Regulatory allospecific NK cell function is differentially associated with HLA C allotypes

Major histocompatibility complex I (MHC I) molecules 'silence' natural killer (NK) cell activity. Conversely, NK cell activity is triggered through cells lacking expression of autologous MHC I. Unexpectedly we found that a subset of NK cells is activated rather than silenced when interacting with cells expressing normal levels of autologous MHC I. Instead of inducing an inflammatory phenotype, however, activation led to the secretion of the regulatory cytokines TGF-beta and IL-10. Importantly, in vitro models of allogeneic interactions showed that targets co-expressing HLA C1 and C2 epitopes best supported, or even enhanced, this cell-contact-mediated regulatory NK cell function. Together, these data ascribe a novel pattern of reactivity to NK cells, with potential implications both in autologous and allogeneic systems

Urinary C4d does not correlate with C4d-staining in peritubular capillaries but reflects nonspecific glomerular injury

BACKGROUND: C4d-staining in peritubular capillaries (PTC) in allograft biopsies is a hallmark of antibody-mediated rejection (AMR). This study investigated whether urinary C4d correlates with C4d-staining in PTC, allowing for a noninvasive screening procedure. METHODS: Urine samples from 34 patients with diffuse C4d-staining in PTC (C4d-pos group) and 68 urine samples from patients with negative C4d-staining in PTC (C4d-negative group) matched 1:2 according to proteinuria and time posttransplant were compared regarding urinary C4d-levels. RESULTS: Overall, urinary C4d/creatinine-ratios (C4d/C) were not different between the C4d-positive and the C4d-negative group (P=0.55). Urinary C4d/C strongly correlated with total protein/creatinine-ratios (P/C) (r2=0.53; P50 mg/mmol (P=0.57) and P/C50 mg/mmol than in patients with P/C>50 mg/mmol (P>or=0.005). Furthermore, longitudinal analysis in 3 patients with distinct clinico-pathological courses demonstrated that urinary C4d/C closely followed P/C regardless of C4d-staining in PTC. CONCLUSION: Urinary C4d does not correlate with C4d-staining in PTC but reflects nonspecific glomerular injury. Therefore, urinary C4d is likely not a useful biomarker for non-invasive screening and monitoring of AMR

The number of activating KIR genes inversely correlates with the rate of CMV infection/reactivation in kidney transplant recipients

Viral infection is a common complication after kidney transplantation. The role of natural killer cells (NK cells) in this setting remains unknown. NK cells express activating and inhibitory killer cell immunoglobulin-like receptors (KIR). We analyzed whether activating KIR genes carried by kidney transplant-recipients influence the rate of viral infection during the first year after transplantation. In patients with a KIR A/A genotype (n = 40, KIR2DS4 only activating KIR) the rate of cytomegalovirus (CMV) infection and reactivation was 36%, as compared to 20% in transplant recipients with more than one activating KIR gene (KIR B/X genotype, n = 82, p = 0.04). Adjusting for other risk factors in Cox regression, the relative risk of B versus A genotype patients was 0.34 (95% CI 0.15-0.76, p = 0.009). The degree of protection increased with the number of activating KIR genes. Symptomatic CMV disease was only observed in four individuals, all carrying a KIR A/A genotype. As for viral infections other than CMV, and for bacterial infections, no KIR-linked protective effect could be detected. Also, graft function and the rate-rejection episodes were similar in KIR A/A and KIR B/X genotype individuals. This study supports a role for activating KIR in the control of CMV infection after kidney transplantation

Frequency and determinants of pregnancy-induced child-specific sensitization

The aim of this study was to define the frequency and determinants of pregnancy-induced child-specific sensitization shortly after full-term delivery using sensitive single HLA-antigen beads (SAB) and high resolution HLA-typing of the mothers and their children (n = 301). A positive SAB result was defined by a background normalized ratio >1 or a mean fluorescence intensity (MFI) >300, >500 and >1000, respectively. The overall frequency of pregnancy-induced sensitization determined by SAB shortly after full-term delivery was between 45% (MFI > 1000 cut-off) and 76% (ratio cut-off). The rate of child-specific sensitization at the HLA-A/B/C/DRB1 loci was between 28% (MFI > 1000 cut-off) and 38% (ratio cut-off). The number of live birth was associated with a higher frequency of sensitization, which was driven by child-specific, but not third party HLA-antibodies. There was a clear hierarchy of sensitization among the investigated loci (B-locus: 31%; A-locus: 26%; DRB1-locus: 20%; C-locus: 15%; p < 0.0001). Some mismatched paternal HLA-antigens led to a significantly higher rate of sensitization than the average (e.g. HLA-A2, HLA-B49, HLA-B51, HLA-C*15). Furthermore, the mother's own HLA-phenotype--especially HLA-A/B homozygosity--was associated with a higher rate and broadness of sensitization. The number of mismatched HLA-A/B/C eplets strongly correlated with the rate of child-specific class I sensitization

Association of Checkpoint Inhibitor-Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer.

Immunotherapy with checkpoint inhibitors targeting the PD-1 (programmed cell death 1) axis has brought notable progress in patients with non-small cell lung cancer (NSCLC) and other cancers. However, autoimmune toxic effects are frequent and poorly understood, making it important to understand the pathophysiologic processes of autoimmune adverse effects induced by checkpoint inhibitor therapy. To gain mechanistic insight into autoimmune skin toxic effects induced by anti-PD-1 treatment in patients with non-small cell lung cancer. This prospective cohort study was conducted from July 1, 2016, to December 31, 2018. Patients (n = 73) with non-small cell lung cancer who received anti-PD-1 therapy (nivolumab or pembrolizumab) were recruited from 4 different centers in Switzerland (Kantonsspital St Gallen, Spital Grabs, Spital Wil, and Spital Flawil). Peripheral blood mononuclear cells, tumor biopsy specimens and biopsies from sites of autoimmune skin toxic effects were collected over a 2-year period, with patient follow-up after 1 year. Response to treatment, overall survival, progression-free survival, and development of autoimmune toxic effects (based on standard laboratory values and clinical examinations). Of the cohort of 73 patients with NSCLC (mean [SD] age, 68.1 [8.9] years; 44 [60%] men), 25 (34.2% [95% CI, 24.4%-45.7%]) developed autoimmune skin toxic effects, which were more frequent in patients with complete remission or partial remission (68.2% [95% CI, 47.3%-83.6%]) than those with progressive or stable disease (19.6% [95% CI, 11.0%-32.5%]) (χ2 = 14.02, P &lt; .001). Nine T-cell antigens shared between tumor tissue and skin were identified. These antigens were able to stimulate CD8+ and CD4+ T cells in vitro. Several of the antigen-specific T cells found in blood samples were also present in autoimmune skin lesions and lung tumors of patients who responded to anti-PD-1 therapy. These findings highlight a potential mechanism of checkpoint inhibitor-mediated autoimmune toxic effects and describe the association between toxic effects and response to therapy; such an understanding will help in controlling adverse effects, deciphering new cancer antigens, and further improving immunotherapy