The Lehner Lab introduced Immunology nationally and globally to investigate the mechanism and prevention of dental and oral diseases. Initially they studied dental caries and periodontal disease, preventing Streptococcus mutans and Porphyromonas gingivalis colonisation, leading to clinical trials. Now they investigate stress agents in HIV therapeutic and preventative vaccination and clinical trials.
People
Professor of Basic and Applied Immunology
Projects
Preventative and therapeutic vaccines to HIV or SIV require effective innate immune responses and CD4+ memory stem cells
The most successful smallpox vaccine demonstrates a broad spectrum of immune responses. We followed this principle and utilised oxidative stress agents to stimulate 4 anti-HIV immune pathways; homeostatic, type 1 IFN, inflammasome and HSP70-TLR4 in macaques and humans. We linked HSP70 to HIVgp140 and a stress agent to stimulate DC co-cultured with autologous PBMC. Three pathways were demonstrated by upregulation of IL-15, IFNαβ and IL-1β, and the corresponding receptors. Vaginal immunization in women with HIVp140 linked to HSP70 inhibited HIV-1 by innate and T cell immune responses and generated CD4+ memory stem cells. Specific antibodies were not induced but adding an enhancing agent elicited broadly neutralising HIV-1 antibodies. The mechanism of vaccination can now be expressed in terms of the 3 immune pathways and CD4+ memory stem cells.
Gene expression and DNA methylation of CD4+ stem, central and effector memory T cells stimulated by a stress agent
Gene expression in primary human CD4+ T memory stem (TSCM), central memory (CM) and effector memory (EM) cells were studied with Naïve cells, in the steady state and after stimulation with a stress agent. PCR arrays of selected genes showed a significant decreased expression between TSCM and CM cells, followed by an increase in EM cells. Stimulation with the stress agent upregulated 6 genes in Naïve CD4+ T cells, 4 genes in TSCM cells, 4 genes in CM cells and 1gene in EM cells. Genome-wide analysis of DNA methylation was then studied, to examine the epigenetic landscapes in these populations. Principal component analysis demonstrated a cell-type specific pattern of methylation in the 4 cell populations. Overall, IRFs are likely to be involved in sequential differentiation of Naïve to TSCM, CM and EM CD4+ T cells. TSCM cells were also demonstrated first time following human vaccination.
Comparative immunological study of non-specific with specific stimulation of primary human stem, central and effector T cells
We demonstrated that stimulation with non-specific stress agents induce 3 memory subsets of CD4+ T cell and this was compared with the specific PPD antigen. The CD4+ CD45RO+ or CD45RO- T memory subsets of cells require receptors for the homeostatic, inflammasome and TCR pathways. We treated DC with anti-IL-15 antibodies to inhibit the homeostatic, IL-1β receptor inhibitor the inflammasome and ZAP70 the TCRs pathways, assayed by the proliferative response. The results suggest a differential engagement of the 3 receptors; none by naïve cells, all 3 receptors by stress stimulated TSCM, CM and EM cells but none by PPD stimulation of IL-15, IL-1R1 or ZAP70 inhibitors. The stress agent or PPD stimulated CM and EM cells were engaged by IL-15 and ZAP70 inhibitors. Importantly, significant correlation was found between the stress agent and PPD stimulated proliferation (r=0.651, p=0.004). Arsenic trioxide stress agent combined with ART may eradicate latent HIV in macaques.
Publications
Awards
Awards:
- Life honorary Fellowship of the Royal Society of Medicine (2010).
- Behcet award in recognition of outstanding contribution to the field of Behcet’s disease by the Society for Research in Rheumatology (Turkey, 2010).
- Invitation to give the Distinguished Lecture at the International Association of Dental Research (IADR) in Barcelona (2010)
- Special paper published by Stephen Challacombe in J. Dent. Research, 2013 entitled “Professor Thomas Lehner, Archetypal Translational Scientist”.
Grants:
Thomas Lehner was discouraged to apply for grants over the past 2 years in view of the KCL new spin-out company proposed and based on my HIV-AIDS vaccine studies, for which 2 patents have been submitted in 2017. The approval for the spin-out proposal was prepared by Mike Shaw and approved by Chris Mottershead (Senior Vice-president Quality, Strategy & Innovation) and Steve Large (Vice-President Finance) in 1997.
