Direct Antigen Presentation and Chronic Rejection
To the Editor:
I read with interest the article by Hornick et al.1 They conclude that direct antigen presentation (donor MHC presented by donor antigen-presenting cells) is an unlikely mechanism to explain the accelerated coronary disease (CAD) that develops after cardiac transplantation. I have concerns regarding these data and conclusions.
First and foremost, the data are limited to 10 allograft recipients studied at wide time disparities, with the majority of recipients being at least 4 years past transplantation. Although the development of CAD is progressive, disease occurring later after transplantation is difficult to distinguish from traditional atherosclerosis. Furthermore, most of the alloimmune “action” occurs within the first year after transplantation. Several studies have demonstrated that those patients who develop CAD early have by far the worst prognosis. Only 2 patients were studied in this time frame. Second, only patients with CAD were studied without a control group. The appropriate comparison (assuming consistent time periods) would be those with and without CAD, not donor-specific versus third party. It is important to also point out that 5 of the 10 patients had precursor frequencies to donor-specific antigens similar to third-party antigens, with patients later after transplantation tending to have less aggressive responses.
Third, the progressive loss of donor-specific alloreactivity in stable allograft recipients, based on precursor frequency or MLR, is not a new finding.2 3 More importantly, Rabinowich et al4 demonstrated that an augmented MLR correlated with both acute and chronic rejection in lung transplant recipients using BAL cells as responders and donor spleen cells as stimulators. Our own data5 are somewhat more intriguing because they showed a dichotomy between the standard MLR (using donor lymphocytes as stimulators) and lymphocyte proliferation when donor endothelial cells were used. Although a hyporesponsive effect developed over the first year when the standard MLR was used, recipient lymphocyte reactivity actually increased in response to donor-specific endothelial cells. These data raise the possibility that different costimulatory signals occur in this lymphocyte-endothelial interaction compared with an MLR, or alternatively, this response is less well inhibited by immunosuppression. A subsequent study in 52 cardiac allograft recipients correlated the intensity of this response serially to the development of angiographic coronary disease by 1 year after transplantation.6
On the basis of the above, I would have to conclude that the question of direct antigen presentation as a mechanism for chronic rejection is still an open one.
- Copyright © 1999 by American Heart Association
Hornick PI, Mason PD, Yacoub MG, Rose ML, Batchelor R, Lechler RI. Assessment of the contribution that direct allorecognition makes to the progression of chronic cardiac transplant rejection in humans. Circulation. 1998;97:1257–1263.
Hosenpud JD, Everett JP, Morris TE, Mauck KA, Shipley GD, Wagner CR. Cardiac allograft vasculopathy: association with cell-mediated but not humoral alloimmunity to donor-specific vascular endothelium. Circulation. 1995;92:205–211.
Dr Hosenpud makes several important observations with which we agree. First, we accept that we studied only a small number of patients and that the findings we reported need to be confirmed in a larger series. We are currently accumulating prospective data in renal transplant recipients in order to extend these observations to chronic rejection in another context. Second, we agree that the direct alloresponse is maximally active during the first few weeks and months after transplantation, when the highly immunogenic donor passenger leukocytes are present. Third, we are well aware of the correlation between early transplant coronary artery disease (TxCAD) and acute rejectionR1 ; this implies that the direct alloresponse sets in motion a cycle of events that manifest as TxCAD at a later time point. Fourth, not only are we familiar with previous reports of emerging donor-specific hyporesponsiveness in transplant patients, but we have described this observation ourselves in renal transplant recipientsR2 R3 However, this is the first description of donor-specific hyporesponsiveness in cardiac patients with established and progressive TxCAD, which is thought to be the manifestation of chronic cardiac allograft rejection.
Having identified where we agree with Dr Hosenpud, we would like to highlight where we disagree. First, as stated above, our study makes a novel observation in patients with the clinical manifestation of chronic cardiac allograft rejection. Second, we dispute the importance of a control group without TxCAD. The thrust of our findings is that a continuing strong antidonor direct alloresponse is unlikely to be responsible for continuing TxCAD. This conclusion would be uninfluenced by the study of CAD-free patients, whatever pattern of reactivity they displayed. Finally, Dr Hosenpud’s observation that hyporesponsiveness against donor peripheral blood mononuclear cells (PBMCs) may occur while reactivity against donor endothelial cells (ECs) is preserved is potentially interesting. However, until a mechanism can be identified to explain this dichotomy, it remains a somewhat puzzling phenomenon. Indeed, in our own studies, alloreactive T cells primed against allogeneic PBMCs respond to ECs expressing the same alloantigens when bystander costimulation is provided, suggesting the conservation of alloantigenic epitopes, although accessory molecular interactions may differ.
Further definition of the nature of the T-cell alloresponse that drives chronic allograft rejection is clearly crucially important. Our recent data support the possibility that the indirect rather than the direct alloresponse is of greater significance.