Tumor location determines tissue-specific recruitment of tumor-associated macrophages and antibody-dependent immunotherapy response.

Despite recent advances in activating immune cells to target tumors, the presence of some immune cells, such as tumor-associated macrophages (TAMs) or tumor-associated neutrophils (TANs), may promote rather than inhibit tumor growth. However, it remains unclear how antibody-dependent tumor immunotherapies, such as cytotoxic or checkpoint control antibodies, affect different TAM or TAN populations, which abundantly express activating Fcγ receptors. In this study, we show that the tissue environment determines which cellular effector pathways are responsible for antibody-dependent tumor immunotherapy. Although TAMs derived from Ly6Chigh monocytes recruited by the CCL2-CCR2 axis were critical for tumor immunotherapy of skin tumors, the destruction of lung tumors was CCL2-independent and required the presence of colony-stimulating factor 2-dependent tissue-resident macrophages. Our findings suggest that TAMs may have a dual role not only in promoting tumor growth in certain tissue environments on the one hand but also in contributing to tumor cell destruction during antibody-mediated immunotherapy on the other hand.

A humanized mouse identifies the bone marrow as a niche with low therapeutic IgG activity.

Genetic differences between humans and in vivo model systems, including mice and nonhuman primates, make it difficult to predict the efficacy of immunoglobulin G (IgG) activity in humans and understand the molecular and cellular mechanisms underlying that activity. To bridge this gap, we established a small-animal model system that allowed us to study human IgG effector functions in the context of an intact human immune system without the interference of murine Fcγ receptors expressed on mouse innate immune effector cells in vivo. Using a model of B cell depletion with different human IgG variants that recognize CD20, we show that this humanized mouse model can provide unique insights into the mechanism of human IgG activity in vivo. Importantly, these studies identify the bone marrow as a niche with low therapeutic IgG activity.

FcγRIIB: a modulator of cell activation and humoral tolerance.

An immune response needs to be tightly regulated to prevent excessive inflammation, which may result in the destruction of healthy tissues. At the molecular level, the strength of an immune response is determined by the integration of a multitude of positive and negative signals. This review will focus on IgG-dependent immune responses and discuss how the inhibitory receptor FcγRIIB may be involved in regulating both the afferent and efferent phases of such a response. Furthermore, we will discuss recent evidence suggesting that FcγRIIB may have important functions beyond the negative regulation of signals transduced by the B-cell receptor or activating FcγRs and could be responsible for the activity of agonistic antibodies in vivo.

Short-term growth hormone treatment and microcirculation: effects in patients with chronic kidney disease.

Endothelial dysfunction is common in patients with chronic kidney disease (CKD) and contributes significantly to the high long-term cardiovascular morbidity and mortality. The short-term cardiovascular effects of recombinant human growth hormone (rhGH) in CKD patients (stages III-V) and healthy controls (n=15 each) were explored in a single-center, non-randomized pilot study. Subjects were investigated before, after a 7 day treatment with rhGH, and after a 7 day wash-out period. Microcirculation was assessed by nailfold capillaroscopy and leg strain gauge plethysmography. Echocardiography was performed and serum concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3) were determined. Before the start of rhGH therapy, mean post-ischemic maximum flow velocity of erythrocytes (V(RBC)) and leg blood flow (LBF) in CKD patients were significantly reduced to 68% and 75% of that seen in controls, whereas V(RBC) and LBF under resting conditions were comparable. Treatment with rhGH significantly increased V(RBC) and LBF under resting conditions. Whereas maximum post-ischemic V(RBC) was improved by rhGH in patients and controls, maximum post-ischemic LBF increased in controls only. This was paralleled by a non-significant reduction of total vascular resistance, and increased heart rate and cardiac index. In conclusion, CKD patients respond to short-term rhGH treatment with significantly improved capillary blood flow, whereas only minor effects on total peripheral resistance and cardiac output were noted.

Renal Insufficiency Following Radiocontrast Exposure Trial (REINFORCE): a randomized comparison of sodium bicarbonate versus sodium chloride hydration for the prevention of contrast-induced nephropathy.

INTRODUCTION: For the prevention of contrast-induced nephropathy (CIN) after coronary angiography, hydration by 0.9% sodium chloride solution and N-acetylcysteine is currently recommended. However, it is unclear whether volume supplementation with sodium bicarbonate is better than with sodium chloride when used in conjunction with nonionic, low-osmolar iopamidol. The aim of this study was to analyze and compare the effects of sodium bicarbonate and sodium chloride on renal function in 145 patients exposed to nonionic iso-osmolar contrast medium iodixanol in a randomized study. PATIENTS AND METHODS: Renal Insufficiency Following Radiocontrast Exposure is a prospective, randomized, single-center, double-blinded trial of 145 patients (age 72.6+/-6.7 years) with elevated baseline serum creatinine levels (mean 132.6+/-29.3 micromol/l). Eligible patients were randomized to either a 154 mEq/l infusion of sodium bicarbonate (n=71, group I) or sodium chloride 0.9% solution (n=74, group II). The primary endpoint was serum creatinine elevation beyond 25% or 44 micromol/l on the first or second day following exposure to the contrast medium. Serum creatinine, serum cystatin C, plasma viscosity, urinary enzymes alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase, and alpha1-microglobulin were measured at baseline and on days 1 and 2 after contrast medium administration. RESULTS: An overall proportion of five CIN (3.4%) was observed with equal distribution among the groups (4.2% in sodium bicarbonate group vs. 2.7% in sodium chloride group; P=0.614). Parameters of renal function demonstrated no differences between the two hydration regimens on day 1 after angiography; even on day 2 most parameters were similar in groups I and II. CONCLUSION: Renal Insufficiency Following Radiocontrast Exposure demonstrates a homogeneously low rate of CIN after exposure to nonionic, iso-osmolar iodixanol regardless of the use of either bicarbonate sodium or sodium chloride solution for volume supplementation. Low-toxicity contrast media and any hydration may offset potential antioxidant effects of sodium bicarbonate.