An Immunologically Privileged Retinal Antigen Elicits Tolerance: Major Role for Central Selection Mechanisms

Immunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25+ T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role

Draft Guidance: Response, Restoration, and Recovery Checklist for Biologically Contaminated Facilities

The Checklist for Facility Response, Restoration, and Recovery presented in this document is principally focused on the Consequence Management Phase of a biothreat agent (i.e., Bacillus anthracis) release at a large facility, such as an airport or subway. Information in this document conforms to the National Response Plan (NRP) (DHS 2004) and the National Incident Management System (NIMS 2004). Under these two guidance documents, the personnel responsible for managing biological response and recovery efforts--that is, the decision-makers--are members of an Incident Command (IC), which is likely to transition to a Unified Command (UC) in the event of a biological warfare agent attack. A UC is used when more than one agency has incident jurisdiction or when incidents cross political jurisdictions. The location for primary, tactical-level command and management is referred to as the Incident Command Post (ICP), as described in the NRP. Thus, regardless of whether an IC or an UC is used, the responsible entities are located at an ICP. Agencies work together through designated members of the UC to establish their designated Incident Commanders at a single ICP and to establish a common set of objectives and strategies and a single Incident Action Plan. Initially during the Crisis Management Phase, the Incident Commander is likely to be the Chief of the fire department that serves the affected facility. As life-safety issues are resolved and the Crisis Management Phase shifts to the Consequence Management Phase, the work of characterization, decontamination, and facility clearance begins. There will likely be a coincident transition in organizational structure as well, and new restoration-focused groups, units, and personnel will be added as restoration needs are anticipated. Depending on the specific facility and type of incident, the responsible individual (Incident Commander or Unified Commander) within the UC during the Consequence Management Phase could be the Facility Manager, the Facility Emergency Operations Manager, or their designee. In an incident involving large-scale biological contamination, the Governor of the state would typically request, and the President of the United States would likely declare, an emergency under the Stafford Act (1974; amended 2002). The Secretary of Homeland Security would likely determine that the event is an Incident of National Significance on the basis of criteria established in Homeland Security Presidential Directive 5 (HSPD-5), ''Management of Domestic Incidents''. Incidents of National Significance are those high-impact events that require a coordinated and effective response by an appropriate combination of Federal, state, local, tribal, private-sector, and nongovernmental entities to save lives, minimize damage, and provide the basis for long-term community recovery and mitigation activities. If facility authorities request outside assistance, or if an emergency is declared under the Stafford Act, then other members of the UC could include local and state agencies as well as Federal agencies, such as the Federal Emergency Management Agency (FEMA) and the U.S. Environmental Protection Agency (USEPA). If an Incident of National Significance is declared, a Principal Federal Official will be appointed by the Department of Homeland Security (DHS) to facilitate Federal support to the UC structure. The following Checklist for Facility Response, Restoration, and Recovery presents the critical steps that would be taken by organizations involved in responding to a biological incident. It is intended for use by key decision-makers in the event that an incident occurs and steps must be taken immediately and systematically. The organizations would follow the Incident Command System (ICS). See Appendix A for more information on the ICS and how the responsible personnel identified in the checklist map into the consequence management organizational structure. The Notification and First-Response Phases are cursorily addressed in the checklist, whereas the main focus is on consequence management actions. The order of actions is generally sequential. However, depending on the specifics of an event and how the response is implemented, actions may be reordered. For example, preparing a Remediation Action Plan (RAP) is identified in the checklist as a critical step of the Remediation Phase. However, it is likely that preparation of the RAP would begin before completing all actions identified in the Characterization Phase. In addition to the actions recommended in the checklist, any emergency response conducted at a major metropolitan facility should comply with notification and response procedures established by the facility, as well as applicable procedures established by the jurisdictional responding agencies

Dual Antiplatelet Therapy Duration Based on Ischemic and Bleeding Risks After Coronary Stenting.

