Identification of Selective Imidazopyridine CSF1R Inhibitors.

Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors.

Trocar site hernia after gastric sleeve.

Background: Laparoscopy is common in abdominal surgery. Trocar site hernia (TSH) is a most likely underestimated complication. Among risk factors, obesity, the use of larger trocars and the umbilical trocar site has been described.

Second trimester induced abortions due to fetal anomalies-a population-based study of diagnoses, examinations and clinical management.

Introduction: Two-thirds of induced abortions after gestational week (gw) 18 are performed due to fetal anomalies. The potential of the fetus to survive outside the uterus after birth is the upper limit for induced abortions in Sweden. Due to advances in neonatal medicine, fetal viability and the upper limit of late induced abortions have been converging over the last few decades.

Immunosuppressive activity of a novel peptide analog of α-melanocyte stimulating hormone (α-MSH) in experimental autoimmune uveitis.

Autoimmune uveitis is an inflammatory disorder of the eye that can lead to pain and vision loss. Steroids and immunosuppressive drugs are currently the only therapeutics for uveitis and have serious ocular and systemic toxicities. Therefore, safer alternative therapeutics are desired.

Lowering glycosphingolipid levels in CD4+ T cells attenuates T cell receptor signaling, cytokine production, and differentiation to the Th17 lineage.

Lipid rafts reportedly have a role in coalescing key signaling molecules into the immunological synapse during T cell activation, thereby modulating T cell receptor (TCR) signaling activity. Recent findings suggest that a correlation may exist between increased levels of glycosphingolipids (GSLs) in the lipid rafts of T cells and a heightened response of those T cells toward activation. Here, we show that lowering the levels of GSLs in CD4(+) T cells using a potent inhibitor of glucosylceramide synthase (Genz-122346) led to a moderation of the T cell response toward activation.

A retro-inverso α-melanocyte stimulating hormone analog with MC1R-binding selectivity.

α-melanocyte stimulating hormone (α-MSH) is a tridecapeptide fragment of pro-opiomelanocortin (POMC) with broad effects on appetite, skin pigmentation, hormonal regulation, and potential roles in both inflammation and autoimmunity. The use of this peptide as an anti-inflammatory agent is limited by its low selectivity between the melanocortin receptors, susceptibility to proteolytic degradation, and rapid clearance from circulation. A retro-inverso (RI) sequence of α-MSH was characterized for receptor activity and resistance to protease.

Allogeneic mesenchymal stem cells do not protect NZBxNZW F1 mice from developing lupus disease.

Mesenchymal stem cell (MSC) therapy has shown promise clinically in graft-versus-host disease and in preclinical animal models of T helper type 1 (Th1)-driven autoimmune diseases, but whether MSCs can be used to treat autoimmune disease in general is unclear. Here, the therapeutic potential of MSCs was tested in the New Zealand black (NZB)xNew Zealand white (NZW) F1 (NZB/W) lupus mouse model. The pathogenesis of systemic lupus erythematosus involves abnormal B and T cell activation leading to autoantibody formation.

Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-beta in primary pro-B cells.

The growth-inhibitory effects of type 1 interferons (IFNs) (IFNalpha/beta) are complex, and the role of apoptosis in their antigrowth effects is variable and not well understood. We have examined primary murine interleukin-7-dependent bone marrow-derived pro-B cells, where IFNbeta, but not IFNalpha, induces programmed cell death (PCD). IFNbeta-stimulated apoptosis is the same in pro-B cells derived from wild type and Stat1(-/-) mice.

Stem cell reconstitution of autoimmune T cell repertoires.

Maintenance of T cell memory in autoimmune disease may be complex because the unending renewable supply of self provides an inherent high antigen load that effectively precludes clearance, and because the broad array of potential immunogenic targets provides extensive self-recognition plasticity. Autoimmunity is characterized by a dynamic self-recognition process in which the primary autoreactivity initiating disease is soon followed and often displaced by secondary neoautoreactivities, or epitope spreading, that emerge as a result of endogenous self-priming. Here we show that the autoimmune disease process involves a tertiary phase of self recognition characterized by stem cell reconstitution of autoreactive T cells that recapitulates the myelin self recognition process involved in disease initiation and spreading during experimental autoimmune encephalomyelitis (EAE).

Human and murine lymphocyte neurotrophin expression is confined to B cells.

Recent reports indicate that autoreactive T cells may produce neurotrophic factors capable of mediating repair and regeneration of damaged neurons. By using semiquantitative RT-PCR, we examined gene expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and the trkB BDNF receptor in autoreactive T cells from SWXJ mice immunized with the p104-117 encephalitogen of myelin proteolipid protein (PLP 104-117). We observed antigen-inducible expression of NGF and BDNF, but not NT-3 and trkB, in lymph node cells activated with PLP 104-117.

