Anti-CTLA-4 (CD 152) monoclonal antibody-induced autoimmune interstitial nephritis

Targeted immune-modulating agents are entering clinical practice in many specialties, providing novel therapeutic possibilities but introducing new potential toxicities. We present the first reported case, to our knowledge, of immune-mediated nephritis following the administration of Tremelimumab (CP-675, 206), an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody. High-dose steroid therapy led to a rapid improvement in renal function, avoiding the need for renal replacement therapy.Peer reviewe

Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers.

The monoclonal anti-CD20 antibody rituximab (RTX) depletes B cells in the treatment of lymphoma and autoimmune disease, and contributes to alloantibody reduction in transplantation across immunologic barriers. The effects of RTX on T cells are less well described. T-follicular helper (Tfh) cells provide growth and differentiation signals to germinal center (GC) B cells to support antibody production, and suppressive T-follicular regulatory (Tfr) cells regulate this response. In mice, both Tfh and Tfr are absolutely dependent on B cells for their formation and on the GC for their maintenance. In this study, we demonstrate that RTX treatment results in a lack of GC B cells in human lymph nodes without affecting the Tfh or Tfr cell populations. These data demonstrate that human Tfh and Tfr do not require an ongoing GC response for their maintenance. The persistence of Tfh and Tfr following RTX treatment may permit rapid reconstitution of the pathological GC response once the B-cell pool begins to recover. Strategies for maintaining remission after RTX therapy will need to take this persistence of Tfh into account.This work was funded by a Wellcome Trust Programme Grant (083650/Z/07/Z) and a Lister Prize Fellowship to KGCS and supported by the National Institute of Health Research Cambridge Biomedical Research Center. EFW was supported by an Addenbrooke’s Charitable Trust research fellowship; MAL was supported by a NHMRC Overseas Biomedical Fellowship, then by the Biotechnology and Biological Sciences Research Council.This is the accepted manuscript. The final published version is available from Blood at http://dx.doi.org/10.1182/blood-2014-07-58597

Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake.

Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). FcgammaRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcgammaRIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcgammaRIIIb. Reduced FcgammaRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Fast versus gradual adaptation of soft monthly contact lenses in neophyte wearers

AIM: To determine if a gradual adaptation period is necessary for neophytes when fitted with modern hydrogel or silicone hydrogel reusable disposable contact lenses. METHOD: Across four sites, 74 neophytes (18-28 years) were randomly assigned to a reusable lens cleaned nightly with Opti-Free® Puremoist® multi-purpose contact lens solution: Proclear® (hydrogel) or Biofinity® (silicone hydrogel) and an adaptation schedule: fast (10 h wear from the first day) or gradual (4 h on the first day, increasing their wear time by 2 h on each subsequent day until they had reached 10 h). Masked investigators graded ocular surface physiology and non-invasive tear breakup time (NIBUT) and a range of comfort, vision and lens handling subjective ratings (0-100 visual analogue scales) were recorded at the baseline visit and after 10 h of lens wear, 4-6 days and 12-14 days after lens fitting. Subjective scores were also repeated after 7 days. RESULTS: There was no difference (p > 0.05) in ocular surface physiology or NIBUT between fast and gradual adaptation groups at any time point in either lens type with the exception of increased corneal staining (p = 0.019) in the silicone hydrogel fast adaptation group after 4-6 days, but was similar by 12-14 days. Subjective scores were also similar across the visits and lens types with the exception of 'lens awareness' (p = 0.019) which was less in the gradual versus the fast adaptation silicone hydrogel lens group at 12-14 days. CONCLUSION: There seems to be no clinical benefit for recommending a gradual adaptation period in new wearers fitted with modern soft reusable disposable contact lenses. The findings of this work add to a growing body of evidence suggesting that such advice is unnecessary in regular soft contact lens wear, which has important ramifications for the initial clinical management of these patients

Copy number of which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake-5

plate are shown (all of the raw data are shown in Fig. S1, A and B). The horizontal bar indicates the mean. The P values shown indicate comparison of all cases and controls using a stratified Student's test. (A) UK SLE patients, = 171; UK controls, = 176. (B) Hong Kong SLE patients, = 159; Hong Kong controls, = 150.<p><b>Copyright information:</b></p><p>Taken from "Copy number of which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake"</p><p></p><p>The Journal of Experimental Medicine 2008;205(7):1573-1582.</p><p>Published online 7 Jul 2008</p><p>PMCID:PMC2442635.</p><p></p

Copy number of which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake-1

O a gene, and each column to an individual. Red indicates increased expression compared with PBMC reference; green represents reduced expression. The patient (A in panel B) with no expression is marked with an asterisk. (B) Family tree of the -deficient patient A, showing Mendelian inheritance of the null allele. CN was determined using flow cytometry. (C) Flow cytometry of neutrophils stained for PE-labeled antibody to FcγRIIIb demonstrates reduced surface expression on cells from individuals B, C, and D (with a single copy) compared with individuals E and F, who have two copies. Geometric mean fluorescences were 7, 2,265, 2,241, 2,303, 3,484, and 3,730 for A–F, respectively. (D) Gene dosage of relative to , determined by qPCR, for patient A (no ), her daughter patient B, her son patient C, and her brother patient D (with a single copy), as well as for her husband patient E and her other brother patient F (with two copies of ). (E) qPCR was performed on DNA from all family members whose FcγRIIIb expression had been determined by flow cytometry. Gene dosages of relative to (by qPCR) were significantly higher in those individuals who by flow cytometry were shown to have greater surface expression of FcγRIIIb. The horizontal bar indicates the mean. (F) Delineation of the extent of the deletion in patient A and family members B, C, and E using PCR; , , and are absent. (G) A similar delineation using flow cytometry in patient A. FcγRIIa (neutrophils), FcγRIIb (neutrophils shown, confirmed on B cells, and not depicted) and FcγRIIIa (NK cells) are present (isotype control shaded gray), but FcγRIIIb (neutrophils) is absent. CD59 is expressed on neutrophils, thus GPI linkage is intact.<p><b>Copyright information:</b></p><p>Taken from "Copy number of which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake"</p><p></p><p>The Journal of Experimental Medicine 2008;205(7):1573-1582.</p><p>Published online 7 Jul 2008</p><p>PMCID:PMC2442635.</p><p></p