Leptin-based immune intervention: current status and future directions

Current understanding of the role of leptin has expanded from its narrow association with obesity to a variety of effects on different biological processes including immune function. More specifically, leptin links nutritional status and energy balance to regulation of pro-inflammatory T-helper 1 immune responses. This has prompted several studies of targeted intervention with leptin antagonists in rodents to suppress onset and/or progression of chronic inflammation and autoimmunity. This review presents current preclinical evidence and potential applications for leptin-based immune approaches aimed at improving therapy for chronic and autoimmune conditions.     

Human papillomavirus type 16 and 18 L1 protein peptide binding to VERO and HeLa cells inhibits their VLPs binding

Human papillomaviruses (HPVs) are the cause of epithelial lesions, HPV type 16 and type 18 being associated with the development of anogenital cancer. The L1 Major Capsid Protein (L1) represents about 90% of total HPV protein and is involved in virus-host cell interaction, but little is known about this binding process. L1 sequences from HPV types 16 and 18 were synthesized in 56 20-mer peptides, covering the entire protein, HPLC-purified, (125)I-radiolabeled and tested in VERO and HeLa cell-binding assays to identify those peptides with high specific binding activity. Peptides 18283 (residues 54-77) and 18294 (274-308) from HPV16 L1, as well as 18312 (59-78) and 18322 (259-278) from HPV18 L1, presented high specific target cell binding activity. Peptide 18283 and 18294 affinity constants were 300 and 600 nM, respectively. Enzyme cell treatment before binding assay indicated that VERO and HeLa cell peptide receptor is a surface-exposed protein. There was a 60% reduction in peptide 18283 binding to heparin lyase-treated cells. Cross-linking assays showed that these proteins molecular weights were around 69 and 54 kDa. Peptides 18283 and 18294 specifically inhibited HPV-16 VLP binding to HeLa cells. According to the L1- and VLP-reported structure, both peptides are close on the VLP-surface, belonging to the outer surface broad pockets suggested as being potential receptor sites. Furthermore, it has been reported that a conserved motif from peptide 18294 is the target for neutralizing antibodies. These results suggest that such binding sequences are used by the virus as cell-binding regions.     

An alpha helix conformationally restricted peptide is recognized by cervical carcinoma patients' sera

Human papillomavirus type 16 (HPV-16) represents the major cervical carcinoma associated virus among women, especially in Colombia. It has thus become important to develop reliable inexpensive tests for detecting the presence of this virus. It has been shown that HPV16-E7 oncoprotein structural features have three alpha-helical structures and a loop-like structure. The hydrazone link approach was used to mimic helix secondary substructures. Sera from women with invasive cervical carcinoma were tested against conformationally restricted peptides and their respective linear peptides to identify conformational epitopes. One peptide that was conformationally restricted to an alpha-helix showed very strong positive reaction with sera from women having invasive cervical carcinoma; there was no reaction with sera from patients with other carcinomas, children, or healthy women. NMR studies confirmed this peptide's alpha-helical structure. The observation that constrained protein substructure peptidomimetics can identify new conformationally sensitive antibodies in cervical carcinoma patients' sera is very important, since these antibodies are almost all generated by native proteins, providing a new selection of antibodies for diagnostic and vaccine studies.     

Ciliary neurotrophic factor may activate mature astrocytes via binding with the leukemia inhibitory factor receptor

Ciliary neurotrophic factor (CNTF) acts on immature astrocytes that express its trimeric receptor. In contrast, mature astrocytes do not significantly express the specific CNTFalpha receptor subunit, yet they respond to CNTF administration in vivo. Here we show that this controversy may be solved by a shift in astroglial sensitivity to CNTF over time, related to a change in the type of receptor bound by the cytokine on mature astrocytes. A convergent set of results supports the hypothesis that the CNTF effect is due to the illegitimate binding on the leukemia inhibitory factor receptor (LIFR): (i) it requires high concentration of recombinant rat CNTF; (ii) it involves the Jak/Stat and Ras-MAPK pathways; (iii) it is preserved in CNTFRalpha-/- cells; (iv) it is potentiated by soluble CNTFRalpha added to the medium; and (v) it is significantly decreased by a partial antagonist of LIFR. On these bases, we propose a mechanistic model in which, in the adult brain, a CNTF/LIFR interglial system may be modulated by neurons that synthesize CNTFRalpha.     

The role of interferon-gamma in murine pneumococcal pneumonia.

