In vivo CD40 ligation can induce T-cell-independent antitumor effects that involve macrophages

We have previously demonstrated T cell-independent antitumor and antimetastatic effects of CD40 ligation that involved natural killer (NK) cells. As CD40 molecules are expressed on the surface of macrophages (Mphi), we hypothesized that Mphi may also serve as antitumor effector cells when activated by CD40 ligation. Progression of subcutaneous NXS2 murine neuroblastomas was delayed significantly by agonistic CD40 monoclonal antibody (anti-CD40 mAb) therapy in immunocompetent A/J mice, as well as in T and B cell-deficient severe combined immunodeficiency (SCID) mice. Although NK cells can be activated by anti-CD40 mAb, anti-CD40 mAb treatment also induced a significant antitumor effect in SCID/beige mice in the absence of T and NK effector cells, even when noncytolytic NK cells and polymorphonuclear cells (PMN) were depleted. Furthermore, in vivo treatment with anti-CD40 mAb resulted in enhanced expression of cytokines and cell surface activation markers, as well as Mphi-mediated tumor inhibition in A/J mice, C57BL/6 mice, and SCID/beige mice, as measured in vitro. A role for Mphi was shown by reduction in the antitumor effect of anti-CD40 mAb when Mphi functions were inhibited in vivo by silica. In addition, activation of peritoneal Mphi by anti-CD40 mAb resulted in survival benefits in mice bearing intraperitoneal tumors. Taken together, our results show that anti-CD40 mAb immunotherapy of mice can inhibit tumor growth in the absence of T cells, NK cells, and PMN through the involvement of activated Mphi.     

Mechanism of angioedema in first complement component inhibitor deficiency

Since shortly after the discovery that hereditary angioedema resulted from deficiency of first complement component (C1) inhibitor, the characterization of the mediator of angioedema has been a major goal. However, because C1 inhibitor regulates activation of both the contract and complement systems, identification of the mediator was not immediately accomplished. For a number of years, some studies appeared to indicate involvement of one system, whereas other studies suggested involvement of the other. However, the vast majority of the evidence accumulated over the past years indicates quite clearly that the major mediator is bradykinin. Therefore, unregulated contact system activation is the defect that leads directly to the development of angioedema.     

Human neutrophil elastase inhibition with a novel cotton-alginate wound dressing formulation

Occlusion and elasticity were combined in a novel cotton-based alginate dressing containing a nontoxic elastase inhibitor. Cotton gauzes were modified with a textile finishing process for incorporating alginate to yield a dressing material that retains elasticity while enhancing absorption. The algino-cellulose conjugates were formed through citric acid crosslinking of cellulose and alginate. The alginate-citrate finishes were applied to cotton gauzes in various formulations containing citric acid, sodium hypophosphite, and polyethylene glycol. The modified gauzes contain a citrate conjugate of alginate and cellulose that gels upon hydration. The alginate-citrate finishes were combined with the neutrophil elastase inhibitor, oleic acid, to demonstrate the ability of the algino-cellulose fibers to release the inhibitor and neutralize destructively high levels of neutrophil elastase found in nonhealing and burn wounds. Four types of gauzes were examined for the effect of the algino-cellulose finish on cotton gauze absorbency and elasticity. Fourier transform infrared (FTIR) spectroscopy of the film and alginate-citrate finished cotton showed formation of the alginate and citrate cellulose esters. Scanning electron microscopy analysis revealed large areas of the yarn surface covered by the alginate film with a smooth surface on the original fibers. Wetting of the gauze surface resulted in formation of a hydrated gel on the yarns with apparent swelling of the film and the fiber-coated alginate.     

Increased T cell immunosenescence and accelerated maturation phenotypes in older kidney transplant recipients

Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens.We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4+ and CD8+ T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis.This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation.     

Potent inhibition of SARS-associated coronavirus (SCOV) infection and replication by type I interferons (IFN-alpha/beta) but not by type II interferon (IFN-gamma).

We sought to investigate the anti-severe acute respiratory syndrome (SARS)-associated coronavirus (SCoV) activities of type I (alpha and beta) and type II (gamma) interferons (IFN) in vitro. Type I IFNs protected cells from cytopathic effects (CPE) induced by SCoV, and inhibited viral genomic RNA replication in FRhk-4 cells (measured by quantitative RT-PCR) in a dose-dependent manner. Intracellular viral RNA copies were reduced 50% by IFN-alpha at a concentration of 25 U/ml and by IFN-beta at a concentration of 14 U/ml. IFN-gamma had fewer effects on inhibition of viral infection and replication. The type I IFN receptor signaling pathway in host cells is mainly involved in the inhibition of SCoV infection and replication. Type I IFNs could be used as potential agents for anti-SARS treatment.     

Prevalence and correlates of HIV infection among young injection drug users in San Francisco

OBJECTIVE: We assessed the prevalence of HIV infection and associated risk behaviors among street-recruited young injection drug users (IDUs) in San Francisco. METHODS: In a cross-sectional study, 304 young (age <30 years) IDUs with a history of injecting in the previous 30 days were interviewed and tested for antibodies to HIV. Analyses assessing independent associations with HIV infection were limited to males only, due to the low number of infections in women. RESULTS: The prevalence of HIV infection was 5.3% overall but was highly stratified by gender and sexual preference (15.6% among homosexual/bisexual men vs. heterosexual men) and recruitment neighborhood (18% in the Polk Street area). Of 16 HIV infections, 14 (88%) were in males. Factors independently associated with HIV infection in males included sexual preference (homosexual/bisexual vs. heterosexual: adjusted odds ratio [AOR], 7.5; 95% confidence interval [CI], 1.5-36.6), recruitment neighborhood (Polk Street neighborhood vs. other neighborhoods: AOR, 4.8; 95% CI, 1.4-16.7), and duration of residence in San Francisco (>or=1 year vs. <1 year: AOR, 11.8; 95% CI, 1.4-95.8). CONCLUSIONS: The prevalence of HIV infection was highest among male IDUs who have sex with men. The strong associations between HIV infection and sexual orientation and HIV infection and recruitment locale suggest that risk may be attributable largely to sexual risk. In addition to successful prevention efforts aimed at reducing needle-associated risk, current intervention models aimed at young IDUs should target high-risk neighborhoods and emphasize sexual risk reduction measures, in particular among men who have sex with men.     

New Calicivirus isolated from walrus

The nucleotide sequence and genome organization of a new member of Caliciviridae was determined. Cell culture inoculated with fecal matter from walrus was used to recover fragments of a new virus by Suppression Subtractive Hybridization (SSH). The isolate was identified as a member of the Vesivirus genus of Caliciviridae and designated the name Walrus Calicivirus (WCV). Sets of PCR primers spanning the entire putative genome were designed using known sequences of other vesiviruses. The assembled genome was 8289 nucleotides (nt) long and shared no more than 87% identity with sequences of the other members of the genus Vesivirus. The largest open reading frame (ORF1) between positions 4-5646 encoded a polyprotein. ORF2, found at position 5652-7778, encoded a putative capsid protein. ORF3 overlapped ORF2 and encoded a small basic protein. Comparative analysis of multiple caliciviral capsid proteins was performed to propose a uniform capsid structural organization for this viral family.