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Transplant tolerance: models, concepts and facts

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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.

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Authors and Affiliations

  1. Department of Nephrology & Transplantation, King's College, Guy's, King's and St Thomas' Medical School, 5th Floor TGH, Guy's Hospital, SE1 9RT, London, UK

    Nicola J. Monk, Roseanna E. G. Hargreaves & Stipo Jurcevic

  2. Transplantation Biology Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, W12 ONN, London, UK

    Elizabeth Simpson & Julian P. Dyson

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  1. Nicola J. Monk
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  2. Roseanna E. G. Hargreaves
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  3. Elizabeth Simpson
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  4. Julian P. Dyson
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  5. Stipo Jurcevic
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Correspondence to Julian P. Dyson or Stipo Jurcevic.

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Monk, N.J., Hargreaves, R.E.G., Simpson, E. et al. Transplant tolerance: models, concepts and facts. J Mol Med 84, 295–304 (2006). https://doi.org/10.1007/s00109-005-0006-4

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