To determine the role of interferon (IFN)-gamma in pneumonia, IFN-gamma receptor-deficient (IFN-gamma R(-/-)) and 129/Sv (wild-type [wt]) mice were inoculated intranasally with Streptococcus pneumoniae. Although mortality did not differ between the groups 48 h after inoculation, IFN-gamma R(-/-) mice had significantly fewer pneumococci in their lungs than the wt mice. Similarly, IFN-gamma(-/-) mice had fewer colony-forming units in lungs than wt mice. The relatively increased resistance of IFN-gamma R(-/-) mice was not related to favorable effects on defense mechanisms known to contribute to antibacterial immunity-that is, the neutrophilic influx was reduced and the cytokine and nitric oxide levels were similar or lower in IFN-gamma R(-/-) mice. In contrast, mice treated with anti-IFN-gamma did not demonstrate a consistently altered bacterial outgrowth, compared with mice treated with a control antibody. These data suggest that endogenous IFN-gamma, despite its protective role in defense against intracellular pathogens, does not serve a protective role during pneumococcal pneumonia.     

Predicting the carcinogenicity of the aromatic amine derivatives tested in the second UKEMS collaborative study

The carcinogenicity prediction and battery selection (CPBS)procedure was used to analyze the short-term in vitro and invivo genotoxicity results obtained during the Second UKEMS CollaborativeStudy. In accordance with preliminary animal bioassay results,CPBS predicted correctly the carcinogenicity of benzidine, 4,4'-diaminoterphenyland 4-dimethylaminoazobenzene. CPBS predicted the non-carcino-genkityof 4-cyanodimethylaniline, a chemical of as yet unknown carcinogenicity.Moreover, CPBS indicated that for the chemicals included inthe UKEMS study, highly predictive as well as cost-effectivebatteries consisting of three short-term assays could be identified.     

Cardiovascular influence of dental anxiety during local anesthesia for tooth extraction.

OBJECTIVE: The present study evaluated whether dental patient anxiety has an effect on the cardiovascular response to the delivery of anesthetic to achieve mandibular anesthesia. STUDY DESIGN: One hundred eighty adult patients scheduled to receive routine dental extraction under local anesthesia were enrolled in this prospective study. Anxiety was measured at 15 minutes before local anesthetic delivery using Corah's Dental Anxiety Scale (Corah's DAS). Anesthetic was delivered using a standard technique for mandibular nerve block with the same dose (2 cartridges) given to all patients. Cardiovascular response data including blood pressure, heart rate, O(2) saturation, and electrocardiographic changes were measured at 5 time points from 5 minutes before to 15 minutes after the administration of anesthetic. RESULTS: The mean anxiety scale score before administration of anesthetic was 9.3 (SD +/- 2.5) with a range from 4 to 20. Women had a significantly higher mean dental anxiety level than men (P < .05). Younger age was associated with a higher anxiety scale score. Severe preoperative anxiety (Corah's DAS >12) was associated with significantly increased heart rate during administration of anesthetic. Patients with severe anxiety also had a significantly greater increase in heart rate during anesthetic administration (P < .001). Younger age was associated with increased likelihood of high dental anxiety and associated cardiovascular response to dental anesthesia (P = .001). Pain on injection was also associated with increased heart rate during anesthetic administration. CONCLUSION: This study showed that Corah's dental anxiety scale is a useful tool for estimating the impact of anxiety on the heart rate during local anesthetic delivery to achieve mandibular block for dental extraction. Younger patients undergoing tooth extraction were more likely to have high anxiety levels, and younger patients with high anxiety were more likely to report a traumatic dental history. High anxiety, younger age, and traumatic dental history were correlated with greater increases in heart rate during the administration of local dental anesthesia.     

Intricate isavuconazole therapy of a subcutaneous nodule caused by Alternaria infectoria in a heart transplant recipient

Invasive fungal infections have appeared to be increasingly emergent in immunocompromised patients, especially in solid organ transplant (SOT) recipients. The Alternaria genus encompasses more than 80 dematiaceus species. Among them, Alternaria alternata and Alternaria infectoria are the most frequent isolated as responsible for infection in humans.To our knowledge, we report the first case of a heart transplant recipient suffering from subcutaneous nodule caused by Alternaria infectoria and who was treated with isavuconazole. Despite all the promises of this new azole drug, one should keep in mind the potential great variability of the inter-individual responses for such complex patients. We demonstrate herein how it can be challenging to manage Alternaria infection in SOT recipients. More comprehensive studies and recommendations are expected in the context of Alternaria infections.