The Economic Impact of Originator-to-Biosimilar Non-medical Switching in the Real-World Setting: A Systematic Literature Review.

Introduction: To save costs to the healthcare system, forced non-medical switch (NMS) policies that cut drug coverage for originator biologics and fund only less expensive biosimilars are being implemented. However, costs related to the impact of NMS on healthcare resource utilization (HCRU) must also be considered. This study aims to summarize the evidence on the economic impact of an originator-to-biosimilar NMS.

Serum Analyte Profiles Associated With Crohn's Disease and Disease Location.

Background: Crohn's disease (CD) can affect any segment of the digestive tract but is most often localized in the ileal, ileocolonic, and colorectal regions of the intestines. It is believed that the chronic inflammation in CD is a result of an imbalance between the epithelial barrier, the immune system, and the intestinal microbiota. The aim of the study was to identify circulating markers associated with CD and/or disease location in CD patients.

MHC-Independent Thymic Selection of CD4 and CD8 Coreceptor Negative αβ T Cells.

It is becoming increasingly clear that unconventional T cell subsets, such as NKT, γδ T, mucosal-associated invariant T, and CD8αα T cells, each play distinct roles in the immune response. Subsets of these cell types can lack both CD4 and CD8 coreceptor expression. Beyond these known subsets, we identify CD4CD8TCRαβ, double-negative (DN) T cells, in mouse secondary lymphoid organs.

Double-Negative T Cell Levels Correlate with Chronic Graft-versus-Host Disease Severity.

Chronic graft-versus-host disease (cGVHD) is a major complication, affecting 50% to 80% of long-term survivors of allogeneic hematopoietic stem cell transplantation. Current cGVHD therapies are neither specific nor curative, and patients are typically maintained for several months to years under immunosuppressive regimens that are associated with important side effects and increased susceptibility to life-threatening infections. As a result, continued investigation into the pathology of the disease and the search for novel diagnostic and therapeutic strategies to treat cGVHD remains a high priority.

Genetic interaction between two insulin-dependent diabetes susceptibility loci, Idd2 and Idd13, in determining immunoregulatory DN T cell proportion.

Several immune regulatory cell types participate in the protection against autoimmune diseases such as autoimmune diabetes. Of these immunoregulatory cells, we and others have shown that peripheral CD4CD8 double negative (DN) T cells can induce antigen-specific immune tolerance. Particularly, we have described that diabetes-prone mice exhibit a lower number of peripheral DN T cells compared to diabetes-resistant mice.

An Unbiased Linkage Approach Reveals That the p53 Pathway Is Coupled to NK Cell Maturation.

Natural killer cells constitute potent innate lymphoid cells that play a major role in both tumor immunosurveillance and viral clearance via their effector functions. A four-stage model of NK cell functional maturation has been established according to the expression of CD11b and CD27, separating mature NK (mNK) cells into distinct populations that exhibit specific phenotypic and functional properties. To identify genetic factors involved in the regulation of NK cell functional maturation, we performed a linkage analysis on F (B6.

TCR transgenic mice reveal the impact of type 1 diabetes loci on early and late disease checkpoints.

Linkage analysis studies for autoimmune diabetes have revealed multiple non-major histocompatibility complex (MHC) chromosomal regions linked to disease susceptibility. To date, more than 20 insulin-dependent diabetes (Idd) loci linked to diabetes susceptibility have been identified in NOD mice and validated via congenic breeding. Importantly, evidence suggests that Idd loci may regulate at least two pathological steps during autoimmune diabetes development, namely the onset of insulitis and the transition from insulitis to overt diabetes.

NK Cell Proportion and Number Are Influenced by Genetic Loci on Chromosomes 8, 9, and 17.

NK cells play a crucial role in innate immunity due to their direct cytotoxicity toward tumors, virally infected cells, and stressed cells, and they also contribute to the orchestration of the adaptive response by their ability to produce immunoregulatory cytokines. In secondary lymphoid organs, NK cells compose the third most abundant lymphocyte subset after T cells and B cells. In this study, we perform an unbiased linkage analysis to determine the genetic loci that may limit the size of the NK cell compartment.

