Tumoricidal efficacy coincides with CD11c up-regulation in antigen-specific CD8+ T cells during vaccine immunotherapy

Background: Dendritic cells (DCs) mount tumor-associated antigens (TAAs), and the double-stranded RNA adjuvant Poly(I:C) stimulates Toll-like receptor 3 (TLR3) signal in DC, which in turn induces type I interferon (IFN) and interleukin-12 (IL-12), then cross-primes cytotoxic T lymphocytes (CTLs). Proliferation of CTLs correlates with tumor regression. How these potent cells expand with high quality is crucial to the outcome of CTL therapy. However, good markers reflecting the efficacy of DC-target immunotherapy have not been addressed. Methods: Using an EG7 (ovalbumin, OVA-positive) tumor-implant mouse model, we examined what is a good marker for active CTL induction in treatment with Poly(I:C)/OVA. Results: Simultaneous administration of Poly(I:C) and antigen (Ag) OVA significantly increased a minor population of CD8+ T cells, that express CD11c in lymphoid and tumor sites. The numbers of the CD11c+ CD8+ T cells correlated with those of induced Ag-specific CD8+ T cells and tumor regression. The CD11c+ CD8+ T cell moiety was characterized by its high killing activity and IFN-γ-producing ability, which represent an active phenotype of the effector CTLs. Not only a TLR3-specific (TICAM-1-dependent) signal but also TLR2 (MyD88) signal in DC triggered the expansion of CD11c+ CD8+ T cells in tumor-bearing mice. Notably, human CD11c+ CD8+ T cells also proliferated in peripheral blood mononuclear cells (PBMC) stimulated with cytomegalovirus (CMV) Ag. Conclusions: CD11c expression in CD8+ T cells reflects anti-tumor CTL activity and would be a marker for immunotherapeutic efficacy in mouse models and probably cancer patients as well

Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's) : an ARChiVe Cohort Study

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n\u2009=\u200948) or GPA (n\u2009=\u2009183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding

Pediatric Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a multisystem autoimmune condition characterized by vascular thromboses associated with persistently positive antiphospholipid antibodies. There is currently a paucity of data (incidence, prevalence, thrombosis risk, and effective treatment) in pediatric APS. The purpose of this report is to review the current literature on APS in children and neonates, identify the gaps in current knowledge, and suggest avenues for studies to fill those gaps

Neutrophil and monocyte cell surface p150,95 has iC3b-receptor (CR4) activity resembling CR3.

Previous investigations of p150,95 (CD11c), the third member of the CD18 membrane glycoprotein family that includes CR3 (Mac-1 or CD11b) and LFA-1 (CD11a), had demonstrated that solubilized p150,95 bound to iC3b-agarose in a manner similar to isolated CR3. The current study showed that membrane surface p150,95 also expressed iC3b-receptor activity and was probably the same as the neutrophil receptor for iC3b- or C3dg-coated erythrocytes (EC3bi or EC3dg) that had been previously designated CR4. Normal neutrophil and macrophage CR4-dependent EC3bi rosettes were inhibited by monoclonal anti-p150,95, and cells from a patient with CD18 deficiency did not form CR4-dependent EC3bi rosettes. With neutrophils that bore large amounts of CR1 and CR3 and little p150,95, EC3bi were found primarily via CR1 and CR3, and demonstration of p150,95-dependent rosettes required large amounts of fixed iC3b, low-ionic strength buffer, and antibody blockade of CR1 and CR3. By contrast, culture-derived macrophages expressed eight times more p150,95 than did monocytes and EC3bi were bound to both p150,95 and CR3 when EC3bi bore small amounts of fixed iC3b and assays were carried out in isotonic buffer. Comparison of the amounts of CR1, CR3, and CR4 in various tissues by immunoperoxidase staining revealed that CR4 was the most abundant C3 receptor molecule on tissue macrophages, and suggested that CR4 might be involved in clearance of C3-opsonized particles or immune complexes