Suppression of Xeno- and Allo-Antibody Production by Treatment with ILT3Fc

Resent studies from our laboratory have shown that ILT3 is a powerful suppressor of T cell reactivity and exposure of T cells to membrane or soluble ILT3 during priming results in the generation of CD8 T suppressor cells and CD4 Th anergy. ILT3Fc treated T cells fail to upregulate the costimulatory marker CD40L and do not secrete Th1, Th2 and Th17 cytokines following activation. Experiments in which supernatants from MLC reactions performed in the presence or absence of ILT3Fc were tested for their cytokine content demonstrated that IL-5 and IL-4 were among the most powerfully inhibited cytokines. We therefore hypothesized the ILT3Fc may be a strong inhibitor of class switching and antibody production in B cells, by removing the T cell help required for these processes. In vitro, ILT3Fc strongly inhibited IgG and IgM antibody production in PWM-stimulated cultures of PBMC. The suppressive effect of ILTfC on antibody production was confirmed in vivo in NOD/SCID/gamma-null (NSG) mice humanized by injection of 50×106 human PBMC, which subsequently received either 10 daily injections with ILT3Fc or mock treatments. We showed that mock-treated NSG mice developed GVHD with a a strong humoral component which included IgM and IgG human anti-mouse xeno-antibodies. Both GVHD and xenoantibody production was significantly ameliorated by ILT3Fc treatment. The finding that T cells primed in the presence of ILT3 are greatly inhibited in their capacity to transcribe and secrete Th2 and consequently to help B cells to produce antibodies opens up the possibility that the suppression cascade triggered by this molecule can be harnessed for therapeutic use in transplantation, autoimmunity and allergy.