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Long-Term Cardiac Allograft Survival across an MHC Mismatch after "Pruning" of Alloreactive CD4 T Cells¹

Min Hu^*, Debbie Watson^*, Geoff Y. Zhang^*, Nicole Graf, Yuan M. Wang^*, Mary Sartor, Brian Howden, Jeffrey Fletcher^* and Stephen I. Alexander^2,*

^* Centre for Kidney Research and Department of Pathology, the Children’s Hospital at Westmead, University of Sydney, New South Wales, Australia; Westmead Institute for Cancer Research, Westmead Hospital, University of Sydney, New South Wales, Australia; and Microsurgical Consultants, Melbourne, Victoria, Australia

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 β-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a postgraduate award scholarship from the University of Sydney, Australia (to M.H.).

² Address correspondence and reprint requests to Dr. Stephen I. Alexander, Conner Hawkesbury Road and Hainsworth Street, Centre for Kidney Research, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail address: stephena{at}chw.edu.au

³ Abbreviations used in this paper: CAV, cardiac allograft vasculopathy; D, dividing; ND, nondividing; MST, median survival time; PB, peripheral blood; TRBC_uni, universal TCR constant region of β-chain; TRBV, TCR variable gene of β-chain.