HLA class I antibody mediated accommodation of endothelial cells via the activation of PI3K/cAMP dependent PKA pathway

Narayanan, Kishore; Jendrisak, Martin D.; Phelan, D.; Mohanakumar, Thalachallour

doi:10.1016/j.trim.2005.09.005

Cited by 57 publications

(50 citation statements)

References 38 publications

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“…These data are consistent with the results of other studies showing that rapamycin strongly inhibits Akt phosphorylation at Ser 473 (22). Activated Akt can promote cell survival and graft accommodation by upregulating the anti-apoptotic protein Bcl-2 (15,33,45,46) or by maintaining nutrient transporters and receptors through an mTOR-dependent mechanism (47). Based on our previous work showing that anti-MHC class I Abs stimulate Bcl-2 expression through the PI3K/Akt pathway (15), we reasoned that rapamycin may prevent class Imediated up-regulation of Bcl-2.…”

Section: Discussionsupporting

confidence: 93%

HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway

Jindra¹,

Jin²,

Rozengurt

et al. 2008

The Journal of Immunology

145

144

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Anti-HLA Abs have been shown to contribute to the process of transplant vasculopathy by binding to HLA class I molecules expressed by the endothelial and smooth muscle cells of the graft and transducing intracellular signals that elicit cell proliferation. The aim of this study was to determine the role of mammalian target of rapamycin (mTOR) in HLA class I-induced endothelial cell proliferation and to explore in depth the relationship between mTOR complexes and their downstream targets following ligation of HLA class I molecules by anti-HLA Abs. We used small interfering RNA technology to abrogate mTOR, rapamycin-insensitive companion of mTOR (rictor), or regulatory associated protein of mTOR (raptor) to study the function of these gene products to activate proteins involved in MHC class I-induced cell proliferation and survival. Knockdown of mTOR inhibited class I-mediated phosphorylation of proteins downstream of mTOR complex 1 and mTOR complex 2. Furthermore, knockdown of mTOR, rictor, or raptor blocked HLA class I-induced endothelial cell proliferation. Long-term pretreatment with the mTOR inhibitor rapamycin significantly blocked both mTOR-raptor and mTOR-rictor complex formation. Interestingly, rapamycin also blocked class I-induced Akt phosphorylation at Ser473 and Bcl-2 expression. These results support the role of anti-HLA Abs in the process of transplant vasculopathy and suggest that exposure of the graft endothelium to anti-HLA Abs may promote proliferation through the mTOR pathway.

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Section: Discussionsupporting

confidence: 93%

HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway

Jindra¹,

Jin²,

Rozengurt

et al. 2008

The Journal of Immunology

145

144

View full text Add to dashboard Cite

show abstract

“…Bcl-2 is an antiapoptotic protein and a marker of accommodation in allografts and xenografts (5,6,10,13,15). The present study confirms and extends the evidence that anti-MHC class I Abs can stimulate phosphorylation of Akt at Ser 473 and expression of Bcl-2 that have the potential to promote accommodation.…”

Section: Discussionsupporting

confidence: 84%

“…Ligation of MHC class I molecules on cultured EC induces tyrosine phosphorylation of Src family protein tyrosine kinases, c-Src, Fyn, and the focal adhesion proteins focal adhesion kinase (FAK) and paxillin (14). Class I-mediated activation of FAK triggers a prosurvival signaling cascade, resulting in the activation of the PI3K/ Akt-signaling pathway and up-regulation of the antiapoptotic proteins Bcl-2 and Bcl-x L (11,13,15,16). Class I-mediated upregulation of antiapoptotic proteins renders endothelial cells refractory to activation and resistant to complement-mediated lysis (11).…”

mentioning

confidence: 99%

Anti-MHC Class I Antibody Activation of Proliferation and Survival Signaling in Murine Cardiac Allografts

Jindra

Hsueh

Hong

et al. 2008

The Journal of Immunology

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Anti-MHC class I alloantibodies have been implicated in the process of acute and chronic rejection because these Abs can bind to endothelial cells and transduce signals leading to the activation of cell survival and proliferation pathways. To characterize the role of the MHC class I-signaling pathway in the pathogenesis of Ab-mediated rejection, we developed a mouse vascularized heterotopic cardiac allograft model in which B6.RAG1 KO hosts (H-2Kb/Db) received a fully MHC-incompatible BALB/c (H-2Kd/Dd) heart transplant and were passively transfused with anti-donor MHC class I Ab. We demonstrate that cardiac allografts of mice treated with anti-MHC class I Abs show characteristic features of Ab-mediated rejection including microvascular changes accompanied by C4d deposition. Phosphoproteomic analysis of signaling molecules involved in the MHC class I cell proliferation and survival pathways were elevated in anti-class I-treated mice compared with the isotype control-treated group. Pairwise correlations, hierarchical clustering, and multidimensional scaling algorithms were used to dissect the class I-signaling pathway in vivo. Treatment with anti-H-2Kd Ab was highly correlated with the activation of Akt and p70S6Kinase (S6K). When measuring distance as a marker of interrelatedness, multidimensional scaling analysis revealed a close association between members of the mammalian target of rapamycin pathway including mammalian target of rapamycin, S6K, and S6 ribosomal protein. These results provide the first analysis of the interrelationships between these signaling molecules in vivo that reflects our knowledge of the signaling pathway derived from in vitro experiments.

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“…The mechanisms of this proposed accommodation are subject to ongoing debate, and amongst others, disruption of normal signal transduction, attenuation of cellular adhesion, the prevention of apoptosis (13), delayed T cell help (14) and the activation of the PI3K/cAMP-dependent PKA pathway have been suggested (15). We feel that the additional cost of this treatment could be justified by the prospect of a live-saving therapy for high-urgency blood group O recipients.…”

Section: Begun Only Hours After Administering the Anti-cd20 Antibodymentioning

confidence: 98%

Intentional ABO‐Incompatible Lung Transplantation

Strüber¹,

Warnecke²,

Hafer³

et al. 2008

American Journal of Transplantation

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We report on a case of intentional blood group incompatible lung transplantation. A blood group O cystic fibrosis patient was mechanically ventilated and put on interventional lung assist for severe respiratory decompensation. Since timely allocation of a blood group O donor lung was impossible, an AB deceased donor lung rescue allocation was accepted and the transplant performed using a pre-, peri-and postoperative antibody depletion protocol including plasmapheresis, ivIg administration, rituximab and immunoadsorption. Nine months after the transplant the patient is at home and well.

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HLA class I antibody mediated accommodation of endothelial cells via the activation of PI3K/cAMP dependent PKA pathway

Cited by 57 publications

References 38 publications

HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway

HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway

Anti-MHC Class I Antibody Activation of Proliferation and Survival Signaling in Murine Cardiac Allografts

Intentional ABO‐Incompatible Lung Transplantation

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