- Advanced Immunization Technologies (European Union, ADITEC).
Lehner and Y. Wang. 2011-2016 £168,000. - The Henry M Jackson Foundation for AMM (RV144) to investigate the mechanism of the successful Thailand HIV vaccine.
Lehner 2010-2013 $327,360. - Grand Challenges Explorations grant of the Gates Foundation
Peters and T Lehner 2010-2012 $100,000. - Mucosal vaccine strategy against HIV, utilizing innate and adaptive immunity. Grant by the Gates Foundation.
Lehner and directing an International Consortium 2007-2012 $5,761,970. - Combined microbicidal-immunizing strategy against SIV and HIV infection (Allomicrovac. European Union).
Lehner 2007-2011 £261,482 - Mucosal Vaccines for Poverty Related Diseases (MUVAPRED, European Union)
T. Lehner 2003 - 2010 £539,109.00
Activities
Activity
1.Thomas Lehner was appointed to the Editorial Board of Nature Research, Scientific Reports 2018-onwards. He assess the submitted papers, firstly whether they should be reviewed and if so to appoint 2-3 expert reviewers. Secondly, on the basis of the reports he takes the decision whether to reject or accept the paper, subject to revisions suggested by the reviewers. 2.Invitations to lecture at the International Meetings of the Institute of Human Virology in Baltimore, Maryland; 2014, 2015, 2016, 2017. 3. Member of the Scientific Committee of the Institute of Virology of the University of Maryland, (2007 to 2012). 4. Member of the Steering Committee of the Gates Foundation Collaboration for AIDS Vaccine Research (CAVD, 2006 to 2011). 5. External Scientific Advisor to the Gates Foundation (2007-2011). 6. He was invited by the Chinese Academy of Sciences to adjudicate on the present vaccine studies and advise on future vaccine investigations at the Guangzhou Institute of Biomedicine and Health (2015). He was the only non-Chinese scientist of the appointed committee of 10 scientists assessing about 25 presentations by Chinese medical scientists. This was followed by detailed recommendation on future vaccine studies. 7. He was invited as “The Honoured Guest” to present the Plenary Lecture and chair the 21st World Congress on “Vaccines, Vaccination & Immunization“at Vienna, Austria in 2017. 8. He was invited to present a paper at the 9th Blizzard Institute HIV Symposium 2017 on “A novel mechanism of memory stem cells in HIV infection”.
Intellectual Property-Patents (King's College London)
Two patent applications have been filed relating to compositions, methods and uses of prophylactic and therapeutic KCL vaccines in the prevention and treatment of HIV-1 infections in women and men. Covered in the claims, among others, are: 1. Various vaccine compositions primarily comprising: An HIV envelope glycoprotein and immunogenic fragments or immunogenic derivatives thereof, conjugated to a heat shock protein; CC chemokine receptor type 5 (CCR5) protein and immunogenic fragments or immunogenic derivatives thereof; plus either one of two enhancing agents that are currently used in clinical practice. 2. Also covered are methods of providing prophylaxis in HIV infections, as well as methods of treating HIV infections. Patent filings were made to the UK Intellectual Property Office (UKIPO) and were allotted a filing date of 9 November 2018. We are projecting an earliest expiry for these patent filings in the 2038 timeframe.
Publicty
The London Times published within one month in 2017 two of Prof Lehner's letters formally from King's College London. One was entitled ‘Controlled Aid’ and the 2nd was ‘Higg’s Bosom Value’.
People
Professor of Basic and Applied Immunology
Projects
Preventative and therapeutic vaccines to HIV or SIV require effective innate immune responses and CD4+ memory stem cells
The most successful smallpox vaccine demonstrates a broad spectrum of immune responses. We followed this principle and utilised oxidative stress agents to stimulate 4 anti-HIV immune pathways; homeostatic, type 1 IFN, inflammasome and HSP70-TLR4 in macaques and humans. We linked HSP70 to HIVgp140 and a stress agent to stimulate DC co-cultured with autologous PBMC. Three pathways were demonstrated by upregulation of IL-15, IFNαβ and IL-1β, and the corresponding receptors. Vaginal immunization in women with HIVp140 linked to HSP70 inhibited HIV-1 by innate and T cell immune responses and generated CD4+ memory stem cells. Specific antibodies were not induced but adding an enhancing agent elicited broadly neutralising HIV-1 antibodies. The mechanism of vaccination can now be expressed in terms of the 3 immune pathways and CD4+ memory stem cells.
