LBP28: A ROLE FOR IFN-G STIMULATED MONOCYTES IN ANTIBODY-MEDIATED DAMAGE BY C1Q+ DSA

Abstract

Background Complement (C′) fixing DSA increases the risk of kidney allograft loss and degree of antibody-mediated damage. However, the immunologic mechanisms responsible for this process remain ill defined. We hypothesized that IFN-g-activated monocytes would play a key role in the rejection process involving C′ fixing DSA given the NK cell Fc receptor CD16 preference for IgG1 and IgG3 subclasses. Methods Global gene expression was assessed in kidney transplant biopsies from 150 patients with DSA detected in the first year post-transplant (48 C1Q+ DSA), and on purified monocytes stimulated with IFN-g over a time course (2, 4, and 8 h). Results Compared to biopsies from C1Q-DSA patients, those from C1Q+ DSA patients showed higher expression of transcripts depicting monocyte activation (p = 0.0014), IFN-g effects (p = 0.02), and endothelial activation (p = 0.0273). With in vivo evidence of increased monocyte activation and IFN-g effects in the presence of C1Q+ DSA, we examined an IFN-g time course treatment of monocytes. IFN-g treatment of monocytes induced 189 transcripts by >5-fold at either 2, 4, or 8 h compared to 2 h unstimulated monocytes. 7 IFN-g responsive transcripts showed a direct contribution to antibody-mediated damage (Fig. 1): Chemokines CCL2 and CCL7 are both potent monocyte chemoattractants while CXCL11 contributes to NK cell recruitment, IL15 and IL15RA maximize monocyte’s ability to express and present this key NK cell growth factor, the high affinity FcR (FCGR1) was also highly inducible by IFN-g as were transcripts for C1Q components which allows for higher local concentrations of C1Q in addition to that present in blood. Conclusion Patients with C1Q+ DSA show a distinct molecular phenotype characterized by higher expression of genes related to monocyte activation, IFN-g effects, and endothelial activation. Multiple transcripts are rapidly upregulated by IFN-g in monocytes which elucidate the significant contribution that these cells make towards injury by C′ fixing DSA.