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Ag presentation via the anterior chamber of the eye results in a form of immune deviation termed anterior chamber-associated immune deviation (ACAID). The hallmarks of this response are the suppression of delayed-type hypersensitivity with simultaneous induction of Ab production. In this study, we examined the role of the neuropeptides vasoactive intestinal peptide (VIP) and substance P (SP) and found that the levels of these two peptides are controlled by neurogenic stimulation of the eye by light, and that these molecules determine the outcome of Ag presentation in the eye. Mice reared under diurnal conditions had VIP in the iris and ciliary body (not free in aqueous humor) and low levels of SP. Mice that were reared in the dark (or dark-adapted) did not contain detectable levels of VIP but had high levels of SP. The adaptation of diurnal mice to the dark eliminated VIP and increased SP, while adapting dark-reared mice to the diurnal cycle increased VIP and reduced SP. We then tested the hypothesis that immune reactions resulting from Ag presentation in the eye were linked to SP and VIP. We found that a VIP receptor antagonist, when injected into the eye with Ag, reversed ACAID in diurnal mice, while a SP receptor antagonist restored ACAID to dark-adapted mice. We further determined that injection of Ag or TNF-alpha induced VIP release, while SP was liberated into the aqueous humor following reexposure of dark-reared mice to light. Our results demonstrate a close linkage of intraocular immune reactions to neuropeptide levels in the eye.

Ts65Dn is a mouse model of Down syndrome; a syndrome that results from Chromosome (Chr) 21 trisomy and is associated with congenital defects, cognitive impairment, and ultimately Alzheimer’s Disease. Ts65Dn mice have segmental trisomy for distal mouse Chr 16, a region sharing conserved synteny with human Chr 21. As a result, this strain harbors three copies of over half of the human Chr 21 orthologs. The trisomic segment of Chr 16 is present as a translocation chromosome (Mmu 1716), with breakpoints that have not been defined previously. To molecularly characterize the Chr 16 and Chr 17 breakpoints on the translocation chromosome in Ts65Dn mice, we used a selective enrichment and high-throughput, paired end sequencing approach. Analysis of paired end reads flanking the Chr 16, Chr 17 junction on Mmu1716 and de-novo assembly of the reads directly spanning the junction provided the precise locations of the Chr 16 and Chr 17 breakpoints at 84,351,351 bp and 9,426,822 bp, respectively. These data provide the basis for low cost, highly efficient genotyping of Ts65Dn mice. More importantly, these data provide, for the first time, complete characterization of gene dosage in Ts65Dn mice.

1 We have used isolated arterial preparations from the rabbit and dog to investigate whether non-ionic iodinated radiographic contrast media (IRCM) modulate nitric oxide (NO) release. The tri-iodinated monomers iopromide and iohexol were compared with the hexa-iodinated dimer iodixanol. 2 The vasodilator effects of iohexol (300 mg ml-1) and iodixanol (320 mg ml-1) were assessed in cascade bioassay. Increasing concentrations of iohexol or iodixanol caused concentration-dependent relaxations of the detector tissue which were insensitive to 100 microM NG-nitro L-arginine methyl ester (L-NAME) and 10 microM indomethacin, whereas viscosity-associated relaxations induced by the 'inert' agent dextran (MW 80,000; 1-4%) were attenuated by inhibition of NO synthesis. 3 Relaxations of endothelium-intact rings to acetylcholine (ACh) were attenuated by preincubation with iohexol or iodixanol, whereas relaxations to sodium nitroprusside (SNP) in endothelium-denuded rings were unaffected. Inhibitory activity did not correlate with either molarity or iodine concentration. Mannitol caused inhibition of both ACh- and SNP-induced responses. 4 In isolated perfused arteries the depressor responses to iodixanol (320 mg ml-1) and iopromide (300 mg ml-1) administered as close arterial bolus attained a plateau with maximal dilatations of approximately 25% and approximately 60%, respectively. Addition of 100 microM NG-nitro L-arginine (L-NOARG) and/or 10 microM indomethacin to the perfusate had no effect on the responses to either agent. 5 We conclude that IRCM exert direct effects on the endothelium that inhibit NO production rather than its action on vascular smooth muscle. Shear stress-induced stimulation of NO production by IRCM is unlikely to contribute to their vasodilator activity in vivo when administered during angiography despite high intrinsic viscosity.