Tolerance and chronic rejection

Abstract

The most common cause of chronic allograft loss is an incompletely understood clinicopathological entity called chronic rejection (CR). Recent reports suggest an improvement in long-term renal allograft survival, although it is not clear from these data whether a true reduction of biopsy-proven CR has occurred. Although newer immunosuppressive medications have greatly reduced the incidence of acute rejection (AR) in the early post-transplantation period, the ideal therapy for both AR and CR would be to achieve a state of tolerance. By de¢nition, such a state should allow for inde¢nite allograft survival, with no histopathological evidence of CR, despite immunocompetence in the host (i.e. without the need for chronic immunosuppression). Although several experimental studies are able to achieve tolerance, with clear improvement in allograft survival, detailed studies on graft function and morphology are often not included. This review will discuss possible ways that tolerance induction could lead to a CR-free state. General mechanisms of CR and transplantation tolerance induction are discussed as well as the di¤culties in translating small animals studies into large animals and humans.

Biological and Biomaterial Approaches for Improved Islet Transplantation

“…Hyperacute rejection of xenografts can be obviated with use of animals knocked out for specific genes, e.g., ␣-(1,3)-galactose, or a component for complement fixation (White and Yannoutsos, 1996) or use of complement inhibitors, complement depletion, and plasmapheresis of the recipient to remove natural antibodies . The acute rejection process has been addressed predominantly through the use of immunosuppressant drugs, whereas chronic rejection is being addressed through the use of tolerogenic strategies (Womer et al, 2001a). The combination of immunosuppression and tolerance approaches is now being proposed for improved clinical outcomes in both islet and solid organ transplantation (Adams et al, 2001).…”

Renal Transplantation

“…Since it is also the side effects of therapeutical immunosuppression that contribute to graft damage, the induction of specific immunotolerance is one of the remaining requirements in clinical transplantation. First attempts at tolerance induction have been undertaken (20,37).…”

134 Impact of combined mycophenolate mofetil and low dose calcineurin inhibitor therapy on T cell function

“…MMF treatment may be expected to have beneficial effects not only on acute but also on chronic rejection as a result of suppression of IL-10 secretion. However, the exact phenotype and mechanisms of action of regulator T cells remain controversial (Womer et al, 2001). The Th1 and Th2 paradigm which holds that rejection is dependent on the expression of Th1 cytokines (IL-2, IFN-γ) and that tolerance is dependent on Th2 cytokines (IL-4, IL-5, IL-10 and IL-13) has been recently challenged.…”

“…The Th1 and Th2 paradigm which holds that rejection is dependent on the expression of Th1 cytokines (IL-2, IFN-γ) and that tolerance is dependent on Th2 cytokines (IL-4, IL-5, IL-10 and IL-13) has been recently challenged. The existence of specific cytokine gene knock out mice indicates that Th1 cytokines may function not only to initiate cell-mediated immune responses but also to regulate T-cell responses (Womer et al, 2001).…”