Different types of FC γ -receptors are involved in anti-Lewis Y antibody induced effector functions in vitro

Stimulation of monocytes by interaction of monoclonal antibodies (mAbs) with Fc gamma receptors (FcγRs) results in the activation of various monocyte effector functions. In the present investigation we show that the anti-Lewis Y (LeY) anti-tumour mAb ABL 364 and its mouse/human IgG1 chimaera induce both antibody-dependent cellular cytotoxicity (ADCC) and the release of tumour necrosis factor α (TNF-α) during mixed culture of monocytes with LeY+SKBR5 breast cancer cells in vitro. Although anti-LeY mAb-mediated TNF-α release paralleled ADCC activity, cytokine release required a higher concentration of sensitizing mAb than the induction of cytolysis. The determination of the FcγR classes involved in the induction of the distinct effector functions showed that anti-LeY mAb-induced cytolysis was triggered by interaction between anti-LeY mAbs and FcγRI. In contrast, mAb-induced TNF-α release mainly depended on the activation of monocyte FcγRII. Neutralization of TNF-α showed no influence on monocyte ADCC activity towards SKBR5 target cells. Our data indicate an independent regulation of anti-LeY mAb induced effector functions of ADCC and TNF-α release which seemed to be triggered by activation of different types of FcγR. © 2000 Cancer Research Campaig

Expression profile of human Fc receptors in mucosal tissue: implications for antibody-dependent cellular effector functions targeting HIV-1 transmission

The majority of new Human Immunodeficiency Virus (HIV)-1 infections are acquired via sexual transmission at mucosal surfaces. Partial efficacy (31.2%) of the Thai RV144 HIV-1 vaccine trial has been correlated with Antibody-dependent Cellular Cytotoxicity (ADCC) mediated by non-neutralizing antibodies targeting the V1V2 region of the HIV-1 envelope. This has led to speculation that ADCC and other antibody-dependent cellular effector functions might provide an important defense against mucosal acquisition of HIV-1 infection. However, the ability of antibody-dependent cellular effector mechanisms to impact on early mucosal transmission events will depend on a variety of parameters including effector cell type, frequency, the class of Fc-Receptor (FcR) expressed, the number of FcR per cell and the glycoslyation pattern of the induced antibodies. In this study, we characterize and compare the frequency and phenotype of IgG (CD16 [FcγRIII], CD32 [FcγRII] and CD64 [FcγRI]) and IgA (CD89 [FcαR]) receptor expression on effector cells within male and female genital mucosal tissue, colorectal tissue and red blood cell-lysed whole blood. The frequency of FcR expression on CD14+ monocytic cells, myeloid dendritic cells and natural killer cells were similar across the three mucosal tissue compartments, but significantly lower when compared to the FcR expression profile of effector cells isolated from whole blood, with many cells negative for all FcRs. Of the three tissues tested, penile tissue had the highest percentage of FcR positive effector cells. Immunofluorescent staining was used to determine the location of CD14+, CD11c+ and CD56+ cells within the three mucosal tissues. We show that the majority of effector cells across the different mucosal locations reside within the subepithelial lamina propria. The potential implication of the observed FcR expression patterns on the effectiveness of FcR-dependent cellular effector functions to impact on the initial events in mucosal transmission and dissemination warrants further mechanistic studies

Origin of microsatellite instability in gastric cancer.

