Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine

Judy L. Bourget, David W. Mathes, G. Petur Nielsen, Mark A. Randolph, Yumi N. Tanabe, Vincent R. Ferrara, Anette Wu, Scott Arn, David H. Sachs, W. P.Andrew Lee

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background. Although transplantation of musculoskeletal allografts in humans is technically feasible, the adverse effects of long-term immunosuppression subject the patient to high risks for correcting a nonlife-threatening condition. Achieving immunologic tolerance to musculoskeletal allografts, without the need for chronic immunosuppression, could expand the clinical application of limb tissue allografting. Tolerance to musculoskeletal allografts has been accomplished previously in miniature swine in our laboratory. Although stable, mixed chimerism has been suggested as the mechanism underlying long-term tolerance in a rat limb model, the mechanism of this tolerance induction has not been established. This report explores the possible relationship between hematopoietic chimerism and tolerance to musculoskeletal allografts in swine. Methods. Twelve miniature swine underwent vascularized musculoskeletal allograft transplantation from histocompatibility complex (MHC) matched, minor antigen-mismatched donors. Eight animals received a 12-day course of cyclosporine, one of which was excluded due to subtherapeutic levels. Four recipients were not immunosuppressed. Serial biopsies to assess graft viability and flow cytometry to assess chimerism were performed. Donor and third-party skin grafts were placed on recipients with surviving allografts greater than 100 days to validate tolerance. Results. Both groups developed early peripheral chimerism, but this chimerism became undetectable by postoperative day 19 in the cyclosporine group and by day 13 in the control group. Animals receiving cyclosporine developed permanent tolerance to their allografts, whereas those not receiving cyclosporine rejected their allografts in 6-9 weeks. Animals demonstrating tolerance to their bone allografts also demonstrated prolonged donor skin graft survival. Conclusions. Induction of tolerance to musculoskeletal allografts can be achieved in the MHC matched swine. Although hematopoietic chimerism is present in the immediate postoperative period, persistent, long-term chimerism does not seem to be necessary for maintenance of such tolerance.

Original languageEnglish (US)
Pages (from-to)851-856
Number of pages6
JournalTransplantation
Volume71
Issue number7
DOIs
StatePublished - Apr 15 2001
Externally publishedYes

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Miniature Swine
Chimerism
Allografts
Lymphocytes
Cyclosporine
Tissue Donors
Immunosuppression
Swine
Extremities
Transplantation
Transplants
Skin
Homologous Transplantation
Graft Survival
Major Histocompatibility Complex
Postoperative Period
Flow Cytometry
Maintenance
Biopsy

ASJC Scopus subject areas

  • Transplantation

Cite this

Bourget, J. L., Mathes, D. W., Nielsen, G. P., Randolph, M. A., Tanabe, Y. N., Ferrara, V. R., ... Lee, W. P. A. (2001). Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine. Transplantation, 71(7), 851-856. https://doi.org/10.1097/00007890-200104150-00005

Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine. / Bourget, Judy L.; Mathes, David W.; Nielsen, G. Petur; Randolph, Mark A.; Tanabe, Yumi N.; Ferrara, Vincent R.; Wu, Anette; Arn, Scott; Sachs, David H.; Lee, W. P.Andrew.

In: Transplantation, Vol. 71, No. 7, 15.04.2001, p. 851-856.

Research output: Contribution to journalArticle

Bourget, JL, Mathes, DW, Nielsen, GP, Randolph, MA, Tanabe, YN, Ferrara, VR, Wu, A, Arn, S, Sachs, DH & Lee, WPA 2001, 'Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine', Transplantation, vol. 71, no. 7, pp. 851-856. https://doi.org/10.1097/00007890-200104150-00005
Bourget JL, Mathes DW, Nielsen GP, Randolph MA, Tanabe YN, Ferrara VR et al. Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine. Transplantation. 2001 Apr 15;71(7):851-856. https://doi.org/10.1097/00007890-200104150-00005
Bourget, Judy L. ; Mathes, David W. ; Nielsen, G. Petur ; Randolph, Mark A. ; Tanabe, Yumi N. ; Ferrara, Vincent R. ; Wu, Anette ; Arn, Scott ; Sachs, David H. ; Lee, W. P.Andrew. / Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine. In: Transplantation. 2001 ; Vol. 71, No. 7. pp. 851-856.
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AU - Tanabe, Yumi N.

AU - Ferrara, Vincent R.

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AB - Background. Although transplantation of musculoskeletal allografts in humans is technically feasible, the adverse effects of long-term immunosuppression subject the patient to high risks for correcting a nonlife-threatening condition. Achieving immunologic tolerance to musculoskeletal allografts, without the need for chronic immunosuppression, could expand the clinical application of limb tissue allografting. Tolerance to musculoskeletal allografts has been accomplished previously in miniature swine in our laboratory. Although stable, mixed chimerism has been suggested as the mechanism underlying long-term tolerance in a rat limb model, the mechanism of this tolerance induction has not been established. This report explores the possible relationship between hematopoietic chimerism and tolerance to musculoskeletal allografts in swine. Methods. Twelve miniature swine underwent vascularized musculoskeletal allograft transplantation from histocompatibility complex (MHC) matched, minor antigen-mismatched donors. Eight animals received a 12-day course of cyclosporine, one of which was excluded due to subtherapeutic levels. Four recipients were not immunosuppressed. Serial biopsies to assess graft viability and flow cytometry to assess chimerism were performed. Donor and third-party skin grafts were placed on recipients with surviving allografts greater than 100 days to validate tolerance. Results. Both groups developed early peripheral chimerism, but this chimerism became undetectable by postoperative day 19 in the cyclosporine group and by day 13 in the control group. Animals receiving cyclosporine developed permanent tolerance to their allografts, whereas those not receiving cyclosporine rejected their allografts in 6-9 weeks. Animals demonstrating tolerance to their bone allografts also demonstrated prolonged donor skin graft survival. Conclusions. Induction of tolerance to musculoskeletal allografts can be achieved in the MHC matched swine. Although hematopoietic chimerism is present in the immediate postoperative period, persistent, long-term chimerism does not seem to be necessary for maintenance of such tolerance.

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