Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis

Abstract Background Imiquimod (IMQ) produces a cutaneous phenotype in mice frequently studied as an acute model of human psoriasis. Whether this phenotype depends on strain or sex has never been systematically investigated on a large scale. Such effects, however, could lead to conflicts among studies, while further impacting study outcomes and efforts to translate research findings. Methods RNA-seq was used to evaluate the psoriasiform phenotype elicited by 6 days of Aldara (5% IMQ) treatment in both sexes of seven mouse strains (C57BL/6 J (B6), BALB/cJ, CD1, DBA/1 J, FVB/NJ, 129X1/SvJ, and MOLF/EiJ). Results In most strains, IMQ altered gene expression in a manner consistent with human psoriasis, partly due to innate immune activation and decreased homeostatic gene expression. The response of MOLF males was aberrant, however, with decreased expression of differentiation-associated genes (elevated in other strains). Key aspects of the IMQ response differed between the two most commonly studied strains (BALB/c and B6). Compared with BALB/c, the B6 phenotype showed increased expression of genes associated with DNA replication, IL-17A stimulation, and activated CD8+ T cells, but decreased expression of genes associated with interferon signaling and CD4+ T cells. Although IMQ-induced expression shifts mirrored psoriasis, responses in BALB/c, 129/SvJ, DBA, and MOLF mice were more consistent with other human skin conditions (e.g., wounds or infections). IMQ responses in B6 mice were most consistent with human psoriasis and best replicated expression patterns specific to psoriasis lesions. Conclusions These findings demonstrate strain-dependent aspects of IMQ dermatitis in mice. We have shown that IMQ does not uniquely model psoriasis but in fact triggers a core set of pathways active in diverse skin diseases. Nonetheless, our findings suggest that B6 mice provide a better background than other strains for modeling psoriasis disease mechanisms.http://deepblue.lib.umich.edu/bitstream/2027.42/136167/1/13073_2017_Article_415.pd

Polarization Transfer in the ^4He(\vec e,e'\vec p)^3H Reaction up to Q^2 = 2.6 (GeV/c)^2

We have measured the proton recoil polarization in the ^4He(\vec e,e'\vec p)^3H reaction at Q^2 = 0.5, 1.0, 1.6, and 2.6 (GeV/c)^2. The measured ratio of polarization transfer coefficients differs from a fully relativistic calculation, favoring the inclusion of a predicted medium modification of the proton form factors based on a quark-meson coupling model. In contrast, the measured induced polarizations agree reasonably well with the fully relativistic calculation indicating that the treatment of final-state interactions is under control.Comment: 5 pages, 3 figures, uses revtex.sty, submitted to Physical Review Letter

Precision Measurement of the p(e,e ' p)pi(0) Reaction at Threshold

New results are reported from a measurement of $\pi^0$ electroproduction near threshold using the $p(e,e^{\prime} p)\pi^0$ reaction. The experiment was designed to determine precisely the energy dependence of $s-$ and $p-$wave electromagnetic multipoles as a stringent test of the predictions of Chiral Perturbation Theory (ChPT). The data were taken with an electron beam energy of 1192 MeV using a two-spectrometer setup in Hall A at Jefferson Lab. For the first time, complete coverage of the $\phi^*_{\pi}$ and $\theta^*_{\pi}$ angles in the $p \pi^0$ center-of-mass was obtained for invariant energies above threshold from 0.5 MeV up to 15 MeV. The 4-momentum transfer $Q^2$ coverage ranges from 0.05 to 0.155 (GeV/c)$^2$ in fine steps. A simple phenomenological analysis of our data shows strong disagreement with $p-$wave predictions from ChPT for $Q^2>0.07$ (GeV/c)$^2$, while the $s-$wave predictions are in reasonable agreement.Comment: 5 pages, 6 figure

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

Polarization Transfer in the He-4(polarized-e, e-prime polarized-p)H-3 Reaction up to Q{sup 2}=2.6 (GeV/c){sup 2}

We have measured the proton recoil polarization in the {sup 4}He(polarized-e, e-prime, p){sup 3}H reaction at Q{sup 2} = 0.5, 1.0, 1.6, and 2.6 (GeV/c){sup 2}. The measured ratio of polarization transfer coefficients differs from a fully relativistic calculation, favoring the inclusion of a predicted medium modification of the proton form factors based on a quark-meson coupling model. In contrast, the measured induced polarizations agree reasonably well with the fully relativistic calculation indicating that the treatment of final-state interactions is under control