An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination
Tumour immunotherapy is dependent upon activation and expansion of tumour targetting immune cells, known as Cytotoxic T-Lymphocytes (CTLs). Cancer vaccines developed in the past have had limited success and the mechanisms resulting in failure are not well characterised. To elucidate these mechani...
| Main Authors: | , , , |
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| Format: | Journal article |
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Royal Society
2018
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| _version_ | 1826292974156251136 |
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| author | Brown, L Gaffney, E Wagg, J Coles, M |
| author_facet | Brown, L Gaffney, E Wagg, J Coles, M |
| author_sort | Brown, L |
| collection | OXFORD |
| description | Tumour immunotherapy is dependent upon activation and expansion of tumour targetting immune cells, known as Cytotoxic T-Lymphocytes (CTLs). Cancer vaccines developed in the past have had limited success and the mechanisms resulting in failure are not well characterised. To elucidate these mechanisms, we developed a human parameterised, in silico, agent based model of vaccination-driven CTL activation within a clinical short-peptide vaccination context. The simulations predict a sharp transition in the probability of CTL activation, which occurs with variation in the separation rate (or off-rate) of tumour specific immune-response inducing peptides (cognate antigen) from the major histocompatibility class I receptors (MHC-I) of dendritic cells originally at the vaccination site. For peptides with MHC-I off-rates beyond this transition, it is predicted that no vaccination strategy will lead to successful expansion of CTLs. For slower off-rates, below the transition, the probability of CTL activation becomes sensitive to the numbers of dendritic cells and T cells that interact subsequent to dendritic cell migration to the draining lymph node of the vaccination site. Thus, the off-rate is a key determinant of vaccine design. |
| first_indexed | 2024-03-07T03:22:57Z |
| format | Journal article |
| id | oxford-uuid:b80bb612-dfee-4ebe-ab44-8d3112f4ea1c |
| institution | University of Oxford |
| last_indexed | 2024-03-07T03:22:57Z |
| publishDate | 2018 |
| publisher | Royal Society |
| record_format | dspace |
| spelling | oxford-uuid:b80bb612-dfee-4ebe-ab44-8d3112f4ea1c2022-03-27T04:53:11ZAn in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccinationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b80bb612-dfee-4ebe-ab44-8d3112f4ea1cSymplectic Elements at OxfordRoyal Society2018Brown, LGaffney, EWagg, JColes, MTumour immunotherapy is dependent upon activation and expansion of tumour targetting immune cells, known as Cytotoxic T-Lymphocytes (CTLs). Cancer vaccines developed in the past have had limited success and the mechanisms resulting in failure are not well characterised. To elucidate these mechanisms, we developed a human parameterised, in silico, agent based model of vaccination-driven CTL activation within a clinical short-peptide vaccination context. The simulations predict a sharp transition in the probability of CTL activation, which occurs with variation in the separation rate (or off-rate) of tumour specific immune-response inducing peptides (cognate antigen) from the major histocompatibility class I receptors (MHC-I) of dendritic cells originally at the vaccination site. For peptides with MHC-I off-rates beyond this transition, it is predicted that no vaccination strategy will lead to successful expansion of CTLs. For slower off-rates, below the transition, the probability of CTL activation becomes sensitive to the numbers of dendritic cells and T cells that interact subsequent to dendritic cell migration to the draining lymph node of the vaccination site. Thus, the off-rate is a key determinant of vaccine design. |
| spellingShingle | Brown, L Gaffney, E Wagg, J Coles, M An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination |
| title | An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination |
| title_full | An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination |
| title_fullStr | An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination |
| title_full_unstemmed | An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination |
| title_short | An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination |
| title_sort | in silico model of cytotoxic t lymphocyte activation in the lymph node following short peptide vaccination |
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