Vigorous Allograft Rejection in the Absence of Danger

Abstract

Tolerance to self is a necessary attribute of the immune system. It is thought that most autoreactive T cells are deleted in the thymus during the process of negative selection. However, peripheral tolerance mechanisms also exist to prevent development of autoimmune diseases against peripheral self-Ags. It has been proposed that T cells develop tolerance to peripheral self-Ags encountered in the absence of inflammation or “danger” signals. We have used immunodeficient Rag 1−/− mice to study the response of T cells to neo-self peripheral Ags in the form of well-healed skin and vascularized cardiac allografts. In this paper we report that skin and cardiac allografts without evidence of inflammation are vigorously rejected by transferred T cells or when recipients are reconstituted with T cells at a physiologic rate by nude bone graft transplantation. These results provide new insights into the role of inflammation or “danger” in the initiation of T cell-dependent immune responses. These findings also have profound implications in organ transplantation and suggest that in the absence of central deletional tolerance, peripheral tolerance mechanisms are not sufficient to inhibit alloimmune responses even in the absence of inflammation or danger.

The Innate Immune System in Allograft Rejection and Tolerance

“…Relevant to transplantation biology, as posed by the "missing self" response, NK cells are cytotoxic to target cells mismatched for MHC class I molecules. Despite this, prior studies show that NK cells are not sufficient to reject solid organs directly because cardiac and skin allografts transplanted into mice that have intact NK cell function but absent adaptive immunity survive indefinitely (such as in Rag1 Ϫ/Ϫ or Scid mice) (43,77). However, recent studies show NK cells to act as facilitators of solid organ rejection by amplifying early graft inflammation and supporting the activity of alloreactive T cells (78 -80).…”

GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro

“…This innate immune response to the acute injury associated with the transplant procedure, however, was not shown to elicit allograft rejection (4 -6). Moreover, studies using T cell-deficient mice have shown that prompt rejection can occur only after T cell reconstitution, even when skin or allografts have been allowed to recover or heal for Ͼ100 days (7). Rather, concomitant stimulation of the innate immune system leads to increased expression of factors, such as cytokines, that may influence the adaptive immune system to promote the injury of the transplant organ (4).…”

Cell-Based Therapies in the Prevention of Solid Organ Transplant Rejection

“…Notably, danger signals seem to persist within allografts long after transplantation, as T cell-deficient mice transplanted with mismatched skin or cardiac allografts that are allowed to heal for 50 days, rapidly reject their grafts upon T cell reconstitution (Anderson et al, 2001;Bingaman et al, 2000). If homeostatic proliferation is taken into account using a model devoid of secondary lymphoid organs but containing a normal T cell compartment, allografts display histological evidence of chronic rejection, but are not acutely rejected (Chalasani et al, 2004).…”

“…Based on the 'missing self' hypothesis, NK cells recognize cells lacking expression of self-MHC class I molecules. NK cells are not sufficient to reject solid organ allografts, as Rag-/-or SCID mice, that lack T and B cells, fail to reject skin or heart allografts (Bingaman et al, 2000;Kitchens et al, 2006). NK cells do however contribute to tissue damage and amplify graft inflammation through release of the proinflammatory cytokines IFN-γ and TNF-α and through contact-mediated cytotoxicity (Obara et al, 2005).…”