Avid Bioservices Inc (CDMO)

[jazzbeerman]

relevant items from most recent CHAVI update -

(focus on innate immune response to acute HIV infection, and passive antibody therapy taking front seat as a way to see if and what antibodies may be important to elicit...)

- also Haynes most recent conf. poster, from Seattle, Sept 07






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Note Haynes colleague David Pisetsky on the most recent PS work above, since apoptotic debris (PS-exposing microparticles) are now seen as the hurdle to deal with, as explained in the protocol of the most recently initiated CHAVI study, CHAVI 012.




More Pisetsky -




Duke's David Pisetsky, & microparticles....


(Pisetsky is the Director of the dept of rheumatology at Duke, a position formerly held by Barton Haynes)






The release of microparticles by apoptotic cells and their effects on macrophages


Apoptosis: Volume 10, Number 4 / August, 2005



J. H. W. Distler3, L. C. Huber1, A. J. Hueber2, C. F. Reich III3, S. Gay1, O. Distler1 and D. S. Pisetsky3

(1) Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, CH-8091, Switzerland

(2) Department of Rheumatology and Internal Medicine, University of Erlangen-Nuremberg, Erlangen, D-91054, Germany

(3) Division of Rheumatology, Durham VA Hospital and Duke University Medical Center, Durham, NC, USA

Microparticles are small membrane vesicles released from the cell membrane by exogenous budding. To elucidate the interactions of microparticles with macrophages, the effect of microparticles released from Jurkat T cells on RAW 264.7 cells was determined. Microparticles were isolated by differential centrifugation, using FACS analysis with annexin V and cell surface markers for identification. Various inducers of apoptosis increased the release of microparticles from Jurkat cells up to 5-fold. The released microparticles were then cultured with RAW 264.7 cells. As shown by confocal microscopy and FACS analysis, RAW 264.7 macrophages cleared microparticles by phagocytosis. In addition, microparticles induced apoptosis in RAW 264.7 cells in a dose-dependent manner with up to a 5-fold increase of annexin V positive cells and 9-fold increase in caspase 3 activity. Cell proliferation as determined by the MTT test was also reduced. Furthermore, microparticles stimulated the release of microparticles from macrophages. These effects were specific for macrophages, since no apoptosis was observed in NIH 3T3 and L929 cells. These findings indicate that microparticles can induce macrophages to undergo apoptosis, in turn resulting in a further increase of microparticles. The release of microparticles from apoptotic cells may therefore represent a novel amplification loop of cell death.




Pisetsky Dec 06



Autoimmunity. 2006 Dec

Microparticles as mediators of cellular cross-talk in inflammatory disease.


Distler JH, Huber LC, Gay S, Distler O, Pisetsky DS.


Microparticles are a heterogeneous population of membrane-coated vesicles which can be released from virtually all cell types during activation or apoptosis. Release occurs from the cell surface in an exogenous budding process involving local rearrangement of the cytoskeleton. Given their origin, these particles can be identified by staining for cell surface markers and annexin V. As shown in in vitro studies, microparticles may represent a novel subcellular element for intercellular communication in inflammation. Thus, microparticles can transfer chemokine receptors and arachidonic acid between cells, activate complement, promote leukocyte rolling and stimulate the release of pro-inflammatory mediators. Under certain conditions, however, microparticles may also exert anti-inflammatory properties by inducing immune cell apoptosis and the production of anti-inflammatory mediators. Microparticles may play an important role in the pathogenesis of rheumatologic diseases as evidenced by their elevation in diseases such as systemic sclerosis (SSc), systemic vasculitis and antiphospholipid antibody syndrome and correlation with clinical events. A role in inflammatory arthritis is suggested by the finding that leukocyte-derived microparticles induce the production of matrix metalloproteinases and cytokines by synovial fibroblasts. Together, these findings point to novel signaling pathways of cellular cross-talk that may operate along the spectrum of soluble cytokines and mediators of direct cell-cell contact.





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Pisetsky's latest - microparticles, Aug/Sept 2007


Duke's Pisetsky Aug/Sept 2007



Scand J Immunol. 2007 Aug-Sep

The role of microparticles in inflammation and thrombosis.

Ardoin SP, Shanahan JC, Pisetsky DS.

Division of Rheumatology and Immunology, Duke University Medical Center, Medical Research Service, Durham VA Hospital, Durham, NC, USA.


Microparticles (MP) are small membrane-bound vesicles that circulate in the peripheral blood and play active roles in thrombosis, inflammation and vascular reactivity. While MP can be released from nearly every cell type, most investigation has focused on MP of platelet, leucocyte and endothelial cell origin. Cells can release MP during activation or death. Flow cytometry is the usual method to quantify MP; the small size of these structures and lack of standardization in methodology complicate measurement. As MP contain surface and cytoplasmic contents of the parent cells and bear phosphatidylserine, antibodies to specific cell surface markers and annexin V can be used for identification. Through various mechanisms, MP participate in haemostasis and have procoagulant potential in disease. MP contribute to inflammation via their influence on cell-cell interactions and cytokine release, and MP also function in mediating vascular tone. In several disease states characterized by inflammation and vascular dysfunction, MP subpopulations are elevated, correlate with clinical events, and may have important roles in pathogenesis. In the rheumatic conditions such as rheumatoid arthritis and systemic lupus erythematosus, MP are potentially important markers of disease activity and have an increasingly recognized role in immunopathogenesis. It is clear that MP play an important role in atherosclerosis, and study of these structures may provide insight into the link between chronic inflammatory conditions and accelerated atherosclerosis. As biomarkers, MP allow access to usually inaccessible tissues such as the endothelium. Further research will hopefully lead to interventions targeting MP release and function.








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Duke's Bart Haynes, & microparticles....


(Haynes: CHAVI director, Gates CAVD leader, Duke Human Vaccine Institute Director, former director of Duke rheumatology, replaced by ...)



January 07 CHAVI Administrators meeting-





January 07 CHAVI Administrators meeting-







Bart Haynes Gates CAVD webpage- March 07 -









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new from the Pasteur Institute -


TGF-beta in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells
and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus



http://www.nature.com/cdd/journal/v14/n10/abs/4402192a.html


SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8+ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8+ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-beta and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8+ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8+ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/memory CD8+ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1+ expressing cells. Finally, we provide evidence that abrogation of TGF-beta in vitro enhances T-cell proliferation and reduces CD8+ T-cell death.Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS.

Keywords:AIDS, reservoir, IDO, apoptosis, PD-1, p53


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