Notes 20100325.123045 Special Exosomes Tiny Bubbles

From SnOwy - Ed's Wiki Notebook

Contents 1 Abbreviations 2 Notes 3 Exosome Backgrounds 4 Endosomal Origin 5 Discovery 6 Today 7 MHC I Background 8 MHC II Background 9 Dendritic cell derived exosomes (DEX) 10 Dendritic Cell + DEX 11 Future

Abbreviations

• MHC: Major Histocompatibility Complex
• APC: Antigen Presenting Cells

Notes

• immunological significance
• exosome background
• immunology background
• dendritic cell derived exosomes

Exosome Backgrounds

• nanovesicles from endosomes
• 30-100nm diameter circles
• supernatant at 100kG ultracentrifugation
• suite of proteins
• exosomes contain particular proteins
• adhesion molecules on membrane
• MHC molecules on membrane

Endosomal Origin

• exosomes are produced in multivesicular bodies which fuse to plasmalemma to release exosomes
• exosomes MHC may bind with plasmalemma
• exosomes are formed by plasmalemma invagination

Discovery

• transferrin receptor degredation
• RBCs do not have them, instead of lysosomal degredation, these transferrin receptors are launched on exosomes
• 1996 exosomes with MHC II molecules secreted by B cells, stimulated research...
• immune function of exosomes
• especially dendritic cells
• secreted by many (all?) cell types
• can spread prions between cells
• virus spreading (Trojan exosome hypothesis)

Today

• exosomes contain mRNA and microRNA
• transcripts can shuttle between cells!
• shown that the transcripts are actually translated in recipient cells

MHC I Background

• a protein that loads and presents proteins on a cell surface

MHC II Background

• may only be used by antigen-presenting cells
• a T cell will dock with a corresponding MHC and an antigen
• dendritic cells as APCs
• dendritic cells present three signals to T cells -- look up later
• cancer immunotherapy
• tumour cells express antigens that aren't self

Dendritic cell derived exosomes (DEX)

• method: pulsing a dendritic cell with transcripts from a tumour
• result: dendritic cells able to present tumour translations
• allowed killer T cells to now recognize tumour cells
• Thery et al., 2002
• with this method, mouse immune system able to clear away 40% to 60% of transformed tumour cells
• when injected with irrelevant tumour: no protection (negative control OK)
• if athymic: no protection (negative control OK)
• exosomes used to deliver such antigens to the dendritic cells
• Morelli et al., 2004
• Phase I clinical trials underway, Curie, Duke
• Able to get enough DEX in terms of MHC II molecules
• Curie: no T cell response?
• Duke: increased survival time, T cell (1 patient), NK cell activation (1 patient)
• Andre et al., 2004
• immature DEX (iDEX) needed by mature dendritic cells (mDC) to be present
• same in vivo
• many other studies mentioned which varied the treatment and the corresponding antigens etc.,

Dendritic Cell + DEX

• naked peptides degrade too quickly
• DEX are more stable than dendritic cells and can be artificially manufactured
• activates NK cells
• possible activation of more cell mediated immune responses?
• other cells that release exosomes that have immune function
• intestinal epithelial cells (uses MHC II)
• what about the basement membrane?
• secretion of exosomes, T cells can read the exosomes-- easily fits through basement membrane
• macrophages release exosomes carrying PAMPs when they contact pathogens
• mast cells activate B cells and T cells with exosomes?

Future

• DEX vaccines to suppress immune responses
• appears to work in mice to address autoimmune disorders