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 Scopus citations

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

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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

Hartnett, B. J., Yao, D. P., Suter, S. E., Ellinwood, N. M., Henthorn, P. S., Moore, P. F., McSweeney, P. A., Nash, R. A., Brown, J. D., Weinberg, K. I., & 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.