Comparison of Immunologic Responses Between Mice Differing at the Agouti Locus : Immunologic Abnormalities in Lethal Yellow (Ay) Mice are Augmented by Obesity

The agouti locus, located on chromosome 2 of the house mouse (mus musclus), functions in the complex regulation of pigment synthesis. The complexity of its regulatory role is revealed through the aberrations that become manifest when a mutation, specifically the lethal yellow (AY) mutation, occurs at the agouti locus. The lethal yellow mutation is associated with an alteration in pigment synthesis, onset of obesity at approximately 120 days, and an increased susceptibility to cancer. Based on the putative relationship between cancer and immunity, this mutation may be correlated with altered immune mechanisms. This correlation was investigated by comparing a delayed-type hypersensitivity (DTH) response to dinitrofluorobenzene (DNFB), in vivo hormonal immunity to sheep red blood cell (SRBC), and in vitro lymphocyte reactivity of C57BL/6J Ay/a mice with congeneic a/a controls. Responses were compared between 42-day-old and 120-day-old mice to determine the correlation, if any, between altered immunity and age-onset obesity. Data indicate that the AY mutation is directly liked to a suppressed DIH response and, to some extent, a decreased reactivity to mitogen-induced lymphocyte proliferation. Obesity appears to play a role in the alteration in humoral immunity as demonstrated by an enhanced anti-SRBC IgM response and suppressed antibody-fanning cell (AFC) response to SRBC. Finally, serum from obese yellow (AY/a) mice was markedly suppressive in in vitro lymphocyte proliferation assays

Broad-Spectrum Antiherpes Activities of 4-Hydroxyquinoline Carboxamides, a Novel Class of Herpesvirus Polymerase Inhibitors

Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human α, δ, and γ polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpesviruses. However, these compounds were not active against several nonherpesviruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpesviruses