The Bidirectional Transfer and Fetal Vascular Pressure Changes Due to the Presence of [Formula: see text] I-Labeled Inhibin A in the ex-vivo Human Placental Model

Objective: The purpose of this study was to investigate the transport of inhibin A and to determine its effects on fetal vascular pressure at elevated levels in the human placenta using (125)I -labeled synthetic glycoprotein. Methods: Synthetic inhibinAwas prepared and was shown to be consistent with the natural form by high-pressure liquid chromatography (HPLC) and molecular weight determination by gas-chromatography mass spectrometry. The standardized Na(125)I process yielded (125)I -labeled inhibin A with a radioactivity of 10(6) cpm/μg. This compound was placed in the human placenta in maternal–fetal and fetal–maternal studies using antipyrine and (14)C -labeled inulin as controls to determine the bidirectional transfer of the compound. Results: Maternal–fetal and fetal–maternal clearance indices were 0.045± 0.003 and 0, respectively. In eight placentas there was no evidence of vascular pressure changes due to the presence of up to 5000 pg of inhibin A. Conclusions: There is minimal maternal–fetal transfer and no detectable fetal–maternal transfer in normotensive and pregnancy-induced hypertensive placentas. In addition, there are no pressure changes in the fetal vascular system due to the clinically significant levels of inhibin A

The Enigma of Vasculitis

We describe the case of an 86-year-old man presenting with clinical symptoms suggestive of Temporal Arteritis. The evolution of the case prompted extensive work-up, including temporal artery and kidney biopsy. Based on the clinical and pathological findings, a diagnosis of ANCA-negative granulomatous necrotizing vasculitis involving the small-, medium-, and large-size vessels was made. The patient was treated with prednisone and cyclophosphamide, which was later switched to rituximab. The patient remained asymptomatic under this regimen and stabilization of his kidney function was achieved

A Comparison of the Anti-Tumor Effects of a Chimeric versus Murine Anti-CD19 Immunotoxins on Human B Cell Lymphoma and Pre-B Acute Lymphoblastic Leukemia Cell Lines

Precursor B cell acute lymphoblastic leukemia (pre-B ALL) affects five to six thousand adults and almost three thousand children every year. Approximately 25% of the children and 60% of the adults die from their disease, highlighting the need for new therapies that complement rather than overlap chemotherapy and bone marrow transplantation. Immunotherapy is a class of therapies where toxicities and mechanisms of action do not overlap with those of chemotherapy. Because CD19 is a B cell- restricted membrane antigen that is expressed on the majority of pre-B tumor cells, a CD19-based immunotherapy is being developed for ALL. In this study, the anti-tumor activities of immunotoxins (ITs) constructed by conjugating a murine monoclonal antibody (MAb), HD37, or its chimeric (c) construct to recombinant ricin toxin A chain (rRTA) were compared both in vitro using human pre-B ALL and Burkitt’s lymphoma cell lines and in vivo using a disseminated human pre-B ALL tumor cell xenograft model. The murine and chimeric HD37 IT constructs were equally cytotoxic to pre-B ALL and Burkitt’s lymphoma cells in vitro and their use in vivo resulted in equivalent increases in survival of SCID mice with human pre-B ALL tumors when compared with control mice

A common theme in interaction of bacterial immunoglobulin-binding proteins with immunoglobulins illustrated in the equine system

The M protein of Streptococcus equi subsp. equi known as fibrinogen-binding protein (FgBP) is a cell wall-associated protein with antiphagocytic activity that binds IgG. Recombinant versions of the seven equine IgG subclasses were used to investigate the subclass specificity of FgBP. FgBP bound predominantly to equine IgG4 and IgG7, with little or no binding to the other subclasses. Competitive binding experiments revealed that FgBP could inhibit the binding of staphylococcal protein A and streptococcal protein G to both IgG4 and IgG7, implicating the Fc interdomain region in binding to FgBP. To identify which of the two IgG Fc domains contributed to the interaction with FgBP, we tested two human IgG1/IgA1 domain swap mutants and found that both domains are required for full binding, with the CH3 domain playing a critical role. The binding site for FgBP was further localized using recombinant equine IgG7 antibodies with single or double point mutations to residues lying at the CH2-CH3 interface. We found that interaction of FgBP with equine IgG4 and IgG7 was able to disrupt C1q binding and antibody-mediated activation of the classical complement pathway, demonstrating an effective means by which S. equi may evade the immune response. The mode of interaction of FgBP with IgG fits a common theme for bacterial Ig-binding proteins. Remarkably, for those interactions studied in detail, it emerges that all the Ig-binding proteins target the CH2-CH3 domain interface, regardless of specificity for IgG or IgA, streptococcal or staphylococcal origin, or host species (equine or human)

Contribution of Renal and Non‐Renal Clearance on Increased Total Clearance of Adalimumab in Glomerular Disease

