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We tested the hypothesis that tumor necrosis factor-[Alpha] (TNF-[Alpha]) would be teratogenic in mice due in part to its effects on zinc metabolism. In Experiment 1, nonpregnant mice were injected with a single dose of TNF-[Alpha] (40,000 U) or PBS and then received a 65Zn-labeled meal. Mice killed 10 h after TNF-[Alpha] treatment had high liver 65Zn and low plasma 65Zn, compared with controls. In Experiment 2, gestation day 8 (GD 8) mice were injected with PBS or TNF-[Alpha] and then received a 65Zn-labeled meal. Dams killed 10 h after TNF-[Alpha] treatment had higher liver and kidney 65Zn and lower plasma and embryonic 65Zn accumulation than controls. in Experiment 3, TNF-[Alpha] dosing from GD 7-12 was associated with high maternal liver Zn and metallothionein concentrations on GD 13 and a high frequency of exencephaly on GD 18. In Experiment 4, dams fed diets containing 4.5, 12.5 or 50.0 [[micro]gram] Zn/g were given PBS or TNF-[Alpha] on GD 7-12. Gross fetal defects were not observed in the PBS-treated litters evaluated on GD 18. In contrast, TNF-[Alpha]-treated litters were characterized by multiple defects, with the incidence and severity being highest in the low Zn diet group. In Experiment 5, embryos cultured in serum from TNF-[Alpha]-treated animals exhibited a high frequency of defects; the developmental toxicity of this serum was ameliorated when it was supplemented with Zn. Thus, the developmental toxicity of TNF-[Alpha] is due in part to its influence on Zn metabolism. INDEXING KEY WORDS: development; mice; zinc; tumor necrosis factor-[Alpha]; metallothionein

Dietary polyunsaturated fatty acids alter the lipid composition and immune systems of mice. To date, most studies have been of short duration and focused on a particular immunologic assay. Adult female mice were therefore fed diets rich in 18:1(n-9) (olive oil), 18:2(n-6) (safflower oil), 18:3(n-3) (linseed oil) or 20:5(n-3) and 22:6(n-3) (fish oil-safflower oil, 9:1, wt/wt), for a 5-mo period, encompassing two breeding cycles. Offspring from the second breeding cycle were then fed these diets for 42 d, and a spectrum of immune functions was assessed. Dietary fat had a small effect on gestational weight gain and total and relative organ weights of the offspring. The relative amounts of splenic Ly-2 and gamma-delta receptor-expressing T cells were proportional to the concentration of 18:2(n-6), and inversely proportional to the concentration of long chain (n-3) polyenes in the diet. In contrast, Ly-1, immunoglobulin M, GM1+, and Ly-1 B suppressor inducer cells were not significantly affected by dietary fat. Splenic natural killer cell and lymphokine activated killer cell activities were attenuated by (n-3) polyunsaturated fatty acids, in contrast to superoxide production of stimulated macrophages which was increased. Those immune functions that were sensitive to dietary fat modulation will be the focus of continued research.

Transplantation of fetal brain tissue may be an effective and safe treatment for some patients with advanced Parkinson's disease. Parkinson's disease is a neurodegenerative disorder characterized by loss of brain cells that produce dopamine. Among seven patients with advanced Parkinson's disease who no longer responded to medication, two patients received injections of fetal brain tissue with dopamine cells on one side of their brain and five received injections on both sides of their brain. A neurological examination six months after surgery found that the motor skills of five patients had improved during the 'on' state, which is a period of excessive movement. Patients were able to reduce their dose of anti-Parkinson medication by an average of 39% after transplantation. A PET scan revealed that one patient still had functioning fetal tissue present in his brain almost four years after surgery.

Abstract Background Small chemical compounds which target chemokine receptors have been developed against human immunodeficiency virus type 1 (HIV-1) and are under investigation for use as anti-HIV-1 microbicides. In addition, monoclonal antibodies (mAbs) against chemokine receptors have also been shown to have anti-HIV-1 activities. The objective of the present study was to screen a panel of three anti-CXCR4 specific monoclonal antibodies (mAbs) for their ability to block the HIV-1 infection using in vitro activated primary peripheral blood mononuclear cells (PBMCs). Results PBMCs from normal donors were pre-activated with anti-CD3 and anti-CD28 mAbs for 1 day, and aliquots were infected with a low dose of CCR5-tropic (R5), CXCR4 tropic (X4) or dual tropic (X4R5) HIV-1 isolates and cultured in the presence of a panel of anti-CXCR4 mAbs. The panel included clones A145 mAb against the N-terminus, A120 mAb against a conformational epitope consisting of extracellular loops (ECL)1 and ECL2, and A80 mAb against ECL3 of CXCR4. Among these mAbs, the A120 mAb showed the most potent inhibition of infection, by not only X4 but surprisingly also R5 and X4R5 HIV-1. The inhibition of R5 HIV-1 was postulated to result from the novel ability of the A120 mAb to induce the levels of the CCR5-binding β-chemokines MIP-1α, MIP-1β and/or RANTES, and the down modulation of CCR5 expression on activated CD4+ T cells. Neutralizing anti-MIP-1α mAb significantly reversed the inhibitory effect of the A120 mAb on R5 HIV-1 infection. Conclusions The data described herein have identified a unique epitope of CXCR4 whose ligation not only directly inhibits X4 HIV-1, but also indirectly inhibits R5 HIV-1 infection by inducing higher levels of natural CCR5 ligands.

Abstract Background Enveloped viruses including the simian immunodeficiency virus (SIV) replicating within host cells acquire host proteins upon egress from the host cells. A number of studies have catalogued such host proteins, and a few have documented the potential positive and negative biological functions of such host proteins. The studies conducted herein utilized proteomic analysis to identify differences in the spectrum of host proteins acquired by a single source of SIV replicating within CD4+ T cells from disease resistant sooty mangabeys and disease susceptible rhesus macaques. Results While a total of 202 host derived proteins were present in viral preparations from CD4+ T cells from both species, there were 4 host-derived proteins that consistently and uniquely associated with SIV replicating within CD4+ T cells from rhesus macaques but not sooty mangabeys; and, similarly, 28 host-derived proteins that uniquely associated with SIV replicating within CD4+ T cells from sooty mangabeys, but not rhesus macaques. Of interest was the finding that of the 4 proteins uniquely present in SIV preparations from rhesus macaques was a 26 S protease subunit 7 (MSS1) that was shown to enhance HIV-1 'tat" mediated transactivation. Among the 28 proteins found in SIV preparations from sooty mangabeys included several molecules associated with immune function such as CD2, CD3ε, TLR4, TLR9 and TNFR and a bioactive form of IL-13. Conclusions The finding of 4 host proteins that are uniquely associated with SIV replicating within CD4+ T cells from disease susceptible rhesus macaques and 28 host proteins that are uniquely associated with SIV replicating within CD4+ T cells from disease resistant sooty mangabeys provide the foundation for determining the potential role of each of these unique host-derived proteins in contributing to the polarized clinical outcome in these 2 species of nonhuman primates.