ovalbumin and Pancreatitis

Proinsulin is the first autoantigen in type 1 diabetes (T1D). We reasoned that coupling hematopoietic stem cells (HSCs) transplantation with ex vivo transduction of syngeneic HSCs with lentiviral vectors to express proinsulin II could prevent T1D in nonobese diabetic (NOD) mice.. Hematopoietic stem cells were isolated from 6- to 8-week-old NOD female mice and transduced in vitro with lentiviral vectors encoding proinsulin II. Preconditioned 3- to 4-week-old female NOD mice were transplanted with transduced or nontransduced HSCs and compared with age-matched unmanipulated control. The insulitis, T1D development, and immune reconstitution were assessed.. The mean (SD) insulitis score was significantly reduced (1.156 [0.575] vs 2.156 [0.892] or 3.043 [0.728], P = 0.009 or <0.001), and diabetes was nearly completely prevented (1/13 vs 5/12 or 4/9, P = 0.031 or 0.013) in recipients of transduced HSCs expressing proinsulin II as compared with recipients of nontransduced HSCs or unmanipulated control. Sialitis, reconstitution of peripheral blood leukocytes, and in vitro recall responses to ovalbumin were not different between 3 groups of mice.. Syngeneic transplantation of HSCs transduced ex vivo with lentiviral vectors to encode proinsulin II is a novel strategy to prevent T1D.

Topics: Animals; Cytokines; Diabetes Mellitus, Type 1; Enzyme-Linked Immunospot Assay; Female; HEK293 Cells; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immune Tolerance; Mice, Inbred NOD; Ovalbumin; Pancreatitis; Proinsulin; Sialadenitis; T-Lymphocytes; Transfection

Gastrointestinal tract failure may be involved in the development of systemic septic complications in acute pancreatitis. Systemic and intestinal circulation, intestinal permeability and absorptive function were evaluated in the early course of acute pancreatitis induced in rats by retrograde intraductal injection of 0.2 ml of 5 per cent sodium taurodeoxycholate and 0.4 nmol trypsin. A decrease in systemic arterial pressure and intestinal blood flow and an increase in intestinal permeability as measured by the leakage of 125I-labelled human serum albumin from blood to lumen were noted in the distal ileum and colon, reaching statistically significant differences 6 h after induction of pancreatitis. The transport of small molecular markers (sodium fluorescein and 51Cr-labelled ethylenediamine tetra-acetic acid) through the distal ileum and colon in vitro from the mucosal to the serosal site in Ussing chambers significantly increased in the early periodic (20-60 min) of incubation, while the passage of a macromolecular marker (ovalbumin) demonstrated a definite increase at 60-120 min of incubation. D-Xylose absorption from the gut lumen to the portal vein was significantly less in acute pancreatitis than after sham operation. Intravenous administration of the hydroxyl radical scavenger dimethylsulphoxide prevented the compromised intestinal permeability and gut absorptive capacity induced by acute pancreatitis, but did not affect the reduced arterial pressure and intestinal microcirculation. Cytotoxic oxygen-derived free radicals may contribute to the development of alterations in intestinal permeability and absorptive function found in the early stage of acute pancreatitis in the rat.

Topics: Acute Disease; Animals; Blood Pressure; Dimethyl Sulfoxide; Edetic Acid; Fluoresceins; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Microcirculation; Ovalbumin; Pancreatitis; Rats; Rats, Sprague-Dawley; Xylose

A novel and potent antagonist of platelet-activating factor (PAF), Y-24180 (4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepine) was investigated for the effects on the skin reactions induced by chemical mediators and the Arthus reactions. In the rat dorsal skin, Y-24180 (0.1-10 mg/kg, p.o.) inhibited increase in vascular permeability by the intradermal PAF injection in a dose dependent manner and the inhibitory activity was 60 times more potent than that of WEB 2086. While even at doses as large as 10 mg/kg, p.o., it had no effect on vascular permeability in the rat skin induced by histamine, serotonin, bradykinin and leukotriene D4. On a reversed passive Arthus reaction in rat dorsal skin, Y-24180 (0.1-1 mg/kg, p.o.) markedly inhibited vascular permeability in a dose dependent manner and the inhibitory activity was 15 times more potent than that of WEB 2086. Y-24180 also inhibited the Arthus dermal reaction in rabbits (0.03-0.3 mg/kg, p.o.) and guinea pigs (0.1-1 mg/kg, p.o.). In addition, Y-24180 (0.1-10 mg/kg, p.o.) significantly reduced the exudate volume and the number of infiltrated inflammatory cells in the reversed passive Arthus pleural reaction in rats. Furthermore, in rat passive Arthus pancreatitis, Y-24180 (0.3-10 mg/kg, p.o.) significantly inhibited the dye extravasation from the pancreas. These results provide strong evidence that endogenous PAF plays an important role as a mediator in the type III allergic inflammation.

Topics: Animals; Arthus Reaction; Azepines; Capillary Permeability; Disease Models, Animal; Female; Guinea Pigs; Male; Molecular Structure; Ovalbumin; Pancreatitis; Platelet Activating Factor; Rabbits; Rats; Rats, Inbred Strains; Skin; Skin Diseases; Triazoles