Avid Bioservices Inc (CDMO)

[jazzbeerman]

As for blocking "pathways"..............

Scientists are saying that PS is the impetus that shifts the immune response away from an antigen-specific response.

I often post papers from the growing body of evidence that discusses this. If I had to pick one that best points to the new "grand unification" perspective of pathogenesis, I suppose this paper by Peter Henson sums it up well.



Immunological Consequences of Apoptotic Cell Phagocytosis

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17591947



Immunological Consequences of Apoptotic Cell Phagocytosis

Abstract

Cells undergo apoptosis in development, tissue homeostasis, and disease and are subsequently cleared by professional and nonprofessional phagocytes. There is now overwhelming evidence that phagocyte function is profoundly altered following apoptotic cell uptake, with consequences for the ensuing innate and adaptive immune response. Pathogens and tumors exploit the changes in macrophage function following apoptotic cell uptake. Here, we will outline the consequences of apoptotic cell phagocytosis and illustrate how apoptotic cells could be used to manipulate the immune response for therapeutic gain.


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Exploitation of Apoptotic Cells by Tumors and Pathogens

In some ways, the most convincing evidence for the anti-inflammatory consequences of apoptotic cell phagocytosis is the exploitation of these immune inhibitory signals by pathogens and tumors to aid their survival. Plasmodium falciparum-infected erythrocytes inhibit the maturation of DCs by binding to CD36, a known recognition receptor for apoptotic cells. Infected DCs still secrete tumor necrosis factor α but fail to activate T cells and secrete interleukin-10.56 This response can be mimicked by antibodies to CD36 or apoptotic cells and suggests that the pathogen and apoptotic cells engage the same pathway regulating DC function. It seems that plasmodium almost inadvertently profits from using the same entry mechanism as apoptotic cells, whereas other pathogens not only exploit recognition mechanism but also profit from the microenvironment created by apoptotic cell phagocytosis. Intense lymphocyte apoptosis occurs in Chagas disease, a debilitating cardiac illness caused by the protozoan Trypanosoma cruzi. In a mouse model of the disease, interaction of apoptotic but not necrotic T lymphocytes with macrophages infected with T. cruzi fuels parasite growth in a manner dependent on prostaglandins, TGF-β, and polyamine biosynthesis.57 Work by Freire-de-Lima et al57 further show that the vitronectin receptor is critical in both apoptotic-cell binding to phagocytes and the induction of prostaglandin E2/TGF-β release and ornithine decarboxylase activity in macrophages. These results suggest that continual lymphocyte apoptosis and phagocytosis of apoptotic cells by macrophages have a role in parasite persistence in the host.

A blunted immune response to rapidly growing tumors is frequently observed and thought to be at least partly mediated by the immune inhibitory effects of apoptotic cell phagocytosis. Reiter et al58 showed that exposure of bone marrow-derived macrophages to apoptotic tumor cells (but not necrotic) tumor cell inhibits their cytotoxicity and nitric oxide production in response to interferon γ and lipopolysaccharide. Furthermore, unstimulated bone marrow-derived macrophages exposed to apoptotic tumor cells enhanced growth of live tumor cells by 40%. Therefore, treatment of cancers with chemotherapy or radiation, which leads to massive tumor cell apoptosis, is likely to inhibit macrophage-mediated antitumor responses.

These examples clearly illustrate the profound effects of apoptotic cell recognition on the outcome of the immune response to pathogens and tumors. It shows that pathogens and tumors use endogenous anti-inflammatory pathways to aid their survival, suggesting possibilities for developing similar avenues to treat inflammatory disease. A recent article by Rossi et al59 establishes that we are already in position to apply this principle to treat experimental lung and joint inflammation. They show that human neutrophils contain functionally active cyclin-dependent kinases (CDKs) and that structurally diverse CDK inhibitors induce caspase-dependent apoptosis and override powerful anti-apoptosis signals from survival factors such as granulocyte-macrophage colony-stimulating factor. Furthermore, the CDK inhibitor R-roscovitine markedly enhances resolution of established neutrophil-dependent inflammation in carrageenan-elicited acute pleurisy, bleomycin-induced lung injury, and passively induced arthritis in mice. In the pleurisy model, the caspase inhibitor zVAD-fmk prevents R-roscovitine-enhanced resolution of inflammation, indicating that this CDK inhibitor augments inflammatory cell apoptosis. Thus, they show that CDK inhibitors enhance the resolution of established inflammation by promoting apoptosis of inflammatory cells.


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Conclusions

Resolution of inflammation is not a passive process but rather an active response to terminate the immune response.60 We show here that the effective recognition and clearance of apoptotic cells is critically important in this process and that this important endogenous mechanism of controlling the immune response is exploited by pathogens and tumors. The challenge for the future is to manipulate effectively and coordinately the clearance of dying cells to develop new therapies for inflammatory and autoimmune disease and prevent inappropriate immune inhibition in the context of pathogens and cancer.



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Evolution has favored pathogenesis that resembles apoptosis.

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