The contribution of renal and non‐renal clearance toward targeted concentrations and/or effects of therapeutic proteins in nephrotic patients are unknown. This study dissected the contribution of clearance pathways to adalimumab elimination in patients with focal segmental glomerulosclerosis (FSGS). Urine was collected from seven patients treated with adalimumab. Renal clearance (Cl R ) was measured and non‐renal clearance (Cl NR ) was calculated as the difference between total clearance and Cl R . Differences in cumulative amount in urine, Cl R , and Cl NR between study weeks 1 and 16 and relationships between proteinuria (protein:creatinine ratio (Up/c)), and Cl R and Cl NR were evaluated. Up to 13% of the adalimumab dose was lost in urine. Cl NR contributed more than Cl R to enhanced total clearance. There was a nonlinear relationship between Up/c and Cl R (R 2 0.7059); an increase in Cl R beginning at Up/c of 12 mg/mg [slope 1.755, (C.I. −7.825 to 11.34)]. There was a linear relationship between Up/c and Cl NR (R 2 0.5039); for every one unit increase in Up/c, Cl NR would increase by 3.5 mL/hr ( P  = 0.01). Both Cl R and Cl NR contribute to enhanced total clearance of adalimumab in glomerular disease secondary to FSGS. Additional research is needed to identify mechanisms for the increased Cl NR pathways.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99679/1/jcph121.pd

A biophysical model of cell adhesion mediated by immunoadhesin drugs and antibodies

A promising direction in drug development is to exploit the ability of natural killer cells to kill antibody-labeled target cells. Monoclonal antibodies and drugs designed to elicit this effect typically bind cell-surface epitopes that are overexpressed on target cells but also present on other cells. Thus it is important to understand adhesion of cells by antibodies and similar molecules. We present an equilibrium model of such adhesion, incorporating heterogeneity in target cell epitope density and epitope immobility. We compare with experiments on the adhesion of Jurkat T cells to bilayers containing the relevant natural killer cell receptor, with adhesion mediated by the drug alefacept. We show that a model in which all target cell epitopes are mobile and available is inconsistent with the data, suggesting that more complex mechanisms are at work. We hypothesize that the immobile epitope fraction may change with cell adhesion, and we find that such a model is more consistent with the data. We also quantitatively describe the parameter space in which binding occurs. Our results point toward mechanisms relating epitope immobility to cell adhesion and offer insight into the activity of an important class of drugs.Comment: 13 pages, 5 figure

Spontaneous expectoration of pulmonary metastases in a child with osteogenic sarcoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148355/1/pbc27611.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148355/2/pbc27611_am.pd

The Chicken Yolk Sac IgY Receptor, a Mammalian Mannose Receptor Family Member, Transcytoses IgY across Polarized Epithelial Cells

In mammals the transfer of passive immunity from mother to young is mediated by the MHC-related receptor FcRn, which transports maternal IgG across epithelial cell barriers. In birds, maternal IgY in egg yolk is transferred across the yolk sac to passively immunize chicks during gestation and early independent life. The chicken yolk sac IgY receptor (FcRY) is the ortholog of the mammalian phospholipase A2 receptor, a mannose receptor family member, rather than an FcRn or MHC homolog. FcRn and FcRY both exhibit ligand binding at the acidic pH of endosomes and ligand release at the slightly basic pH of blood. Here we show that FcRY expressed in polarized mammalian epithelial cells functioned in endocytosis, bidirectional transcytosis, and recycling of chicken FcY/IgY. Confocal immunofluorescence studies demonstrated that IgY binding and endocytosis occurred at acidic but not basic pH, mimicking pH-dependent uptake of IgG by FcRn. Colocalization studies showed FcRY-mediated internalization via clathrin-coated pits and transport involving early and recycling endosomes. Disruption of microtubules partially inhibited apical-to-basolateral and basolateral-to-apical transcytosis, but not recycling, suggesting the use of different trafficking machinery. Our results represent the first cell biological evidence of functional equivalence between FcRY and FcRn and provide an intriguing example of how evolution can give rise to systems in which similar biological requirements in different species are satisfied utilizing distinct protein folds

Syndactyly in Pigs: A Review of Previous Research and the Presentation of Eight Archaeological Specimens

This paper reviews evidence for the rare condition of porcine syndactyly. It describes eight archaeological examples from Britain, Northern Ireland and France. Syndactyly refers to the partial or complete fusion of two or more adjacent phalanges on the medio-lateral border. The degree and character of fusion are variable, but phalanges frequently unite to create a single skeletal element. This condition has been identified by veterinarians, zoologists and naturalists in individuals and populations in a range of species, but in spite of substantial research on the condition in humans and to a lesser extent cattle, it remains relatively poorly understood in other mammals. Syndactyly is generally agreed to be primarily congenital in origin, although factors affecting its incidence remain far from fully understood. In light of the general paucity of discussion of specific conditions of animal palaeopathology, this paper presents an analysis of these newly discovered syndactyle pig specimens, offers a review of research with particular reference to pigs and discusses the etiology of the condition