Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation.

Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation. Research Abstract Details 

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Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation. Abstract Text:

Hong Xu,Paula M Chilton,Yiming Huang,Carrie L Schanie,Jun Yan,Suzanne T Ildstad,

BACKGROUND: Bone marrow (BM) chimerism has been shown to have a beneficial effect on allograft survival. We recently found that production of donor T-cells was highly correlated with induction of tolerance in minimally conditioned chimeras. In the present studies, we demonstrate that nonmyeloablative conditioning and BM cell infusion modulate innate and adaptive host immune responses. METHODS: Chimeras were generated by bone marrow transplantation (B10.BR to B10). Recipients were preconditioned with T-cell depleting antibodies and total body irradiation with or without cyclophosphamide. Donor-specific tolerance was tested by skin grafting. RESULTS: Transfer of tolerant splenocytes to immunocompetent secondary recipients did not transfer tolerance, nor did infusion of tolerant CD4+/CD25+ T-cells into chimeras without donor T-cell production, demonstrating that linked suppression is an unlikely mechanism in tolerance induction in the context of BM cell infusion. The addition of a single dose of cyclophosphamide to the conditioning enhanced engraftment and tolerance. This was associated with production of donor T-cells and effective clonal deletion, and a significant reduction in activated recipient plasmacytoid dendritic cells (pDC) and natural killer (NK) cells. Chimeras without donor T-cell production that eventually lost their chimerism did not generate an antidonor humoral response, whereas unconditioned controls infused with similar numbers of BM cells did, indicating that infusion of donor BM cells into conditioned recipients induced immune deviation for adaptive B-cell immunity, preventing sensitization to major histocompatibility complex (MHC) alloantigens. CONCLUSIONS: These results demonstrate that recipient T-cells, pDC, and NK cells contribute to the host barrier for establishing chimerism, implicate deletional tolerance as the mechanism for total body irradiation-based nonmyeloablative conditioning for BM transplantation, and show a beneficial effect of BM cells in preventing sensitization to MHC alloantigens.

Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation. Publishing Authors By Initials

H Xu,PM Chilton,Y Huang,CL Schanie,J Yan,ST Ildstad,

For similar therapeutics: biological therapy: immunotherapy: immunosuppression: transplantation conditioning research abstracts see: therapeutics: biological therapy: immunotherapy: immunosuppression: transplantation conditioning research

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Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Transplantation

VOLUME: 83

Page Numbers: 954-63

Journal Abbreviation:

ISSN: 0041-1337

DAY: 15

MONTH: Apr

YEAR: 2007

Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation. Information

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LANGUAGE: eng

NlmUniqueID: 132144

Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation. Keywords Mesh Terms:

KEYWORDS: Transplantation Conditioning

MESH TERMS: immunology

Chemical & Substance for Abstract: Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation. Information

Substance Name: Cyclophosphamide

Registry Number: 50-18-0

Grant and Affiliation Information for Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation.

AFFILIATION: Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202-1760, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: R01 HL63442

ACRONYM: HL

MEDLINETA: Transplantation

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