Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of myeloid regulatory cells that were originally described in cancer. Several studies in animal models point to MDSC as important players in the induction of allograft tolerance due to their immune modulatory function. Most of the published studies have been performed in animal models, and the data addressing MDSCs in human organ transplantation are scarce. We evaluated the phenotype and function of different MDSCs subsets in 38 kidney transplant recipients (KTRs) at different time points. Our data indicate that monocytic MDSCs (Mo-MDSC) increase in KTR at 6 and 12 months posttransplantation. On the contrary, the percentages of polymorphonuclear MDSC (PMN-MDSC) and early-stage MDSC (e-MDSC) are not significantly increased. We evaluated the immunosuppressive activity of Mo-MDSC in KTR and confirmed their ability to increase regulatory T cells (Treg) in vitro. Interestingly, when we compared the ability of Mo-MDSC to suppress T cell proliferation, we observed that tacrolimus, but not rapamycin-treated KTR, was able to inhibit CD4+ T cell proliferation in vitro. This indicates that, although mTOR inhibitors are widely regarded as supportive of regulatory responses, rapamycin may impair Mo-MDSC function, and suggests that the choice of immunosuppressive therapy may determine the tolerogenic pathway and participating immune cells that promote organ transplant acceptance in KTR.

BACKGROUND Non-invasive biomarkers of graft rejection are needed to optimize the management and outcomes of kidney transplant recipients. Urinary excretion of IFN-g-related chemokine CXCL10 is clearly associated with clinical and subclinical T cell-mediated graft inflammation, but its relationship with antibody-mediated damage has not been fully addressed. Further, the variables influencing levels of urinary CXCL10 excretion are unknown. MATERIAL AND METHODS A total of 151 kidney graft biopsies (92 surveillance and 59 indication biopsies) and 151 matched urine samples obtained before biopsy were prospectively analyzed. T cell-mediated rejection (TCMR) and antibody-mediated rejection (AbMR) were defined according to the 2017 Banff classification criteria. Urinary CXCL10 levels were measured by ELISA and corrected by urinary creatinine. RESULTS Banff scores 't', 'i', 'g', and 'ptc' were significantly related to urinary CXCL10 levels. Multivariate analysis showed that 't' (ß=0.107, P=0.001) and 'ptc' (ß=0.093, P=0.002) were significantly associated with urinary CXCL10. Donor-specific antibodies (DSAs) were related to the high excretion of urinary CXCL10 at 1 year after transplantation (odds ratio [OR] 17.817, P=0.003). Urinary CXCL10 showed good discrimination ability for AbMR (AUC-ROC 0.760, P=0.001). The third tertile of urinary CXCL10 remained significantly associated with AbMR (OR 4.577, 95% confidence interval 1.799-11.646, P=0.001) after multivariate regression analysis. CONCLUSIONS DSA was the only variable clearly related to high urinary CXCL10 levels. Urinary CXCL10 is a good non-invasive candidate biomarker of AbMR and TCMR, supplying information independent of renal function and other variables normally used to monitor kidney transplants.

Autosomal recessive congenital ichthyoses (ARCI) have been associated with different phenotypes including: harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). While pathogenic variants in all ARCI genes are associated with LI and CIE phenotypes, the unique gene associated with HI is ABCA12. In HI, the most severe ARCI form, pathogenic variants in both ABCA12 gene alleles usually have a severe impact on protein function. The presence of at least one non-truncating variant frequently causes a less severe congenital ichthyosis phenotype (LI and CIE).