Trading off fiscal budget adherence and child protection.

Many countries delegate a substantial part of social service decisions to local administrative levels, while federal laws provide the overall framework for service levels. Strict regulations to reduce budget overruns may however leave local governments with a potential trade-off between adhering to fiscal budgets and supplying critical welfare services as e.g. programs to protect vulnerable children. We investigate if budgetary constraints influence child protection decisions using high-quality register data. We show that the introduction of fiscal sanctions to improve budget adherence contributed to a sharp decline in budget overruns on child protective services by reducing the number of children in out-of-home care. Our results further show that monthly variation in budget adherence within a fiscal year affects the probability of a placement in out-of-home care for children in need of help towards the end of a fiscal year. We estimate that a budget overrun of 10 percentage points by mid-year leads to a 1.2 percent reduction in the number of children in care over the remaining part of the fiscal year. Municipalities reduced child protection expenditure by choosing cheaper types of care and ending placement for children in out-of-home care, particularly for children turning 18. Our paper contributes to the literature on fiscal federalism by documenting the trade-off between managing public expenditure and providing safety and equal opportunity for vulnerable children. We thus highlight that enforcing strict budget adherence may be in conflict with social policy goals. Our results raise an important discussion about centralization versus delegation of critical public services.

The contagious nature of a vaccine scare: How the introduction of HPV vaccination lifted and eroded MMR vaccination in Denmark.

BACKGROUND: Human papillomavirus (HPV) vaccine coverage was high in Denmark until it plunged following negative media coverage. We examined whether the decline in HPV vaccination undermined uptake of another adolescent vaccine, measles, mumps and rubella (MMR). METHODS: The Danish national health register provided data on uptake of MMR vaccine dose 2 (at age 13) for children born from 1991 to 2003 (n = 827,716). The primary exposure variable comprised three time periods: before HPV vaccine introduction, during high HPV vaccine coverage, and after the drop in HPV vaccine coverage. To examine the effect of HPV vaccination on MMR2 uptake, we estimated MMR2 uptake by age 13 using logistic regression, controlling for gender, birth month, birth year, and maternal education. FINDINGS: MMR2 vaccination coverage was high for both girls and boys (86% and 85%) in 2009. Following the introduction of HPV vaccine for girls in 2009, MMR2 coverage increased for girls even as it decreased for boys (gender gap 4·6 percentage points, 95% CI 4·3 to 4·8). Coverage with MMR2 for girls continued to be high over the following four years, and almost all girls (91%) who received MMR2 vaccination also received HPV1 vaccination within the same week. When negative media coverage led to a decline in HPV vaccination, MMR2 uptake for girls also declined. By 2015, MMR2 coverage for girls and boys had become similar again (80% and 79%). Families with the highest level of maternal education showed the strongest decline in MMR2 coverage for girls. INTERPRETATION: Concomitant vaccine provision can increase overall vaccine uptake. However, reduced demand for one vaccine may reduce concomitant vaccination and undermine resiliency of a country's vaccination program. FUNDING: Drs. Gørtz and Ejrnæs appreciate generous funding from the Novo Nordisk Foundation (grant no. NNF17OC0026542) and from the Danish National Research Foundation through its grant (DNRF-134) to the Center for Economic Behavior and Inequality (CEBI) at the University of Copenhagen.

Cure of chronic viral infection by neutralizing antibody treatment.

Persistent infections can pose severe health risks. In many cases individuals fail to clear the virus and consequently chronic infection, often associated with severe immunopathology, occurs. For some chronic infections it is known that systemic IL-10 production can be increased. However, it is unclear, whether IL-10 affects the outcome of infection, amount of immunopathology and could be the actual cause for persistence. Conventional interferons (IFN) or anti-viral immunotherapies attempting to augment anti-viral immunity directly in persistent infected individuals have failed to affect the outcome so far, but lowering the viral antigenic load has clear beneficial effects. Therefore, approaching the problem from a different angle is important. The use of neutralizing antibodies is one of the most successful methods to interfere with receptor-ligand interactions in vivo. Optimal designs of therapeutic antibody treatment regimen are important in order to achieve maximal effects with minimal duration of immunosuppression or hyperactivation. In this review we reflect on the effects of a short time administration of a neutralizing cytokine receptor antibody treatment of a chronic infection resulting in the establishment of anti-viral immune responses and viral clearance and speculate on the potential mechanisms involved in this successful therapeutic treatment.

Minimal impact of a de novo-expressed beta-cell autoantigen on spontaneous diabetes development in NOD mice.

During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such "antigenic spreading" can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic beta-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo-expressed beta-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present.

Cure of chronic viral infection and virus-induced type 1 diabetes by neutralizing antibodies.

The use of neutralizing antibodies is one of the most successful methods to interfere with receptor-ligand interactions in vivo. In particular blockade of soluble inflammatory mediators or their corresponding cellular receptors was proven an effective way to regulate inflammation and/or prevent its negative consequences. However, one problem that comes along with an effective neutralization of inflammatory mediators is the general systemic immunomodulatory effect. It is therefore important to design a treatment regimen in a way to strike at the right place and at the right time in order to achieve maximal effects with minimal duration of immunosuppression or hyperactivation. In this review we reflect on two examples of how short time administration of such neutralizing antibodies can block two distinct inflammatory consequences of viral infection. First, we review recent findings that blockade of IL-10/IL-10R interaction can resolve chronic viral infection and second, we reflect on how neutralization of the chemokine CXCL10 can abrogate virus-induced type 1 diabetes.

Resolution of a chronic viral infection after interleukin-10 receptor blockade.

A defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses cellular immune responses by modulating the function of T cells and antigen-presenting cells. In this paper, we report that IL-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection. IL-10 secretion was diminished and interferon gamma production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8alpha+ dendritic cell (DC) numbers declined early after infection, whereas CD8alpha- DC numbers were not affected. CD8alpha- DCs supported IL-10 production and subsequent dampening of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10-mediated immune suppression, preventing IL-10 priming by CD8alpha- DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology.

SOCS-1 protects from virally-induced CD8 T cell mediated type 1 diabetes.

CD8(+) cytotoxic T lymphocytes (CTL) can rapidly kill beta-cells and therefore contribute to the development of type 1 diabetes (T1D). CTL-mediated beta-cell killing can occur via perforin-mediated lysis, Fas-Fas-L interaction, and the secretion of TNF-alpha or IFN-gamma. The secretion of IFN-gamma can contribute to beta-cell death directly by eliciting nitric oxide production, and indirectly by upregulating MHC class I and 'unmasking' beta-cells for recognition by CTL. Earlier studies in the RIP-LCMV mouse model of diabetes showed that disruption of beta-cell IFN-gamma signaling alone abolished the direct detrimental effects of IFN-gamma, but not MHC class I upregulation. Suppressor of cytokine signaling-1 (SOCS-1) represses several crucial cytokine signaling pathways simultaneously, among them IFN-gamma and IL-1-beta. We therefore evaluated the protective capacity of islet cell SOCS-1 expression in the CD8(+) mediated RIP-LCMV diabetes model. Clinical disease was prevented in over 90% of the mice. Not only absence of MHC-I and Fas upregulation, but also resistance to cytokine-induced killing of beta-cells and a complete lack of CXCL-10 (IP10) production in islets led to a lack of islet infiltration and impaired activation of autoaggressive CD4(+) and CD8(+) T-cells in these mice. Thus, SOCS expression renders beta-cells resistant to CTL attack in a mouse model of T1D.

Cure of chronic viral infection and virus-induced type 1 diabetes by neutralizing antibodies.

The use of neutralizing antibodies is one of the most successful methods to interfere with receptor-ligand interactions in vivo. In particular blockade of soluble inflammatory mediators or their corresponding cellular receptors was proven an effective way to regulate inflammation and/or prevent its negative consequences. However, one problem that comes along with an effective neutralization of inflammatory mediators is the general systemic immunomodulatory effect. It is, therefore, important to design a treatment regimen in a way to strike at the right place and at the right time in order to achieve maximal effects with minimal duration of immunosuppression or hyperactivation. In this review, we reflect on two examples of how short time administration of such neutralizing antibodies can block two distinct inflammatory consequences of viral infection. First, we review recent findings that blockade of IL-10/IL-10R interaction can resolve chronic viral infection and second, we reflect on how neutralization of the chemokine CXCL10 can abrogate virus-induced type 1 diabetes.

Immunomodulatory dendritic cells require autologous serum to circumvent nonspecific immunosuppressive activity in vivo.

In immunotherapy, dendritic cells (DCs) can be used as powerful antigen-presenting cells to enhance or suppress antigen-specific immunity upon in vivo transfer in mice or humans. However, to generate sufficient numbers of DCs, most protocols include an ex vivo culture step, wherein the cells are exposed to heterologous serum and/or antigenic stimuli. In mouse models of virus infection and virus-induced autoimmunity, we tested how heterologous serum affects the immunomodulatory capacity of immature DCs generated in the presence of IL-10 by comparing fetal bovine serum (FBS)- or normal mouse serum (NMS)-supplemented DC cultures. We show that FBS-exposed DCs induce a systemic immune deviation characterized by reduction of virus-specific T cells, delayed viral clearance, and enhanced systemic production of interleukin 4 (IL-4), IL-5, and IL-10 to FBS-derived antigens, including bovine serum albumin (BSA). By contrast, DCs generated in NMS-supplemented cultures modulated immunity and autoimmunity in an antigen-specific fashion. These cells did not induce systemic IL-4, IL-5, or IL-10 production and inhibited generation of virus-specific T cells or autoimmunity only if pulsed with a viral antigen. These data underscore the importance of using autologous serum-derived immature DCs in preclinical animal studies to accurately assess their immunomodulatory potential in future human therapeutic settings, where application of FBS is not feasible.

Different diabetogenic potential of autoaggressive CD8+ clones associated with IFN-gamma-inducible protein 10 (CXC chemokine ligand 10) production but not cytokine expression, cytolytic activity, or homing characteristics.

Type 1 diabetes mellitus is an autoimmune disease characterized by T cell-mediated destruction of the insulin-producing beta cells in the islets of Langerhans. From studies in animal models, CD8(+) T cells recognizing autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit-related protein, insulin, or glutamic acid decarboxylase (GAD) are believed to play important roles in both the early and late phases of beta cell destruction. In this study, we investigated the factors governing the diabetogenic potential of autoreactive CD8(+) clones isolated from spleens of NOD mice that had been immunized with GAD65(515-524) or insulin B-chain(15-23) peptides. Although these two clones were identical in most phenotypic and functional aspects, for example cytokine production and killing of autologous beta cells, they differed in the expression of IFN-gamma-inducible protein-10, which was only produced at high levels by the insulin-specific clone, but not by the GAD65-specific clone, and other autoantigen-specific nonpathogenic CD8 T cell clones. Interestingly, upon i.p. injection into neonatal mice, only the insulin B-chain(15-23)-reactive CD8(+) T clone accelerated diabetes in all recipients after 4 wk, although both insulin- and GAD-reactive clones homed to pancreas and pancreatic lymph nodes with similar kinetics. Diabetes was associated with increased pancreatic T cell infiltration and, in particular, recruitment of macrophages. Thus, secretion of IFN-gamma-inducible protein-10 by autoaggressive CD8(+) lymphocytes might determine their diabetogenic capacity by affecting recruitment of cells to the insulitic lesion.