeld, T. Clackson, and S. R. Riddell
Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model
Blood,
February 15, 2004;
103(4):
1261 - 1269.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Andersson, B. M. W. Illigens, K. W. Johnson, D. Calderhead, C. LeGuern, G. Benichou, M. E. White-Scharf, and J. D. Down
Nonmyeloablative conditioning is sufficient to allow engraftment of EGFP-expressing bone marrow and subsequent acceptance of EGFP-transgenic skin grafts in mice
Blood,
June 1, 2003;
101(11):
4305 - 4312.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. P. Ponder, J. R. Melniczek, L. Xu, M. A. Weil, T. M. O'Malley, P. A. O'Donnell, V. W. Knox, G. D. Aguirre, H. Mazrier, N. M. Ellinwood, et al.
From the Cover: Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs
PNAS,
October 1, 2002;
99(20):
13102 - 13107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. D. Brown and D. Lillicrap
Dangerous liaisons: the role of "danger" signals in the immune response to gene therapy
Blood,
July 30, 2002;
100(4):
1133 - 1140.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. D. Tran, C. D. Porada, G. Almeida-Porada, H. A. Glimp, W. F. Anderson, and E. D. Zanjani
Induction of stable prenatal tolerance to {beta}-galactosidase by in utero gene transfer into preimmune sheep fetuses
Blood,
June 1, 2001;
97(11):
3417 - 3423.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Rosenzweig, M. Connole, R. Glickman, S.-P. S. Yue, B. Noren, M. DeMaria, and R. P. Johnson
Induction of cytotoxic T lymphocyte and antibody responses to enhanced green fluorescent protein following transplantation of transduced CD34+ hematopoietic cells
Blood,
April 1, 2001;
97(7):
1951 - 1959.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Berger, M.-L. Huang, M. Gough, P. D. Greenberg, S. R. Riddell, and H.-P. Kiem
Nonmyeloablative Immunosuppressive Regimen Prolongs In Vivo Persistence of Gene-Modified Autologous T Cells in a Nonhuman Primate Model
J. Virol.,
January 15, 2001;
75(2):
799 - 808.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
C. Berger, S. Xuereb, D. C. Johnson, K. S. Watanabe, H.-P. Kiem, P. D. Greenberg, and S. R. Riddell
Expression of Herpes Simplex Virus ICP47 and Human Cytomegalovirus US11 Prevents Recognition of Transgene Products by CD8+ Cytotoxic T Lymphocytes
J. Virol.,
May 15, 2000;
74(10):
4465 - 4473.
[Abstract]
[Full Text]
|
|
|
|
|
