title: Transplant tolerance: models, concepts and facts.
abstract: Despite extensive research, our understanding of immunological tolerance to self-antigens is incomplete, and the goal of achieving tolerance to allogeneic transplanted tissue remains elusive. Currently, it is generally believed that the blockade of T cell co-stimulation offers considerable potential for achieving tolerance in the clinical setting. However, the recent finding that CD154-specific antibody may act through the depletion of activated T cells rather than co-stimulation blockade alone highlights the need for a re-evaluation of published data and the role of co-stimulation blockade in transplant tolerance. Activated T cells are programmed to die unless they receive sufficient survival signals in the form of inflammatory and lymphotropic cytokines produced by activated antigen-presenting cells or the T cells themselves. In conditions where the threshold for surviving activation is not reached, for example when a small number of responder T cells are activated in the absence of substantial injury or inflammation, the ensuing death of all activated T cells can result in deletional tolerance. Therefore, we propose that tolerance represents a failure of T cells to survive activation and develop into memory cells. This concept is likely to apply in the transplant setting, where the strength of the alloresponse depends on both the number/phenotype of the recipients' alloreactive T cells and immunogenicity of the transplanted tissue. Hence, in some rodent donor-recipient strain combinations that instigate a weak alloresponse, many treatments that only modestly decrease the alloresponse can achieve tolerance. In contrast, clinical transplantation is characterised by a strong alloresponse and highly immunogenic allografts, and thus, most treatments fail to control allograft rejection, and tolerance is difficult to achieve.
authors.affiliation: Department of Nephrology & Transplantation, King's College, Guy's, King's and St Thomas' Medical School, 5th Floor TGH, Guy's Hospital, London, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Monk
authors.forename: Roseanna E G
authors.initials: RE
authors.lastname: Hargreaves
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Simpson
authors.forename: Julian P
authors.initials: JP
authors.lastname: Dyson
authors.forename: Stipo
authors.initials: S
authors.lastname: Jurcevic
mesh_terms: D000818:Animals; D002470:Cell Survival; D016208:Databases, Factual; D006801:Humans; D008213:Lymphocyte Activation; D023421:Models, Animal; D008954:Models, Biological; D013601:T-Lymphocytes / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*