Transplantation of X-linked severe combined immunodeficient dogs with CD34+ bone marrow cells

Brian J. Hartnett, Da Peng Yao, Steven E. Suter, N. Matthew Ellinwood, Paula S. Henthorn, Peter F Moore, Peter A. McSweeney, Richard A. Nash, Jeffrey D. Brown, Kenneth I. Weinberg, Peter J. Felsburg

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)188-197
Number of pages10
JournalBiology of Blood and Marrow Transplantation
Volume8
Issue number4
StatePublished - 2002
Externally publishedYes

Fingerprint

X-Linked Combined Immunodeficiency Diseases
Bone Marrow Cells
Transplantation
Dogs
T-Lymphocytes
Tissue Donors
Canidae
B-Lymphocytes
Interleukin-21 Receptors
Animal Models
Interleukin-9
Interleukin-15
Interleukin-7
Mutation
Interleukin-4
Genetic Therapy
Interleukin-2
Regeneration
Stem Cells
Bone Marrow

Keywords

  • Bone marrow transplantation
  • Canine
  • CD34
  • Immune reconstitution
  • X-linked severe combined immunodeficiency

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Hartnett, B. J., Yao, D. P., Suter, S. E., Ellinwood, N. M., Henthorn, P. S., Moore, P. F., ... Felsburg, P. J. (2002). Transplantation of X-linked severe combined immunodeficient dogs with CD34+ bone marrow cells. Biology of Blood and Marrow Transplantation, 8(4), 188-197.

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 journalArticle

Hartnett, BJ, Yao, DP, Suter, SE, Ellinwood, NM, Henthorn, PS, Moore, PF, McSweeney, PA, Nash, RA, Brown, JD, Weinberg, KI & Felsburg, PJ 2002, 'Transplantation of X-linked severe combined immunodeficient dogs with CD34+ bone marrow cells', Biology of Blood and Marrow Transplantation, vol. 8, no. 4, pp. 188-197.
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. / Transplantation of X-linked severe combined immunodeficient dogs with CD34+ bone marrow cells. In: Biology of Blood and Marrow Transplantation. 2002 ; Vol. 8, No. 4. pp. 188-197.
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AU - Moore, Peter F

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AU - Weinberg, Kenneth I.

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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.

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