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Long-term cardiac allograft survival across an MHC mismatch after "pruning" of alloreactive CD4 T cells

Journal Article


Abstract


  • Specific tolerance to allografts has been achieved by a variety of means. We have previously shown that ex vivo removal of dividing CD4(+) T cells from an MLR or "pruning" delays skin allograft rejection. We tested pruning of alloreactive T cells as a strategy for retaining a broad T cell repertoire while removing alloreactive T cells in a model of cardiac allograft transplant. Using CFSE staining of responder BALB/c cells with stimulator C57BL/6 cells in an MLR, SCID mice were reconstituted with either dividing (D) or nondividing (ND) CD4(+) T cells derived from an MLR and then challenged with heterotopic cardiac allografts. Mice reconstituted with D CD4(+) T cells rejected cardiac allografts from the stimulator strain with a median survival time (MST) of 29 days, while mice reconstituted with ND CD4(+) T cells maintained allografts from the stimulator strain (MST of >100 days) while rejecting third-party allografts (B10.BR) (MST = 11 days). ELISPOT assays demonstrate donor-specific hyporesponsiveness of the ND CD4(+) T cells. TCR beta-chain V region (TRBV) repertoire analysis demonstrates clonal expansion within both rejecting D cardiac allografts and ND cardiac allografts surviving for the long-term. Histology showed greater allograft infiltration by the D CD4(+) T cells. The surviving ND cardiac allografts demonstrated reduced cellular infiltration and reduced incidence of allograft vasculopathy, but with the development of chronic fibrosis. Thus, pruning of alloreactive T cells allows long-term-specific cardiac allograft survival while retaining the ability to reject third-party allografts.

Authors


  •   Hu, Min (external author)
  •   Watson, Debbie
  •   Zhang, Geoff Yu. (external author)
  •   Graf, Nicole (external author)
  •   Wang, Yuan-Min (external author)
  •   Sartor, Mary (external author)
  •   Howden, Brian (external author)
  •   Fletcher, Jeffery (external author)
  •   Alexander, Stephen I. (external author)

Publication Date


  • 2008

Citation


  • Hu, M., Watson, D., Zhang, G. Y., Graf, N., Wang, Y. M., Sartor, M., Howden, B., Fletcher, J. & Alexander, S. I. (2008). Long-term cardiac allograft survival across an MHC mismatch after "pruning" of alloreactive CD4 T cells. Journal of Immunology, 180 (10), 6593-6603.

Scopus Eid


  • 2-s2.0-45549095345

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1448

Has Global Citation Frequency


Number Of Pages


  • 10

Start Page


  • 6593

End Page


  • 6603

Volume


  • 180

Issue


  • 10

Place Of Publication


  • United States

Abstract


  • Specific tolerance to allografts has been achieved by a variety of means. We have previously shown that ex vivo removal of dividing CD4(+) T cells from an MLR or "pruning" delays skin allograft rejection. We tested pruning of alloreactive T cells as a strategy for retaining a broad T cell repertoire while removing alloreactive T cells in a model of cardiac allograft transplant. Using CFSE staining of responder BALB/c cells with stimulator C57BL/6 cells in an MLR, SCID mice were reconstituted with either dividing (D) or nondividing (ND) CD4(+) T cells derived from an MLR and then challenged with heterotopic cardiac allografts. Mice reconstituted with D CD4(+) T cells rejected cardiac allografts from the stimulator strain with a median survival time (MST) of 29 days, while mice reconstituted with ND CD4(+) T cells maintained allografts from the stimulator strain (MST of >100 days) while rejecting third-party allografts (B10.BR) (MST = 11 days). ELISPOT assays demonstrate donor-specific hyporesponsiveness of the ND CD4(+) T cells. TCR beta-chain V region (TRBV) repertoire analysis demonstrates clonal expansion within both rejecting D cardiac allografts and ND cardiac allografts surviving for the long-term. Histology showed greater allograft infiltration by the D CD4(+) T cells. The surviving ND cardiac allografts demonstrated reduced cellular infiltration and reduced incidence of allograft vasculopathy, but with the development of chronic fibrosis. Thus, pruning of alloreactive T cells allows long-term-specific cardiac allograft survival while retaining the ability to reject third-party allografts.

Authors


  •   Hu, Min (external author)
  •   Watson, Debbie
  •   Zhang, Geoff Yu. (external author)
  •   Graf, Nicole (external author)
  •   Wang, Yuan-Min (external author)
  •   Sartor, Mary (external author)
  •   Howden, Brian (external author)
  •   Fletcher, Jeffery (external author)
  •   Alexander, Stephen I. (external author)

Publication Date


  • 2008

Citation


  • Hu, M., Watson, D., Zhang, G. Y., Graf, N., Wang, Y. M., Sartor, M., Howden, B., Fletcher, J. & Alexander, S. I. (2008). Long-term cardiac allograft survival across an MHC mismatch after "pruning" of alloreactive CD4 T cells. Journal of Immunology, 180 (10), 6593-6603.

Scopus Eid


  • 2-s2.0-45549095345

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1448

Has Global Citation Frequency


Number Of Pages


  • 10

Start Page


  • 6593

End Page


  • 6603

Volume


  • 180

Issue


  • 10

Place Of Publication


  • United States