Published online before print May 13, 2009, doi: 10.1161/CIRCHEARTFAILURE.108.827139
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Original Articles |
Donor CD4 T Cells Contribute to Cardiac Allograft Vasculopathy by Providing Help for Autoantibody Production
From the Department of Surgery (T.S.W., S.R., M.C.R., K.S.P., T.M.C., E.M.B., J.A.B., G.J.P.), Addenbrooke’s Hospital, Cambridge, United Kingdom; and Department of Pathology (M.G.), Papworth Hospital, Papworth Everard, United Kingdom.
Correspondence to Gavin J. Pettigrew, MD, FRCS, Department of Surgery, Box 202, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom. E-mail gjp25{at}cam.ac.uk
Received October 14, 2008; accepted April 20, 2009.
Background— The development of autoantibody after heart transplantation is increasingly associated with poor graft outcome, but what triggers its development and whether it has a direct causative role in graft rejection is not clear. Here, we study the development of antinuclear autoantibody in an established mouse model of heart allograft vasculopathy.
Methods and Results— Humoral vascular changes, including endothelial complement staining, were present in bm12 heart grafts, explanted 50 days after transplantation. Alloantibody was not detectable, but long-lasting autoantibody responses developed in C57BL/6 recipients from the third week after transplantation. No autoantibody was generated if donor CD4 T cells were depleted before heart graft retrieval or in recipients that lacked B-cell major histocompatibility complex class II expression, indicating that humoral autoimmunity is a consequence of donor CD4 T-cell allorecognition of the major histocompatibility complex class II complex on recipient autoreactive B cells. An effector role for autoantibody in graft rejection was confirmed by abrogation of humoral vascular rejection, and attenuation of vasculopathy, in B-cell deficient recipients and by development of vascular obliteration and accelerated rejection in recipients primed for autoantibody before transplantation.
Conclusions— Passenger CD4 T cells within heart transplants can contribute to allograft vasculopathy by providing help to recipient B cells for autoantibody generation.
Key Words: antibodies • rejection • transplantation • allograft vasculopathy • autoantibody • graft-versus-host-disease • allorecognition