Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis

In a lethal West Nile virus (WNV) model, central nervous system infection triggered a threefold increase in CD45int/CD11b+/CD11c− microglia at days 6–7 postinfection (p.i.). Few microglia were proliferating, suggesting that the increased numbers were derived from a migratory precursor cell. Depletion of “circulating” (Gr1−(Ly6Clo)CX3CR1+) and “inflammatory” (Gr1hi/Ly6Chi/CCR2+) classical monocytes during infection abrogated the increase in microglia. C57BL/6 chimeras reconstituted with cFMS–enhanced green fluorescent protein (EGFP) bone marrow (BM) showed large numbers of peripherally derived (GFP+) microglia expressing GR1+(Ly6C+) at day 7 p.i., suggesting that the inflammatory monocyte is a microglial precursor. This was confirmed by adoptive transfer of labeled BM (Ly6Chi/CD115+) or circulating inflammatory monocytes that trafficked to the WNV-infected brain and expressed a microglial phenotype. CCL2 is a chemokine that is highly expressed during WNV infection and important in inflammatory monocyte trafficking. Neutralization of CCL2 not only reduced the number of GFP+ microglia in the brain during WNV infection but prolonged the life of infected animals. Therefore, CCL2-dependent inflammatory monocyte migration is critical for increases in microglia during WNV infection and may also play a pathogenic role during WNV encephalitis

Gliadin Nanoparticles Induce Immune Tolerance to Gliadin in Mouse Models of Celiac Disease

Peer reviewe

Manipulating T cell-mediated pathology: Targets and functions of monoclonal antibody immunotherapy

AbstractMonoclonal antibody (mAb) technology has revolutionized treatment options for T cell mediated diseases. However, a safe, clinically available anti-T cell antibody (ab) remains elusive. Experience with anti-T cell agents and their propensity for causing immune-mediated toxicities have hampered the development of anti-T cell mAb's. Furthermore, misunderstanding regarding mechanism(s) of action of particular antibodies can influence development and clinical prescription habits. For example, the anti-CD3 Ab OKT3 is consistently described as a depleting Ab even though original studies showed the mechanism to be non-lytic. Future anti-T cell mAbs are likely to be non-depletional and focused on the expansion of regulatory T cells. This review discusses how the properties of Abs can be exploited for manipulating pathological T cell responses in the clinic

Current landscape for T-cell targeting in autoimmunity and transplantation

In recent years, substantial advances in T-cell immunosuppressive strategies and their translation to routine clinical practice have revolutionized management and outcomes in autoimmune disease and solid organ transplantation. More than 80 diseases have been considered to have an autoimmune etiology, such that autoimmune-associated morbidity and mortality rank as third highest in developed countries, after cardiovascular diseases and cancer. Solid organ transplantation has become the therapy of choice for many end-stage organ diseases. Short-term outcomes such as patient and allograft survival at 1 year, acute rejection rates, as well as time course of disease progression and symptom control have steadily improved. However, despite the use of newer immunosuppressive drug combinations, improvements in long-term allograft survival and complete resolution of autoimmunity remain elusive. In addition, the chronic use of nonspecifically targeted immunosuppressive drugs is associated with significant adverse effects and increased morbidity and mortality. In this article, we discuss the current clinical tools for immune suppression and attempts to induce long-term T-cell tolerance induction as well as much-needed future approaches to produce more short-acting, antigen-specific agents, which may optimize outcomes in the clinic. </jats:p