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Genetic or pharmaceutical blockade of phosphoinositide 3-kinase p110? prevents chronic rejection of heart allografts.

ABSTRACT: Chronic rejection is the major cause of long-term heart allograft failure, characterized by tissue infiltration by recipient T cells with indirect allospecificity. Phosphoinositol-3-kinase p110? is a key mediator of T cell receptor signaling, regulating both T cell activation and migration of primed T cells to non-lymphoid antigen-rich tissue. We investigated the effect of genetic or pharmacologic inactivation of PI3K p110? on the development of chronic allograft rejection in a murine model in which HY-mismatched male hearts were transplanted into female recipients. We show that suppression of p110? activity significantly attenuates the development of chronic rejection of heart grafts in the absence of any additional immunosuppressive treatment by impairing the localization of antigen-specific T cells to the grafts, while not inducing specific T cell tolerance. p110? pharmacologic inactivation is effective when initiated after transplantation. Targeting p110? activity might be a viable strategy for the treatment of heart chronic rejection in humans.

SUBMITTER: Ying H

PROVIDER: S-EPMC3316549 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Genetic or pharmaceutical blockade of phosphoinositide 3-kinase p110δ prevents chronic rejection of heart allografts.

Ying Huijun H Fu Hongmei H Rose Marlene L ML McCormack Ann M AM Sarathchandra Padmini P Okkenhaug Klaus K Marelli-Berg Federica M FM

PloS one 20120330 3

Chronic rejection is the major cause of long-term heart allograft failure, characterized by tissue infiltration by recipient T cells with indirect allospecificity. Phosphoinositol-3-kinase p110δ is a key mediator of T cell receptor signaling, regulating both T cell activation and migration of primed T cells to non-lymphoid antigen-rich tissue. We investigated the effect of genetic or pharmacologic inactivation of PI3K p110δ on the development of chronic allograft rejection in a murine model in w ...[more]

PMID: 22479345

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Project description:BackgroundVisceral leishmaniasis is the most clinically relevant and dangerous form of human leishmaniasis. Most traditional drugs for treatment of leishmaniasis are toxic, possess many adverse reactions and drug resistance is emerging. Therefore, there is urgent need for identification of new therapeutic targets. Recently, we found that mice with an inactivating knock-in mutation in the p110δ isoform of pi3k, (p110δ(d910a)) are hyper resistant to L. major, develop minimal cutaneous lesion and rapidly clear their parasite. Here, we investigated whether pi3k signaling also regulates resistance to L. donovani, one of the causative agents of visceral leishmaniasis.Methodology/principal findingsWT and p110δ(D910A) mice (on a BALB/c background) were infected with L. donovani. At different time points, parasite burden and granuloma formation were assessed. T and B cell responses in the liver and spleen were determined. In addition, Tregs were expanded in vivo and its impact on resistance was assessed. We found that p110δ(D910A) mice had significantly reduced splenomegaly and hepatomegaly and these organs harbored significantly fewer parasites than those of WT mice. Interestingly, infected p110δ(D910A) mice liver contains fewer and less organized granulomas than their infected WT counterparts. Cells from p110δ(D910A) mice were significantly impaired in their ability to produce cytokines compared to WT mice. The percentage and absolute numbers of Tregs in infected p110δ(D910A) mice were lower than those in WT mice throughout the course of infection. In vivo expansion of Tregs in infected p110δ(D910A) mice abolished their enhanced resistance to L. donovani infection.Conclusions/significanceOur results indicate that the enhanced resistance of p110δ(D910A) mice to L. donovani infection is due to impaired activities of Tregs. They further show that resistance to Leishmania in the absence of p110δ signaling is independent of parasite species, suggesting that targeting the PI3K signaling pathway may be useful for treatment of both visceral and cutaneous leishmaniasis.

Dataset Information

Genetic or pharmaceutical blockade of phosphoinositide 3-kinase p110? prevents chronic rejection of heart allografts.

Publications

Genetic or pharmaceutical blockade of phosphoinositide 3-kinase p110δ prevents chronic rejection of heart allografts.

Similar Datasets

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