Donor CD4 T Cells Contribute to Cardiac Allograft Vasculopathy by Providing Help for Autoantibody Production

Abstract

Background-The development of autoantibody after heart transplantation is increasingly associated with poor graftoutcome, 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. (Circ Heart Fail. 2009;2:361-369.)

Prolongation of allograft survival by passenger donor regulatory T cells

“…6,12,13 In comparison to unmodified WT C57BL/6 recipients, depletion of the T-reg population by administration of anti-CD25 mAb to C57BL/6 mice at, and following, transplantation with bm12 (B6(C)-H2-Ab1bm12/KhEgJ) heart allografts resulted in much more rapid heart graft rejection, and was associated with markedly augmented host autoantibody responses (Figure 2A,B). Our previous work has highlighted that chronic allograft vasculopathy (CAV) in this model is associated with the development of effector autoantibody responses that are triggered by graft-versus-host recognition of MHC class II on host B cells by passenger donor CD4 T lymphocytes.…”

Report from a consensus conference on antibody-mediated rejection in heart transplantation

“…36,39 – 41 Recent data from Harefield has analyzed the contribution of autoantibodies to AMR, defined according to ISHLT criteria, 21 occurring in 16 patients who received allografts between 2004 and 2009. The most common antibody found in the serum at the time of diagnosis was donor-specific HLA antibodies (14 of 16 patients); however, 4 patients had high titres of IgM anti-vimentin antibody, 8 had IgM or IgG anti-cardiac myosin antibodies, and 1 had anti-nuclear antibodies.…”

B cells in cardiac transplants: From clinical questions to experimental models

“…It is also possible that B cells bearing receptors specific for an autoantigen process large fragments of donor cells released during graft damage and present peptides derived from donor MHC molecules thus soliciting help from CD4 T cells recognizing donor MHC peptides through the indirect pathway. Finally, a recent study demonstrated an intriguing possibility that donor passenger CD4 T cells can induce pathogenic autoantibody by self-reactive B cells of the recipient (56). …”