Synergistic activation of innate immunity by double-stranded RNA and CpG DNA promotes enhanced antitumor activity.

Double-stranded RNA (dsRNA) and unmethylated CpG sequences in DNA are pathogen-associated molecular patterns of viruses and bacteria that activate innate immunity. To examine whether dsRNA and CpG DNA could combine to provide enhanced stimulation of innate immune cells, murine macrophages were stimulated with poly-rI:rC (pIC), a dsRNA analog, and CpG-containing oligodeoxynucleotides (CpG-ODN). Combined treatments demonstrated synergy in nitric oxide, interleukin (IL)-12, tumor necrosis factor alpha, and IL-6 production.

Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides.

Autoimmune sensorineural hearing loss (ASNHL) is characterized typically by bilateral, rapidly progressive hearing loss that responds therapeutically to corticosteroid treatment. Despite its name, data implicating autoimmunity in the etiopathogenesis of ASNHL have been limited, and targeted self-antigens have not been identified. In the current study we show that the inner ear-specific proteins cochlin and beta-tectorin are capable of targeting experimental autoimmune hearing loss (EAHL) in mice.

A novel class II-binding motif selects peptides that mediate organ-specific autoimmune disease in SWXJ, SJL/J, and SWR/J mice.

Idiopathic dilated cardiomyopathy (DCM) is responsible for approximately 25% of all cases of congestive heart failure. We have recently shown that immunization of autoimmune-susceptible SWXJ mice with whole cardiac myosin leads to T cell-mediated experimental autoimmune myocarditis (EAMC) and DCM. We have now identified two disease-inducing peptides from cardiac alpha-myosin heavy chain (CAMHC).

An organic CD4 inhibitor reduces the clinical and pathological symptoms of acute experimental allergic encephalomyelitis.

CD4(+) T cells have an important role in mediating the pathogenesis of many human and experimental autoimmune diseases including experimental allergic encephalomyelitis (EAE), a demyelinating animal model for multiple sclerosis (MS). We applied a computer screening approach to select a small organic molecule, TJU103, that would specifically inhibit autoreactive CD4(+) T cells by disrupting the function of the CD4 molecule during activation. Upon studying the therapeutic effect of TJU103 in acute EAE, it was found that administration shortly before or after the onset of clinical symptoms reduced the severity of disease in both SJL and SWXJ-14 mouse models.

Pre-emptive targeting of the epitope spreading cascade with genetically modified regulatory T cells during autoimmune demyelinating disease.

Epitope spreading or endogenous self-priming has been implicated in mediating the progression of autoimmune disease. In the present study we created an immune-deviated, epitope spreading response in SWXJ mice after the onset of experimental autoimmune encephalomyelitis, a prototypic autoimmune animal model widely used in multiple sclerosis research. We established an immunoregulatory spreading repertoire by transferring T cells genetically modified to produce high levels of IL-10 in response to a dominant epitope spreading determinant.

Effect of a cyclic heptapeptide based on the human CD4 domain 1 CC' loop region on murine experimental allergic encephalomyelitis: inhibition of both primary and secondary responses.

The 802-2 peptide, designed from the conserved D1-CC' loop region of human CD4, can disrupt CD4(+) T cell activation in both human and murine systems. Here, 802-2 was investigated for efficacy in acute murine experimental allergic encephalomyelitis (EAE) models, and was found to significantly reduce the severity of disease when administered either before or after the onset of symptoms. 802-2 treatment during PLP139-151 induction of EAE rendered the mice more resistant to subsequent rechallenge with antigen, and was also efficacious when initially administered during a secondary EAE response.

Bioactive peptide design based on protein surface epitopes. A cyclic heptapeptide mimics CD4 domain 1 CC' loop and inhibits CD4 biological function.

The interaction between CD4 and major histocompatibility complex class II proteins provides a critical co-receptor function for the activation of CD4(+) T cells implicated in the pathogenesis of a number of autoimmune diseases and transplantation responses. A small synthetic cyclic heptapeptide was designed and shown by high resolution NMR spectroscopy to closely mimic the CD4 domain 1 CC' surface loop. This peptide effectively blocked stable CD4-major histocompatibility complex class II interaction, possessed significant immunosuppressive activity in vitro and in vivo, and strongly resisted proteolytic degradation.

A computer screening approach to immunoglobulin superfamily structures and interactions: discovery of small non-peptidic CD4 inhibitors as novel immunotherapeutics.

The interaction between CD4 and major histocompatibility complex (MHC) class II proteins is critical for the activation of CD4+ T cells, which are involved in transplantation reactions and a number of autoimmune diseases. In this study we have identified a CD4 surface pocket as a functional epitope implicated in CD4-MHC class II interaction and T-cell activation. A computer-based strategy has been used to screen approximately 150,000 non-peptidic organic compounds in a molecular data base and to identify a group of compounds as ligands of the proposed CD4 surface pocket.