Immunological synapses are the recently characterized microanatomical structures that underlie immune cellular interactions. Establishment of immunological synapses between CTLs and infected or malignant astrocytes precedes the elimination of these astrocytes from the brain. How individual CTL target cells respond to T cell attack remains poorly understood. We have evidence suggesting that infected astrocytes respond in an active manner to the T cell attack. Our data suggests that target infected astrocytes change from multipolar to unipolar cells, i.e. they adopt a novel polarized phenotype that appears to include a reorganization of the cytoskeleton and intracellular organelles. We will test whether this active cellular reorganization could influence the ultimate outcome of the T cell attack, e.g. death or survival of infected astrocytes. In this application we will test the hypothesis that both infected astrocytes and tumor glioma cells respond in an active manner to T cell attack, and that this response is induced by a T cell-dependent activation of a Rho-GTPase signaling pathway. We will study the astrocyte responses to T cell attack in vivo and in vitro, and analyze the molecular signaling pathways underlying these responses. We believe that understanding the cellular and molecular mechanisms by which infected and malignant astrocytes respond to T cell attack should lead to better ways to eliminate neurological viral infections and brain tumors, enhance therapeutic transgene expression from gene therapy viral vectors, or protect the brain from autoimmune attack. To do so, we propose to explore the cellular and molecular basis of glial cell responses to immune attack both in vivo and in vitro in three Specific Aims.
Specific Aim 1 will test the hypothesis that formation of immunological synapses leads to the polarization of infected astrocytes and that this is dependent on the activation of a Rho-GTPase pathway;
Specific Aim 2 will test whether CTL signaling at mature immunological synapses in vivo between anti-viral T cells and infected astrocytes effectively leads to the death of infected astrocytes, or whether astrocytes can withstand such an attack;
and Specific Aim 3 will test the hypothesis that the effects of anti- tumor T cells on glioma cells are mediated through the formation of immunological synapses.
Immunological synapses form in vivo between antiviral CTLs, and virally infected or malignant astrocytes causing a reorganization of their cellular structure. We believe this response influences the ultimate outcome of the T cell attack, e.g. death or survival of infected or tumor glial cells. We believe that understanding the cellular and molecular mechanisms by which infected and malignant astrocytes respond to T cell attack should lead to better ways of eliminating neurological viral infections and brain tumors, enhance therapeutic transgene expression from gene therapy viral vectors, or protect the brain in cases of autoimmune attack.
|Lowenstein, Pedro R; Castro, Maria G (2016) Multiple Expressed Endogenous Glioma Epitopes as Novel Vaccines for Gliomas. Clin Cancer Res 22:4760-4762|
|Kamran, Neha; Calinescu, Alexandra; Candolfi, Marianela et al. (2016) Recent advances and future of immunotherapy for glioblastoma. Expert Opin Biol Ther 16:1245-64|
|Lowenstein, P R; Castro, M G (2016) The Long and Winding Road: From the High-Affinity Choline Uptake Site to Clinical Trials for Malignant Brain Tumors. Adv Pharmacol 76:147-73|
|Kamran, Neha; Chandran, Mayuri; Lowenstein, Pedro R et al. (2016) Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy. Clin Immunol :|
|Kamran, Neha; Candolfi, Marianela; Baker, Gregory J et al. (2016) Gene Therapy for the Treatment of Neurological Disorders: Central Nervous System Neoplasms. Methods Mol Biol 1382:467-82|
|Koschmann, Carl; Calinescu, Anda-Alexandra; Nunez, Felipe J et al. (2016) ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Sci Transl Med 8:328ra28|
|Calinescu, Alexandra A; Yadav, Viveka Nand; Carballo, Erica et al. (2016) Survival and proliferation of neural progenitor derived glioblastomas under hypoxic stress is controlled by a CXCL12/CXCR4 autocrine positive feedback mechanism. Clin Cancer Res :|
|Calinescu, Anda-Alexandra; Kamran, Neha; Baker, Gregory et al. (2015) Overview of current immunotherapeutic strategies for glioma. Immunotherapy 7:1073-104|
|Lowenstein, Pedro R; Castro, Maria G (2015) Glioma trials and viral tribulations: can anything be concluded from non-controlled trials? J Neurol Neurosurg Psychiatry 86:125|
|Calinescu, Anda-Alexandra; NÃºÃ±ez, Felipe Javier; Koschmann, Carl et al. (2015) Transposon mediated integration of plasmid DNA into the subventricular zone of neonatal mice to generate novel models of glioblastoma. J Vis Exp :|
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