Full immunologic reconstitution following nonconditioned bone marrow transplantation for canine X-linked severe combined immunodeficiency

Peter J. Felsburg, Richard L. Somberg, Brian J. Hartnett, Steven F. Suter, Paula S. Henthorn, Peter F Moore, Kenneth I. Weinberg, Hans D. Ochs

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Bone marrow transplantation in human X-linked severe combined immunodeficiency (XSCID) without protransplant conditioning results in engraftment of donor T cells and reconstitution of T-cell function but engraftment of few, if any, donor B cells and poor reconstitution of humoral immune function. Since bone marrow transplantation remains the most effective treatment of XSCID patients, better strategies are necessary to achieve optimum long-term results. Canine XSCID, like human XSCID, is due to mutations in the common γ, chain (γc) gene and has clinical and immunologic features identical to those of human XSCID, making it a true homolog of the human disease. We have successfully performed bone marrow transplantation in three XSCID dogs without pretransplant conditioning, using untreated bone marrow cells from mixed lymphocyte culture-nonreactive normal littermates. Unlike the experience in human XSCID patients, all three dogs engrafted both donor B and T cells and attained full reconstitution of immunologic function. Normal percentages of T cells and T-cell mitogenic responses were attained by 3 months posttransplant. CD3+ T cells after transplantation expressed the CD45RA isoform indicating that the cells were recent thymic emigrants derived from immature progenitors. Serum IgG levels were within normal range by 5 months posttransplant. Immunization with the T-dependent antigen, bacteriophage ΦX174, demonstrated normal antibody tilers, immunologic memory, and class-switching. Polymerase chain reaction (PCR) analysis of the γc locus showed that 100% of circulating T cells and 30% to 50% of circulating B celts were donor-derived. None of the dogs developed clinically evident graft-versus-host disease (GVHD). Thus, canine XSCID provides a model to determine the optimal conditions for bone marrow transplantation in human patients, and to develop and test strategies for somatic gens therapy.

Original languageEnglish (US)
Pages (from-to)3214-3221
Number of pages8
JournalBlood
Volume90
Issue number8
StatePublished - Oct 15 1997

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X-Linked Combined Immunodeficiency Diseases
T-cells
Bone Marrow Transplantation
Canidae
Bone
T-Lymphocytes
Tissue Donors
Dogs
Cells
B-Lymphocytes
Immunization
Immunoglobulin Class Switching
Bacteriophages
Immunologic Memory
Lymphocytes
Polymerase chain reaction
Viral Tumor Antigens
Cell culture
Cell Transplantation
Grafts

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Felsburg, P. J., Somberg, R. L., Hartnett, B. J., Suter, S. F., Henthorn, P. S., Moore, P. F., ... Ochs, H. D. (1997). Full immunologic reconstitution following nonconditioned bone marrow transplantation for canine X-linked severe combined immunodeficiency. Blood, 90(8), 3214-3221.

Full immunologic reconstitution following nonconditioned bone marrow transplantation for canine X-linked severe combined immunodeficiency. / Felsburg, Peter J.; Somberg, Richard L.; Hartnett, Brian J.; Suter, Steven F.; Henthorn, Paula S.; Moore, Peter F; Weinberg, Kenneth I.; Ochs, Hans D.

In: Blood, Vol. 90, No. 8, 15.10.1997, p. 3214-3221.

Research output: Contribution to journalArticle

Felsburg, PJ, Somberg, RL, Hartnett, BJ, Suter, SF, Henthorn, PS, Moore, PF, Weinberg, KI & Ochs, HD 1997, 'Full immunologic reconstitution following nonconditioned bone marrow transplantation for canine X-linked severe combined immunodeficiency', Blood, vol. 90, no. 8, pp. 3214-3221.
Felsburg, Peter J. ; Somberg, Richard L. ; Hartnett, Brian J. ; Suter, Steven F. ; Henthorn, Paula S. ; Moore, Peter F ; Weinberg, Kenneth I. ; Ochs, Hans D. / Full immunologic reconstitution following nonconditioned bone marrow transplantation for canine X-linked severe combined immunodeficiency. In: Blood. 1997 ; Vol. 90, No. 8. pp. 3214-3221.
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abstract = "Bone marrow transplantation in human X-linked severe combined immunodeficiency (XSCID) without protransplant conditioning results in engraftment of donor T cells and reconstitution of T-cell function but engraftment of few, if any, donor B cells and poor reconstitution of humoral immune function. Since bone marrow transplantation remains the most effective treatment of XSCID patients, better strategies are necessary to achieve optimum long-term results. Canine XSCID, like human XSCID, is due to mutations in the common γ, chain (γc) gene and has clinical and immunologic features identical to those of human XSCID, making it a true homolog of the human disease. We have successfully performed bone marrow transplantation in three XSCID dogs without pretransplant conditioning, using untreated bone marrow cells from mixed lymphocyte culture-nonreactive normal littermates. Unlike the experience in human XSCID patients, all three dogs engrafted both donor B and T cells and attained full reconstitution of immunologic function. Normal percentages of T cells and T-cell mitogenic responses were attained by 3 months posttransplant. CD3+ T cells after transplantation expressed the CD45RA isoform indicating that the cells were recent thymic emigrants derived from immature progenitors. Serum IgG levels were within normal range by 5 months posttransplant. Immunization with the T-dependent antigen, bacteriophage ΦX174, demonstrated normal antibody tilers, immunologic memory, and class-switching. Polymerase chain reaction (PCR) analysis of the γc locus showed that 100{\%} of circulating T cells and 30{\%} to 50{\%} of circulating B celts were donor-derived. None of the dogs developed clinically evident graft-versus-host disease (GVHD). Thus, canine XSCID provides a model to determine the optimal conditions for bone marrow transplantation in human patients, and to develop and test strategies for somatic gens therapy.",
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