On the crossroad between tolerance and posttransplant lymphoma

Abstract

The role of the Epstein-Barr virus in the development of post-transplant lymphomas is well established. However, not all lymphomas that arise in these patients contain Epstein-Barr virus, suggesting that other cofactors are involved in tumor pathogenesis. We propose that immunologic interactions that result from the introduction of immunocompetent donor cells during transplantation contribute to a lymphomagenic environment in the host. Murine models of lymphoma that arises following transfer of allogeneic hematopoietic cells are discussed and are related to the transplant setting. One contemporary viewpoint of transplantation immunology holds that interactions between the host and donor components of the immune system determine the ultimate degree of tolerance or reciprocal immunoreactivity (eg, rejection, graft-versus-host disease) within the transplant patient. We conclude that host-donor immunologic microchimerism may also be an over-looked factor in the development of posttransplant lymphomas.At first glance, the title of this paper appears to be an effort to link two entirely unrelated topics. After all, a preponderance of studies have established the Epstein-Barr virus (EBV) as the primal driving force within post-transplant lymphoproliferative disorders (PTLD) [1], and a depressed host antiviral immune response apparently completes the list of factors necessary for production of these tumors. Indeed, direct reestablishment of immunologic control [2], most specifically by means such as adoptive transfer of anti-EBV-specific, HLA-matched cytotoxic T cells [3][4][5], has been associated with tumor regression. Further, some patients who are treated by withdrawal of immunosuppression may also reject their grafts and thus by definition have not achieved donor-specific tolerance. What, then, is the impetus that leads us to suggest an intersection between tolerance and post-transplant lymphomas?On reflection, several features of PTLD are not easily explained by a disease model restricted to understanding the interactions between EBV-induced B-cell lymphoproliferation and defective host immunologic controls. For example, not all PTLDs contain EBV, nor are they necessarily even of B-cell origin [6,7•].Conversely, other EBV-associated tumors, such as nasopharyngeal carcinoma, do not occur in transplant patients with the same frequency as does PTLD. We also do not know why a large number of PTLDs are extranodal, and a virocentric perspective does not fully explain why a disproportionate number of PTLDs occur in the allograft [8]. The occasional donor cell-derived PTLD in the organ recipient [9] may be a probabilistic phenomenon, but it might also reflect other, poorly understood processes. For all of these reasons, it may be worthwhile to first acknowledge the importance of EBV and the associated host anti-EBV immune response in the pathogenesis of these tumors, and then ask where we might seek other, cryptic, cofactors that could explain additional aspects of posttransplant lymphoid neoplasia. NIH Public Acc...