Nature Medicine9, 1275 - 1280 (2003)
Published online: 14 September 2003; | doi:10.1038/nm931
Fc-dependent depletion of activated T cells occurs through CD40L-specific antibody rather than costimulation blockade
Nicola J Monk1, 3, Roseanna E G Hargreaves1, 3, James E Marsh1, Conrad A Farrar1, Steven H Sacks1, Maggie Millrain2, Elizabeth Simpson2, Julian Dyson2
& Stipo Jurcevic1
1
Department of Nephrology & Transplantation, King's College, Guy's, King's and St Thomas' Medical School, Guy's Hospital, London SE1 9RT, UK.
2
Transplantation Biology Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 ONN, UK.
Although the underlying mechanisms are not well understood, it is generally believed that antigen recognition by T cells in the absence of costimulation may alter the immune response, leading to anergy or tolerance. Further support for this concept comes from animal models of autoimmunity and transplantation, where treatments based on costimulation blockade, in particular CD40 ligand (CD40L)-specific antibodies, have been highly effective. We investigated the mechanisms of action of an antibody to CD40L and provide evidence that its effects are dependent on the constant (Fc) region. Prolongation of graft survival is dependent on both complement- and Fc receptor−mediated mechanisms in a major histocompatibility complex (MHC)-mismatched skin transplant model. These data suggest that antibodies to CD40L act through selective depletion of activated T cells, rather than exerting immune modulation by costimulation blockade as currently postulated. This finding opens new avenues for treatment of immune disorders based on selective targeting of activated T cells.
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