UNCORR ECTED PROOF Infectious tolerance and the long- term acceptance of transplanted tissue Herman Waldmann Elizabeth Adams Paul Fairchild Stephen Cobbold Authors’ address Herman Waldmann, Elizabeth Adams, Paul Fairchild, Stephen Cobbold Sir William Dunn School of Pathology, Oxford, UK Correspondence to: Herman Waldmann Sir William Dunn School of Pathology South Parks Road Oxford OX1 3RE UK Tel.: +44 1865275503 Fax: +44 1865275501 E-mail: herman.waldmann@path.ox.ac.uk Summary: Short courses of antibody treatment aimed at blocking the coreceptors CD4 and CD8 and/or costimulatory molecules such as CD40L are able to bring about long-term acceptance and tolerance of allogeneic transplants. This tolerant state is operational, in that potential effector cells remain but are tightly regulated through the induction of antigen-specific CD4 + regulatory T cells (Tregs). CD4 + CD25 + FoxP3 + Tregs appear to play a prominent role, although other categories of Tregs have been documented. Transforming growth factor b (TGFb) has been found to play a major role in the induction of the tolerant state with therapeutic antibodies as well as promoting the induction of FoxP3 + T cells from naı ¨ve populations. The observation that Tregs can be found in tolerated grafts has led to the idea that they may interact with the grafted tissue to establish a state of acquired privilege symmetrical with a similar privileged microenvironment around antigen-presenting cells in lymphoid tissues. Damping of aggressive immune responses by Tregs allows antigen to persist and consequently for such antigen to be presented in an innocuous way to further promote tolerance in new cohorts of T cells throughout the life of the tolerated graft. Regulation may operate at many stages of an immune response, even as a censor at the terminal differentiation stages of effector function. Introduction The prolonged acceptance of transplanted organs requires long-term use of combinations of immunosuppressive drugs. This treatment risks infection and a range of side-effects, which can limit the life of the transplanted organ and the patient. Future improvements in immunosup- pressive therapy should aim to harness tolerance processes and, consequently, minimize the usage of immunosuppressive drugs. It may prove difficult to achieve full tolerance as an upfront routine procedure, but more likely, if one could wean patients off their drugs, once the graft has healed. Following the classical description of acquired tolerance in the neonatal mouse (1), it has long been recognized that the establishment of mixed hemopoietic chimerism in the mature immune system would offer one route to tolerance. Mixed chimerism would ensure inactivation of all potentially allo- aggressive cells through both central and peripheral tolerance Immunological Reviews 2006 Vol. 00: 1–13 Printed in Singapore. All rights reserved Copyright ß Blackwell Munksgaard 2006 Immunological Reviews 0105-2896 1 CE: ANS CSE: MB IMR 406