In vivo blockade of macrophage migration inhibitory factor prevents skin graft destruction after indirect allorecognition.

Background: The effector mechanisms that ultimately destroy transplanted tissues are poorly understood. In particular, it is not clear how CD4+ T cells primed to donor-derived determinants expressed on recipient MHC molecules (the indirect pathway) can mediate graft destruction in the absence of cognate recognition of peptide: MHC on the graft cells themselves. Macrophage migration inhibitory factor (MIF) inhibits macrophage movement and is a proinflammatory and regulatory cytokine known to be essential for development of delayed-type hypersensitivity reactions.

Methods: To test whether MIF participates in graft destruction following indirect recognition, we studied rejection of MHC-II-deficient skin grafts placed on allogeneic SCID recipients adoptively transferred with naïve CD4+ T cells, and the recipients were treated with neutralizing anti-MIF monoclonal antibody or isotype control IgG. In this model graft rejection can only occur indirectly as the graft cells lack MHC II for recognition by the recipient CD4+ T cells.

Results: We found that in vivo blockade of MIF inhibited indirect CD4+ cell-mediated skin graft destruction, and markedly reduced detectable macrophages within the grafts. The neutralizing anti-MIF antibody significantly inhibited alloreactive DTH but did not prevent T cell priming or interferon-gamma release by primed T cells.

Conclusions: The results strongly implicate MIF as an active participant in skin graft destruction after indirect recognition and suggest that this effect is mediated through an inhibition of macrophage migration and/or function.