Mixed chimerism and tolerance without whole body irradiation in a large animal model

Yasushi Fuchimoto, Christene A. Huang, Kazuhiko Yamada, Akira Shimizu, Hiroshi Kitamura, R. B. Colvin, Vincent Ferrara, Michael C. Murphy, Megan Sykes, Mary White-Scharf, David M. Neville, David H. Sachs

Research output: Contribution to journalArticle

159 Citations (Scopus)

Abstract

Mixed hematopoietic chimerism may provide a treatment for patients with nonmalignant hematologic diseases, and may tolerize patients to organ allografts without requiring chronic immunosuppression. However, the toxicity of the usual conditioning regimens has limited the clinical applicability of this approach. These regimens generally include some level of whole body irradiation (WBI), which is thought to facilitate engraftment either by making room for donor hematopoietic stem cells or by providing sufficient host immunosuppression to enable donor cells to engraft. Here, we have established mixed chimerism across both minor and major histocompatibility barriers in swine, by using high doses of peripheral blood stem cells in the absence of WBI. After mixed chimerism was established, swine leukocyte antigen-matched (SLA-matched) donor skin grafts were tolerated and maintained for a prolonged period, whereas third-party SLA-matched skin was rejected promptly. Donor-matched kidney allografts were also accepted without additional immunosuppression. Because of its low toxicity, this approach has potential for a wide range of clinical applications. Our data may indicate that niches for engrafting stem cells are filled by mass action and that WBI, which serves to empty some of these niches, can be omitted if the donor inoculum is sufficiently large and if adequate host T-cell depletion is achieved before transplant.

Original languageEnglish
Pages (from-to)1779-1789
Number of pages11
JournalJournal of Clinical Investigation
Volume105
Issue number12
Publication statusPublished - 2000
Externally publishedYes

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Chimerism
Whole-Body Irradiation
Animal Models
Tissue Donors
Immunosuppression
Allografts
Stem Cell Niche
Transplants
Skin
Histocompatibility
Hematologic Diseases
Hematopoietic Stem Cells
Swine
T-Lymphocytes
Kidney

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fuchimoto, Y., Huang, C. A., Yamada, K., Shimizu, A., Kitamura, H., Colvin, R. B., ... Sachs, D. H. (2000). Mixed chimerism and tolerance without whole body irradiation in a large animal model. Journal of Clinical Investigation, 105(12), 1779-1789.

Mixed chimerism and tolerance without whole body irradiation in a large animal model. / Fuchimoto, Yasushi; Huang, Christene A.; Yamada, Kazuhiko; Shimizu, Akira; Kitamura, Hiroshi; Colvin, R. B.; Ferrara, Vincent; Murphy, Michael C.; Sykes, Megan; White-Scharf, Mary; Neville, David M.; Sachs, David H.

In: Journal of Clinical Investigation, Vol. 105, No. 12, 2000, p. 1779-1789.

Research output: Contribution to journalArticle

Fuchimoto, Y, Huang, CA, Yamada, K, Shimizu, A, Kitamura, H, Colvin, RB, Ferrara, V, Murphy, MC, Sykes, M, White-Scharf, M, Neville, DM & Sachs, DH 2000, 'Mixed chimerism and tolerance without whole body irradiation in a large animal model', Journal of Clinical Investigation, vol. 105, no. 12, pp. 1779-1789.
Fuchimoto Y, Huang CA, Yamada K, Shimizu A, Kitamura H, Colvin RB et al. Mixed chimerism and tolerance without whole body irradiation in a large animal model. Journal of Clinical Investigation. 2000;105(12):1779-1789.
Fuchimoto, Yasushi ; Huang, Christene A. ; Yamada, Kazuhiko ; Shimizu, Akira ; Kitamura, Hiroshi ; Colvin, R. B. ; Ferrara, Vincent ; Murphy, Michael C. ; Sykes, Megan ; White-Scharf, Mary ; Neville, David M. ; Sachs, David H. / Mixed chimerism and tolerance without whole body irradiation in a large animal model. In: Journal of Clinical Investigation. 2000 ; Vol. 105, No. 12. pp. 1779-1789.
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