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

Authors

Min Hu, Children's Hospital at WestmeadFollow
Debbie Watson, Children's Hospital at WestmeadFollow
Geoff Y. Zhang, Children's Hospital at Westmead
Nicole Graf, Children's Hospital at Westmead
Yuan M. Wang, Children's Hospital, Westmead
Mary Sartor, Westmead Hospital
Brian Howden, Microsurgical Consultants
Jeffery Fletcher, Children's Hospital at Westmead
Stephen I. Alexander, Children's Hospital at WestmeadFollow

RIS ID

26762

Publication Details

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.

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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.