Exploration of real-world outcomes and treatment patterns in patients treated with anti-vascular endothelial growth factors for neovascular age-related macular degeneration in Sweden.

PURPOSE: To analyse and compare the number and interval of anti-vascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (nAMD), as well as the visual development in patients followed up for one to three years in clinical practice and during different index periods. METHODS: This observational study included treatment-naïve eyes with nAMD from the Swedish Macula Register that started treatment between 2007 and 2017, stratified by different index periods (2007-2010, 2011-2013, 2014-2015 and 2016-2017) and by follow-up cohorts for each index period of one, two or three years (cohorts 1-3). Their intravitreal anti-VEGF treatment was assessed by number of injections, injection intervals, visual acuity (VA) and near VA change. RESULTS: From the earliest index period 2007-2010 to the latest 2016-2017, the number of injections increased for the comparable follow-up time; 6.2 ± 1.4 versus 8.3 ± 2.0 injections after 1 year of treatment, 4.8 ± 1.6 versus 6.7 ± 2.4 during year 2. The last injection interval was 73 ± 34 days after 1, 71 ± 33 after 2 and 67 ± 32 after 3 years of follow-up for the index period 2014-2015. For the same period, the percentage of eyes with at least two consecutive 12-16 weeks of injection interval over 1-, 2- and 3-year follow-up increased from 5.2%, 15.0%, to 17.5% respectively. Baseline VA for eyes indexed 2016-2017 increased and presented with 62.1 ± 13.4 letters compared with 57.7 ± 13.5 letters in 2007-2010; p < 0.0001. CONCLUSIONS: From the earliest to the latest index periods, the number of injections increased for the comparable follow-up time. Accordingly, baseline VA and near VA and their outcomes improved continuously.

Priming of T cells to Fas-mediated proliferative signals by interleukin-7.

T-cell depletion associated with HIV infection or cytoreductive therapies triggers potential T-cell regenerative mechanisms such as peripheral T-lymphocyte expansion to weak antigenic stimuli and the increased availability of interleukin-7 (IL-7), a cytokine with potent antiapoptotic and proliferative activities. Deleterious mechanisms also associated with lymphopenia, such as increased Fas expression and apoptosis of T cell, however, may result in opposing effects. In this study, we show that Fas molecules, primarily associated with T-cell depletion in lymphopenic settings, may also contribute to compensatory T-cell expansion through transmitting costimulatory signals to suboptimally activated T cells. Proliferation of T lymphocytes in response to concomitant Fas and T-cell receptor (TCR) triggering was shown to be increased in HIV-infected individuals compared with noninfected controls. As IL-7 levels are often elevated in lymphopenic individuals in association with increased Fas expression, we analyzed whether IL-7 would influence Fas-mediated proliferative signals in T cells. We show that IL-7 is able to increase the efficacy of Fas to induce proliferation of suboptimally activated T cells. Thus, high IL-7 levels associated with lymphopenic conditions may simultaneously induce sensitivity to Fas-mediated apoptosis in nonactivated T cells and increase Fas-induced costimulatory signals in T cells recognizing low-affinity antigens.

Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection.

IL-7 promotes survival of resting T lymphocytes and induces T cell proliferation in lymphopenic conditions. As elevated IL-7 levels occur in HIV-infected individuals in addition to high Fas expression on T cells and increased sensitivity to Fas-induced apoptosis, we analyzed whether IL-7 has a regulatory role in Fas-mediated T cell apoptosis. We show that IL-7 up-regulates Fas expression on naive and memory T cells through a mechanism that involves translocation of Fas molecules from intracellular compartments to the cell membrane. IL-7 induced the association of Fas with the cytoskeletal component ezrin and a polarized Fas expression on the cell surface. The potential role of IL-7 in Fas up-regulation in vivo was verified in IL-7-treated macaques and in HIV-infected or chemotherapy treated patients by the correlation between serum IL-7 levels and Fas expression on T cells. IL-7 treatment primed T cells for Fas-induced apoptosis in vitro and serum IL-7 levels correlated with the sensitivity of T cells to Fas-induced apoptosis in HIV-infected individuals. Our data suggest an important role for IL-7 in Fas-mediated regulation of T cell homeostasis. Elevated IL-7 levels associated with lymphopenic conditions, including HIV-infection, might participate in the increased sensitivity of T cells for activation-induced apoptosis.