Microsatellite instability (MSI) is observed in 13-44% of gastric carcinoma. The etiology of MSI in gastric carcinoma has not been clearly defined. To assess the role of mismatch repair in the development of MSI in gastric cancer, expression of hMSH2 and hMLH1 was explored. We examined 117 gastric carcinomas for MSI and observed instability at one or more loci in 19 (16%) of these tumors. Of the 19 tumors with MSI, nine exhibited low-rate MSI (MSI-L) with instability at 33% of loci examined. Immunohistochemical staining for hMLH1 and hMSH2 was performed on eight of the tumors with MSI-H, five with MSI-L, and 15 tumors without MSI. All eight tumors with MSI-H showed loss of staining for either hMLH1 (n = 5) or hMSH2 (n = 3). In contrast, tumors with MSI-L or without MSI all showed normal hMSH2 and hMLH1 protein expression patterns. Moreover, all eight of the tumors with MSI-H also showed instability at BAT-26, whereas none of the MSI-L tumors or tumors without instability showed instability at BAT-26. These findings suggest that the majority of high-level MSI in gastric cancer is associated with defects of the mismatch repair pathway. Although larger studies are needed, BAT-26 appears to be a sensitive and specific marker for the MSI-H phenotype in gastric carcinoma

Air Displacement Plethysmography versus Dual-Energy X-Ray Absorptiometry in Underweight, Normal-Weight, and Overweight/Obese Individuals

BACKGROUND:Accurately estimating fat percentage is important for assessing health and determining treatment course. Methods of estimating body composition such as hydrostatic weighing or dual-energy x-ray absorptiometry (DXA), however, can be expensive, require extensive operator training, and, in the case of hydrostatic weighing, be highly burdensome for patients. Our objective was to evaluate air displacement plethysmography via the Bod Pod, a less burdensome method of estimating body fat percentage. In particular, we filled a gap in the literature by testing the Bod Pod at the lower extreme of the Body Mass Index (BMI) distribution. FINDINGS:Three BMI groups were recruited and underwent both air displacement plethysmography and dual-energy x-ray absorptiometry. We recruited 30 healthy adults at the lower BMI distribution from the Calorie Restriction (CR) Society and followers of the CR Way. We also recruited 15 normal weight and 19 overweight/obese healthy adults from the general population. Both Siri and Brozek equations derived body fat percentage from the Bod Pod, and Bland-Altman analyses assessed agreement between the Bod Pod and DXA. Compared to DXA, the Bod Pod overestimated body fat percentage in thinner participants and underestimated body fat percentage in heavier participants, and the magnitude of difference was larger for underweight BMI participants, reaching 13% in some. The Bod Pod and DXA had smaller discrepancies in normal weight and overweight/obese participants. CONCLUSIONS:While less burdensome, clinicians should be aware that Bod Pod estimates may deviate from DXA estimates particularly at the lower end of the BMI distribution

Artificial Malware Immunization based on Dynamically Assigned Sense of Self

Abstract. Computer malwares (e.g., botnets, rootkits, spware) are one of the most serious threats to all computers and networks. Most malwares conduct their malicious actions via hijacking the control flow of the infected system or program. Therefore, it is critically important to protect our mission critical systems from malicious control flows. Inspired by the self-nonself discrimination in natural immune system, this research explores a new direction in building the artificial malware immune systems. Most existing models of self of the protected program or system are passive reflection of the existing being (e.g., system call sequence) of the protected program or system. Instead of passively reflecting the existing being of the protected program, we actively assign a unique mark to the protected program or system. Such a dynamically assigned unique mark forms dynamically assigned sense of self of the protected program or system that enables us to effectively and efficiently distinguish the unmarked nonself (e.g., malware actions) from marked self with no false positive. Since our artificial malware immunization technique does not require any specific knowledge of the malwares, it can be effective against new and previously unknown malwares. We have implemented a proof-of-concept prototype of our artificial malware immunization based on such dynamically assigned sense of self in Linux, and our automatic malware immunization tool has successfully immunized real-world, unpatched, vulnerable applications (e.g., Snort 2.6.1 with over 140,000 lines C code) against otherwise working exploits. In addition, our artificial malware immunization is effective against return-to-libc attacks and recently discovered returnoriented exploits. The overall run time performance overhead of our artificial malware immunization prototype is no more than 4%. Keywords Malware Immunization, Control Flow Integrity, Sense of Self.