Serum from patients with systemic vasculitis induces alternatively activated macrophage M2c polarization.

Anti-neutrophil cytoplasmic antibody associated vasculitides (AAV) are conditions defined by an autoimmune small vessel inflammation. Dying neutrophils are found around the inflamed vessels and the balance between infiltrating neutrophils and macrophages is important to prevent autoimmunity. Here we investigate how sera from AAV patients may regulate macrophage polarization and function. Macrophages from healthy individuals were differentiated into M0, M1, M2a, M2b or M2c macrophages using a standardized protocol, and phenotyped according to their expression surface markers and cytokine production. These phenotypes were compared with those of macrophages stimulated with serum from AAV patients or healthy controls. While the healthy control sera induced a M0 macrophage, AAV serum promoted polarization towards the M2c subtype. No sera induced M1, M2a or M2b macrophages. The M2c subtype showed increased phagocytosis capacity compared with the other subtypes. The M2c polarization found in AAV is consistent with previous reports of increased levels of M2c-associated cytokines.

Associations Between Childbirth and Urinary Incontinence After Midurethral Sling Surgery.

OBJECTIVE: To assess whether subsequent childbirths affect the outcomes of midurethral sling surgery with regard to stress urinary incontinence (SUI). METHODS: In this population-based cohort study, we used the validated Swedish nationwide health care registers (the Patient Register and the Medical Birth Register) to identify women with a delivery after midurethral sling surgery (n=207, study group). From the same registers we then randomly identified a control group who had no deliveries after their midurethral sling procedure (n=521, control group). The women in the control group were matched to the women in the study group by age and year of surgery. The Urogenital Distress Inventory and the Incontinence Impact Questionnaire were sent out to the study population. Symptomatic SUI was defined as the primary outcome. Secondary outcomes included the total Urogenital Distress Inventory score, Urogenital Distress Inventory subscale scores, and Incontinence Impact Questionnaire scores. RESULTS: A total of 728 women were eligible for the study. The response rate was 74%; 163 in the study group (64 with vaginal delivery and 95 with cesarean delivery) and 374 women in the control group were included in the analysis. The rate of SUI (primary outcome) was 36 of 163 (22%) in the study group and 63 of 374 (17%) in the control group. In a multivariate regression analysis of the primary outcome, we found no significant difference between the groups (odds ratio [OR] 1.2, 95% CI 0.7-2.0). Vaginal childbirth after midurethral sling surgery did not increase the risk of SUI compared with cesarean delivery (22% vs 22%, OR 0.6, 95% CI 0.2-1.4). There were no significant differences in Urogenital Distress Inventory and Incontinence Impact Questionnaire scores between any of the groups. CONCLUSION: Childbirth after a midurethral sling procedure is not associated with an increased risk of patient-reported SUI, and continence status is not affected by the mode of a subsequent delivery.

Pericytes and the pathogenesis of diabetic retinopathy.

Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B(+/-) mice). As assessed by quantitative morphometry of retinal digest preparations, pericyte numbers in nondiabetic PDGF-B(+/-) mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte numbers were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte numbers were decreased by 50% in diabetic PDGF-B(+/-) mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B(+/-) mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B(+/-) mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo.

A human ICAM-1 antibody isolated by a function-first approach has potent macrophage-dependent antimyeloma activity in vivo.

We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used treatments. BI-505 bound to intercellular adhesion molecule-1, identifying a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope was strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 had potent macrophage-dependent antimyeloma activity and conferred enhanced survival compared to currently used treatments in advanced experimental models of multiple myeloma.