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Fc-dependent depletion of activated T cells occurs through CD40L-specific antibody rather than costimulation blockade

Abstract

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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Figure 1: Combined CD40L-specific antibody and rapamycin treatment prolongs allograft survival.
Figure 2: ELISpot assays show delayed priming of IFN-γ-producing alloreactive T cells after combined CD40L-specific antibody and rapamycin treatment.
Figure 3: CD40L-specific antibody fixes mouse complement in vitro.
Figure 4: Colocalization of activated complement fragment C3d and T cells in the draining lymph nodes of transplant recipients receiving CD40L-specific antibody therapy.
Figure 5: Complement- and Fc receptor–mediated mechanisms are necessary for prolonged skin allograft survival after CD40L-specific antibody and rapamycin treatment.
Figure 6: Unlike the whole CD40L-specific antibody, the F(ab′)2 fragment does not prevent development of H-Y–specific CD8+ T cells.

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Acknowledgements

We thank P. Lane for providing us with CD40L transfectants, M. Allen for advice and help with rapamycin supply, M. Goggin for large-scale antibody production, and D. Gray and members of the Sacks and Simpson laboratories for their helpful advice and comments. This work was supported by the Wellcome Trust, Guy's & Saint Thomas' Charitable Foundation and the Medical Research Council UK.

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Correspondence to Elizabeth Simpson or Stipo Jurcevic.

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Monk, N., Hargreaves, R., Marsh, J. et al. Fc-dependent depletion of activated T cells occurs through CD40L-specific antibody rather than costimulation blockade. Nat Med 9, 1275–1280 (2003). https://doi.org/10.1038/nm931

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