Abstract
X-linked severe combined immunodeficiency (X-SCID) is the most common form of human SCID and is caused by mutations in the common γ chain (γc), a shared component of the interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. BMT for human X-SCID results in engraftment of donor T-cells and reconstitution of normal T-cell function but engraftment of few, if any, donor B-cells and poor reconstitution of humoral immune function. Canine X-SCID is also caused by mutations in the γc and has an immunological phenotype identical to that of human X-SCID. We have previously reported that transplantation of nonconditioned X-SCID dogs with unfractionated histocompatible bone marrow results in engraftment of both donor B- and T-cells and reconstitution of normal T-cell and humoral immune function. In this study, we assessed the ability of purified canine CD34+ bone marrow cells to reconstitute lymphoid populations after histocompatible BMT in 6 nonablated X-SCID dogs. All dogs showed engraftment of donor T-cells, with T-cell regeneration occurring through a thymic-dependent pathway, and had reconstituted normal T-cell function. In contrast to our previous studies, only 3 dogs had engraftment of donor B-cells and reconstituted normal antigen-specific B-cell function post-BMT. The variable donor B-cell engraftment and reconstitution of normal humoral immune function observed in this study are similar to the outcomes observed in the majority of human X-SCID patients following BMT. This study demonstrates that canine CD34+ cells contain progenitors capable of immune reconstitution and is the first study to document the ability of CD34+ bone marrow cells to reconstitute normal B- and T-cell function in a nonablated large-animal model of BMT. This study also demonstrates that the quality of immune reconstitution following CD34+ BMT may be dosage dependent. Thus canine X-SCID provides a large-animal preclinical model that can be used not only to determine the optimal conditions for both donor B- and T-cell engraftment following CD34+ BMT, but also to develop and evaluate strategies for gene therapy protocols that target CD34+ cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 188-197 |
| Number of pages | 10 |
| Journal | Biology of Blood and Marrow Transplantation |
| Volume | 8 |
| Issue number | 4 |
| State | Published - 2002 |
| Externally published | Yes |
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Keywords
- Bone marrow transplantation
- Canine
- CD34
- Immune reconstitution
- X-linked severe combined immunodeficiency
ASJC Scopus subject areas
- Hematology
- Transplantation
Cite this
Transplantation of X-linked severe combined immunodeficient dogs with CD34+ bone marrow cells. / Hartnett, Brian J.; Yao, Da Peng; Suter, Steven E.; Ellinwood, N. Matthew; Henthorn, Paula S.; Moore, Peter F; McSweeney, Peter A.; Nash, Richard A.; Brown, Jeffrey D.; Weinberg, Kenneth I.; Felsburg, Peter J.
In: Biology of Blood and Marrow Transplantation, Vol. 8, No. 4, 2002, p. 188-197.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Transplantation of X-linked severe combined immunodeficient dogs with CD34+ bone marrow cells
AU - Hartnett, Brian J.
AU - Yao, Da Peng
AU - Suter, Steven E.
AU - Ellinwood, N. Matthew
AU - Henthorn, Paula S.
AU - Moore, Peter F
AU - McSweeney, Peter A.
AU - Nash, Richard A.
AU - Brown, Jeffrey D.
AU - Weinberg, Kenneth I.
AU - Felsburg, Peter J.
PY - 2002
Y1 - 2002
N2 - X-linked severe combined immunodeficiency (X-SCID) is the most common form of human SCID and is caused by mutations in the common γ chain (γc), a shared component of the interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. BMT for human X-SCID results in engraftment of donor T-cells and reconstitution of normal T-cell function but engraftment of few, if any, donor B-cells and poor reconstitution of humoral immune function. Canine X-SCID is also caused by mutations in the γc and has an immunological phenotype identical to that of human X-SCID. We have previously reported that transplantation of nonconditioned X-SCID dogs with unfractionated histocompatible bone marrow results in engraftment of both donor B- and T-cells and reconstitution of normal T-cell and humoral immune function. In this study, we assessed the ability of purified canine CD34+ bone marrow cells to reconstitute lymphoid populations after histocompatible BMT in 6 nonablated X-SCID dogs. All dogs showed engraftment of donor T-cells, with T-cell regeneration occurring through a thymic-dependent pathway, and had reconstituted normal T-cell function. In contrast to our previous studies, only 3 dogs had engraftment of donor B-cells and reconstituted normal antigen-specific B-cell function post-BMT. The variable donor B-cell engraftment and reconstitution of normal humoral immune function observed in this study are similar to the outcomes observed in the majority of human X-SCID patients following BMT. This study demonstrates that canine CD34+ cells contain progenitors capable of immune reconstitution and is the first study to document the ability of CD34+ bone marrow cells to reconstitute normal B- and T-cell function in a nonablated large-animal model of BMT. This study also demonstrates that the quality of immune reconstitution following CD34+ BMT may be dosage dependent. Thus canine X-SCID provides a large-animal preclinical model that can be used not only to determine the optimal conditions for both donor B- and T-cell engraftment following CD34+ BMT, but also to develop and evaluate strategies for gene therapy protocols that target CD34+ cells.
AB - X-linked severe combined immunodeficiency (X-SCID) is the most common form of human SCID and is caused by mutations in the common γ chain (γc), a shared component of the interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. BMT for human X-SCID results in engraftment of donor T-cells and reconstitution of normal T-cell function but engraftment of few, if any, donor B-cells and poor reconstitution of humoral immune function. Canine X-SCID is also caused by mutations in the γc and has an immunological phenotype identical to that of human X-SCID. We have previously reported that transplantation of nonconditioned X-SCID dogs with unfractionated histocompatible bone marrow results in engraftment of both donor B- and T-cells and reconstitution of normal T-cell and humoral immune function. In this study, we assessed the ability of purified canine CD34+ bone marrow cells to reconstitute lymphoid populations after histocompatible BMT in 6 nonablated X-SCID dogs. All dogs showed engraftment of donor T-cells, with T-cell regeneration occurring through a thymic-dependent pathway, and had reconstituted normal T-cell function. In contrast to our previous studies, only 3 dogs had engraftment of donor B-cells and reconstituted normal antigen-specific B-cell function post-BMT. The variable donor B-cell engraftment and reconstitution of normal humoral immune function observed in this study are similar to the outcomes observed in the majority of human X-SCID patients following BMT. This study demonstrates that canine CD34+ cells contain progenitors capable of immune reconstitution and is the first study to document the ability of CD34+ bone marrow cells to reconstitute normal B- and T-cell function in a nonablated large-animal model of BMT. This study also demonstrates that the quality of immune reconstitution following CD34+ BMT may be dosage dependent. Thus canine X-SCID provides a large-animal preclinical model that can be used not only to determine the optimal conditions for both donor B- and T-cell engraftment following CD34+ BMT, but also to develop and evaluate strategies for gene therapy protocols that target CD34+ cells.
KW - Bone marrow transplantation
KW - Canine
KW - CD34
KW - Immune reconstitution
KW - X-linked severe combined immunodeficiency
UR - http://www.scopus.com/inward/record.url?scp=0035999675&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035999675&partnerID=8YFLogxK
M3 - Article
C2 - 12014808
AN - SCOPUS:0035999675
VL - 8
SP - 188
EP - 197
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
SN - 1083-8791
IS - 4
ER -