Relationship between serum IL-7 concentrations and lymphopenia upon different levels of HIV immune control.

Serum IL-7 levels correlate with T-cell depletion in HIV-infected individuals. In some patients, we observed that serum IL-7 decreases upon progression to AIDS, suggesting a role for IL-7 in T-cell maintenance in sporadic cases. Interestingly, IL-7 levels were significantly lower in stable long-term non-progressors (LTNP) than in patients who lost the LTNP status in a 3-year follow-up (P < 0.001), indicating that the serum IL-7 concentration might be a valuable marker for maintenance of the LTNP state.

FasL and TRAIL induce epidermal apoptosis and skin ulceration upon exposure to Leishmania major.

Receptor-mediated apoptosis is proposed as an important regulator of keratinocyte homeostasis in human epidermis. We have previously reported that Fas/FasL interactions in epidermis are altered during cutaneous leishmaniasis (CL) and that keratinocyte death through apoptosis may play a pathogenic role for skin ulceration. To further investigate the alterations of apoptosis during CL, a keratinocyte cell line (HaCaT) and primary human epidermal keratinocytes were incubated with supernatants from Leishmania major-infected peripheral blood mononuclear cells. An apoptosis-specific microarray was used to assess mRNA expression in HaCaT cells exposed to supernatants derived from L. major-infected cultures. Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA and protein expression were significantly up-regulated, and apoptosis was detected in both HaCaT and human epidermal keratinocyte cells. The keratinocyte apoptosis was partly inhibited through blocking of Fas or FasL and even more efficiently through TRAIL neutralization. Up-regulation of Fas on keratinocytes in epidermis and the presence of FasL-expressing macrophages and T cells in dermis were previously reported by us. In this study, keratinocytes expressing TRAIL, as well as the proapoptotic receptor TRAIL-R2, were detected in skin biopsies from CL cases. We propose that activation of Fas and TRAIL apoptosis pathways, in the presence of inflammatory mediators at the site of infection, leads to tissue destruction and ulceration during CL.

Loss of IL-7Ralpha is associated with CD4 T-cell depletion, high interleukin-7 levels and CD28 down-regulation in HIV infected patients.

OBJECTIVE: Elevated levels of interleukin (IL)-7 are present in the blood of HIV-positive patients and it is known that IL-7 receptor (IL-7R)alpha expression decreases on T cells during HIV infection. The subset(s) of T cells with low IL-7Ralpha and the consequence of low IL-7Ralpha expression for T-cell survival are poorly characterized. DESIGN: The frequency of IL-7Ralpha-negative T cells in HIV-positive patients was studied in relation to CD4 T-cell counts, IL-7 concentration and survival in culture. We analysed IL-7Ralpha expression in different T-cell populations and in relation to Bcl-2 expression. METHODS: Specimens from 38 HIV-1 patients and 17 controls were examined. IL-7Ralpha and Bcl-2 expression in different T-cell populations was studied by flow cytometry. The influence of IL-7Ralpha expression on T-cell survival was studied by culturing T cells in the presence of IL-7. RESULTS: Down-regulation of IL-7Ralpha on T cells correlated with depletion of CD4 T cells (P < 0.001) and also with increased concentration of serum IL-7 (P < 0.05). The decreased IL-7Ralpha expression was associated with low Bcl-2 expression and with the reduced survival capacity of T cells in the presence of IL-7 in vitro. Particularly, T cells with memory phenotype showed a decreased IL-7Ralpha expression in association with CD28 down-regulation. CONCLUSIONS: The positive effects of IL-7 on survival and homeostatic proliferation of T cells might be severely impaired in HIV-infected individuals due to IL-7Ralpha down-regulation. Differentiation towards a CD28-negative memory phenotype in response to chronic activation may lead to an overall decrease of IL-7 mediated survival within the peripheral T-cell pool.