Faculty Bibliography

OBJECTIVES/OBJECTIVE:Most therapies for autoimmune and inflammatory diseases either neutralize or suppress production of inflammatory cytokines produced by activated macrophages (e.g., TNFα, IL-1, IL-6, IL-17, GM-CSF). However, no approved therapies directly target this activated subset of macrophages. METHODS:First, we undertook to examine whether the folate receptor beta (FR-β) positive subpopulation of macrophages, which marks the inflammatory subset in animal models of rheumatoid arthritis, might constitute the prominent population of macrophages in inflamed lesions in humans. Next, we utilized anti-FR-β monoclonal antibodies capable of mediating antibody-dependent cell cytotoxicity (ADCC) to treat animal models of rheumatoid arthritis and peritonitis. RESULTS:Human tissue samples of rheumatoid arthritis, Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, and scleroderma are all characterized by dramatic accumulation of macrophages that express FR-β, a protein not expressed on resting macrophages or any other healthy tissues. A monoclonal antibody to FR-β accumulates specifically in inflamed lesions of murine inflammatory disease models and successfully treats such models of rheumatoid arthritis and peritonitis. More importantly, elimination of FR-β-positive macrophages upon treatment with an anti-FR-β monoclonal antibody promotes the departure of other immune cells, including T cells, B cells, neutrophils, and dendritic cells from the inflamed lesions. CONCLUSIONS:These data suggest that specific elimination of FR-β-expressing macrophages may constitute a highly specific therapy for multiple autoimmune and inflammatory diseases and that a recently developed human anti-human FR-β monoclonal antibody (m909) might contribute to suppression of this subpopulation of macrophages.

Background: Discoid lupus erythematosus (DLE) is a chronic inflammatory disorder mediated by Th1 cells. Apremilast is a novel oral PDE4 enzyme inhibitor capable of blocking leukocyte production of IL-12, IL-23, TNF-a, INF- with subsequent suppression of Th1 and Th17-mediated immune responses, and proven clinical efficacy for psoriasis as well as rheumatoid and psoriatic arthritis. Observations: Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) showed a significant (P<0.05) decrease after 85 days of treatment with apremilast 20 mg twice daily in 8 patients with active discoid lupus. The adverse events related to the drug were mild and transient. Conclusions: This is the first open label study to use apremilast as a treatment modality for discoid lupus. Our observations indicate that apremilast may constitute a safe and effective therapeutic option for DLE.

Psychological stress has long been associated with effects on immune function and disease. In particular, differential effects of acute and chronic stress on skin immunity occur in the rodent restraint stress model, with acute stress enhancing and chronic stress suppressing cutaneous hypersensitivity. Extracellular levels of adenosine are known to modulate diverse biological activities in the CNS and peripheral tissues and serve an important protective function against physiological stressors such as inflammation and ischemia. In this study, we utilized the restraint stress model and the skin sensitizer dinitrofluorobezene to test the hypothesis that perceived stress influences contact hypersensitivity through an adenosine A(1) receptor-mediated mechanism. We subjected hapten-sensitized A(1) receptor knockout (A1 KO) mice and their wild-type (WT) littermates to either acute (2.5 h) or chronic (5 h daily x 4 weeks) restraint stress, followed by hapten re-challenge of the pinna. Daily measurements of the resulting pinna swellings from each group were compared to reactions in non-stressed controls. In WT mice, pinna swelling was augmented in acutely stressed mice and suppressed in the chronically stressed group. In contrast, contact hypersensitivity responses in the A1 KO mice failed to be affected by either acute or chronic stress. Absence of the adenosine A(1) receptor did not affect levels of plasma corticosterone or urine catecholamines under these stressful conditions but did lead to reduced numbers of circulating neutrophil granulocytes compared to stressed WT animals. These results suggest that the adenosine A(1) receptor pathway plays a role in the process by which perceived psychological stress influences the contact hypersensitivity response

Brain-derived neurotrophic factor (BDNF) plays a regulatory role in neuronal differentiation and synaptic plasticity and has been linked to glucose regulation and cognition. Associations among plasma BDNF, cognition, and insulin function were explored. Forty-one participants with impaired insulin function (IIF), ranging from insulin resistance to type 2 diabetes mellitus (T2DM), were matched with 41 healthy controls on gender, age, education, and IQ. Participants received complete medical, neurological, psychiatric, and neuropsychological evaluations. IIF individuals had significantly lower plasma BDNF levels than controls, particularly females, and higher BDNF levels were associated with poorer explicit memory in IIF females, suggesting that higher levels within this group may reflect the body's efforts to respond to damage. After accounting for age, education, and HbA1c, BDNF significantly predicted 13.1-23.5% of the variance in explicit memory in IIF women. These findings suggest that BDNF elevations within diseased groups may not always be a marker of health

BACKGROUND: Injection of regulatory T (Treg) cells into sensitized mice abrogates the elicitation phase of contact hypersensitivity (CHS) reactions by blocking the adherence of leukocytes to vascular endothelium. OBJECTIVE: We set out to analyze whether adenosine, a suppressive factor recently described as produced by Treg cells, can account for the suppression of the effector T-cell-endothelial cell (EC) interaction. METHODS: T cells and ECs were cultured in the presence of adenosine, and expression of adhesion molecules and adhesion of T cells to ECs under shear stress were assessed. Furthermore, we injected Treg cells derived from ectonucleotidase-deficient (CD39-/-) mice into sensitized mice and analyzed the sticking and rolling of leukocytes during a CHS response using intravital microscopy. RESULTS: Adenosine or Treg cells, respectively, abrogated the adherence of effector T cells to ECs in vitro. Likewise, injection of adenosine and Treg cells abrogated the ear-swelling reaction, indicating a role of adenosine during Treg cell-induced suppression of CHS responses. As a source for Treg cell-derived adenosine, we identified the ectonucleotidase CD39 because CD39-deficient Treg cells did not prevent adhesion of leukocytes to the endothelium. Furthermore, we show that the impaired adhesion of effector T cells to inflamed endothelium was induced by adenosine-mediated downregulation of expression of E- and P-selectin on the vascular endothelium. CONCLUSION: Adenosine release by Treg cells is essential to block leukocyte adhesion to endothelium, providing a novel mechanism by which Treg cells mediate immune suppression in vivo