BACKGROUND Complex percutaneous coronary intervention (PCI) is associated with higher ischemic risk, which can be mitigated by long-term dual antiplatelet therapy (DAPT). However, concomitant high bleeding risk (HBR) may be present, making it unclear whether short- or long-term DAPT should be prioritized. OBJECTIVES This study investigated the effects of ischemic (by PCI complexity) and bleeding (by PRECISE-DAPT [PREdicting bleeding Complications in patients undergoing stent Implantation and SubsequEnt Dual AntiPlatelet Therapy] score) risks on clinical outcomes and on the impact of DAPT duration after coronary stenting. METHODS Complex PCI was defined as ≥3 stents implanted and/or ≥3 lesions treated, bifurcation stenting and/or stent length >60 mm, and/or chronic total occlusion revascularization. Ischemic and bleeding outcomes in high (≥25) or non-high (<25) PRECISE-DAPT strata were evaluated based on randomly allocated duration of DAPT. RESULTS Among 14,963 patients from 8 randomized trials, 3,118 underwent complex PCI and experienced a higher rate of ischemic, but not bleeding, events. Long-term DAPT in non-HBR patients reduced ischemic events in both complex (absolute risk difference: -3.86%; 95% confidence interval: -7.71 to +0.06) and noncomplex PCI strata (absolute risk difference: -1.14%; 95% confidence interval: -2.26 to -0.02), but not among HBR patients, regardless of complex PCI features. The bleeding risk according to the Thrombolysis In Myocardial Infarction scale was increased by long-term DAPT only in HBR patients, regardless of PCI complexity. CONCLUSIONS Patients who underwent complex PCI had a higher risk of ischemic events, but benefitted from long-term DAPT only if HBR features were not present. These data suggested that when concordant, bleeding, more than ischemic risk, should inform decision-making on the duration of DAPT

Adaptive Dosing of Nivolumab + Ipilimumab Immunotherapy Based Upon Early, Interim Radiographic Assessment in Advanced Melanoma (The ADAPT-IT Study)

PURPOSE: Nivolumab + ipilimumab (nivo + ipi) is highly efficacious but has high toxicity. Standard treatment in advanced melanoma is four doses of nivo + ipi followed by nivo alone. Whether four doses of nivo + ipi are needed is unclear. METHODS: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT) study (NCT03122522) is a multicenter, single-arm phase II clinical trial. Patients received two doses of nivo (1 mg/kg) + ipi (3 mg/kg) followed by a computed tomography scan at week 6. Patients without new lesions or index lesion tumor growth of \u3e 4% had protocol-defined early favorable antitumor effect (FATE) and ceased nivo + ipi, transitioning to nivo monotherapy. Patients without FATE at week 6 received the standard third and fourth doses of nivo + ipi followed by nivo monotherapy. The primary end point was response rate by RECIST 1.1 at week 12. Secondary end points included additional efficacy assessments and safety. RESULTS: Sixty patients were enrolled; 41 patients (68%) had FATE at week 6 and met criteria for stopping nivo + ipi. Best overall response rates by RECIST at week 12 or any time afterward were 48% (95% CI, 35 to 62) and 58% (95% CI, 45 to 71), respectively. With a median follow-up of 25 months, the estimated 18-month progression-free survival and overall survival are 52% and 80%, respectively. Fifty seven percent of patients had grade 3-5 treatment-related toxicity. CONCLUSION: The efficacy and toxicity of standard four dose nivo + ipi induction therapy in melanoma is likely driven by the first two doses. An interim computed tomography scan after two doses guided cessation of combination dosing and identified almost all responders. Longer follow-up and further study are needed to fully understand the implications of a shortened induction course of nivo + ipi

Early on-treatment assessment of T-cells, cytokines and tumor DNA with adaptively-dosed nivolumab + ipilimumab: final results from the phase 2 ADAPT-IT study.

PURPOSE: ADAPT-IT (NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared to conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported. PATIENTS AND METHODS: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate (ORR) at Week 12. Plasma was assayed for circulating tumor DNA (ctDNA) and ten cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel. RESULTS: Among treated patients, expansion of proliferating T-cell populations was observed in both responders and non-responders. Baseline IL-6 levels were lower in patients achieving an objective radiographic response (median 1.30 vs 2.86 pg/mL; p=0.025). Higher baseline IL-6 levels were associated with shorter progression-freesurvival (PFS; hazard ratio (HR)=1.24, 95% CI:1.01-1.52; p=0.041). At Week 6, patients with response had lower average tumor variant allele fractions (VAF) compared to non-responders (median 0.000 v 0.019; p=0.014). Greater increases in average VAF from baseline to Week 6 correlated with shorter PFS (HR=1.11, 95% CI:1.01-1.21; p=0.023). Week 12 ORR was 47% (95% CI:35-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI:10-not reached); 76% of responses (95% CI:64%-91%) persisted at 36 months. CONCLUSIONS: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL-6 and ctDNA changes during treatment warrant further study as biomarkers of nivo-ipi response