Nearby Construction Impedes the Progression to Overt Autoimmune Diabetes in NOD Mice.

Construction nearby animal houses has sporadically been reported to affect various aspects of animal health. Most of the reports have focussed on the impact on stress hormone levels and the hypersensitivity of animals relative to humans. There has also been an anecdotal report on the impact of construction on autoimmune diabetes in NOD mice.

Immunoregulatory CD4(-)CD8(-) T cells as a potential therapeutic tool for transplantation, autoimmunity, and cancer.

A central objective in organ transplantation and the treatment or prevention of autoimmune disease is the achievement of antigen-specific immune tolerance. An additional challenge in bone marrow transplantation for the treatment of hematological malignancies is the prevention of graft-vs-host disease (GVHD) while maintaining graft-vs-tumor activity. Interestingly, CD4(-)CD8(-) (double negative, DN) T cells, which exhibit a unique antigen-specific immunoregulatory potential, appear to exhibit all of the properties to respond to these challenges.

Unusual selection and peripheral homeostasis for immunoregulatory CD4(-) CD8(-) T cells.

Immunoregulatory CD4(-)  CD8(-) (double-negative; DN) T cells exhibit a unique antigen-specific mode of suppression, yet the ontogeny of DN T cells remains enigmatic. We have recently shown that 3A9 T-cell receptor (TCR) transgenic mice bear a high proportion of immunoregulatory 3A9 DN T cells, facilitating their study. The 3A9 TCR is positively selected on the H2(k) MHC haplotype, is negatively selected in mice bearing the cognate antigen, namely hen egg lysozyme, and there is absence of positive selection on the H2(b) MHC haplotype.

A comprehensive review of the phenotype and function of antigen-specific immunoregulatory double negative T cells.

Double negative T cells that lack the expression of both CD4 and CD8 T cell co-receptors exhibit a most unique antigen-specific immunoregulatory potential first described over a decade ago. Due to their immunoregulatory function, this rare T cell population has been studied in both mice and humans for their contribution to peripheral tolerance and disease prevention. Consequently, double negative cells are gaining interest as a potential cellular therapeutic.

Interleukin-10 limits the expansion of immunoregulatory CD4-CD8- T cells in autoimmune-prone non-obese diabetic mice.

Regulatory T cells appear to show great potential for use in cellular therapy. In particular, CD4(-)CD8(-) (double negative (DN)) T cells, which compose 1-3% of the total number of T lymphocytes, exhibit prominent antigen-specific immune tolerance properties and confer immune tolerance in models of allografts and xenografts. We have recently shown that autoimmune-diabetes-prone mice carry fewer DN T cells and that this phenotype contributes to autoimmune-prone diabetes susceptibility, suggesting that increasing DN T-cell number in autoimmune-prone individuals may be of therapeutic interest.

Implication of the CD47 pathway in autoimmune diabetes.

CD47 and signal regulatory protein (SIRP) interactions have been proposed to take part in autoimmune disease susceptibility. Importantly, a recent genome-wide association study for type 1 diabetes susceptibility highlighted the association of the 20p13 region comprising the SIRP cluster, where some of the SIRP proteins encode functional ligands to CD47. Using a TCR transgenic mouse model at the brink of autoimmune disease, we demonstrate that CD47-deficiency is sufficient to break the immune tolerance and provoke the onset of autoimmune diabetes.

Absence of CD47 in vivo influences thymic dendritic cell subset proportions but not negative selection of thymocytes.

CD47 is a ubiquitously expressed molecule which has been attributed a role in many cellular processes. Its role in preventing cellular phagocytosis has defined CD47 as an obligatory self-molecule providing a 'don't-eat-me-signal'. Additionally, CD47-CD172a interactions are important for cellular trafficking.