Gene expression and DNA methylation of CD4+ stem, central and effector memory T cells stimulated by a stress agent
Gene expression in primary human CD4+ T memory stem (TSCM), central memory (CM) and effector memory (EM) cells were studied with Naïve cells, in the steady state and after stimulation with a stress agent. PCR arrays of selected genes showed a significant decreased expression between TSCM and CM cells, followed by an increase in EM cells. Stimulation with the stress agent upregulated 6 genes in Naïve CD4+ T cells, 4 genes in TSCM cells, 4 genes in CM cells and 1gene in EM cells. Genome-wide analysis of DNA methylation was then studied, to examine the epigenetic landscapes in these populations. Principal component analysis demonstrated a cell-type specific pattern of methylation in the 4 cell populations. Overall, IRFs are likely to be involved in sequential differentiation of Naïve to TSCM, CM and EM CD4+ T cells. TSCM cells were also demonstrated first time following human vaccination.
Comparative immunological study of non-specific with specific stimulation of primary human stem, central and effector T cells
We demonstrated that stimulation with non-specific stress agents induce 3 memory subsets of CD4+ T cell and this was compared with the specific PPD antigen. The CD4+ CD45RO+ or CD45RO- T memory subsets of cells require receptors for the homeostatic, inflammasome and TCR pathways. We treated DC with anti-IL-15 antibodies to inhibit the homeostatic, IL-1β receptor inhibitor the inflammasome and ZAP70 the TCRs pathways, assayed by the proliferative response. The results suggest a differential engagement of the 3 receptors; none by naïve cells, all 3 receptors by stress stimulated TSCM, CM and EM cells but none by PPD stimulation of IL-15, IL-1R1 or ZAP70 inhibitors. The stress agent or PPD stimulated CM and EM cells were engaged by IL-15 and ZAP70 inhibitors. Importantly, significant correlation was found between the stress agent and PPD stimulated proliferation (r=0.651, p=0.004). Arsenic trioxide stress agent combined with ART may eradicate latent HIV in macaques.
Publications
Awards
Awards:
- Life honorary Fellowship of the Royal Society of Medicine (2010).
- Behcet award in recognition of outstanding contribution to the field of Behcet’s disease by the Society for Research in Rheumatology (Turkey, 2010).
- Invitation to give the Distinguished Lecture at the International Association of Dental Research (IADR) in Barcelona (2010)
- Special paper published by Stephen Challacombe in J. Dent. Research, 2013 entitled “Professor Thomas Lehner, Archetypal Translational Scientist”.
Grants:
Thomas Lehner was discouraged to apply for grants over the past 2 years in view of the KCL new spin-out company proposed and based on my HIV-AIDS vaccine studies, for which 2 patents have been submitted in 2017. The approval for the spin-out proposal was prepared by Mike Shaw and approved by Chris Mottershead (Senior Vice-president Quality, Strategy & Innovation) and Steve Large (Vice-President Finance) in 1997.
- Advanced Immunization Technologies (European Union, ADITEC).
Lehner and Y. Wang. 2011-2016 £168,000. - The Henry M Jackson Foundation for AMM (RV144) to investigate the mechanism of the successful Thailand HIV vaccine.
Lehner 2010-2013 $327,360. - Grand Challenges Explorations grant of the Gates Foundation
Peters and T Lehner 2010-2012 $100,000. - Mucosal vaccine strategy against HIV, utilizing innate and adaptive immunity. Grant by the Gates Foundation.
Lehner and directing an International Consortium 2007-2012 $5,761,970. - Combined microbicidal-immunizing strategy against SIV and HIV infection (Allomicrovac. European Union).
Lehner 2007-2011 £261,482 - Mucosal Vaccines for Poverty Related Diseases (MUVAPRED, European Union)
T. Lehner 2003 - 2010 £539,109.00
Activities
Activity
1.Thomas Lehner was appointed to the Editorial Board of Nature Research, Scientific Reports 2018-onwards. He assess the submitted papers, firstly whether they should be reviewed and if so to appoint 2-3 expert reviewers. Secondly, on the basis of the reports he takes the decision whether to reject or accept the paper, subject to revisions suggested by the reviewers. 2.Invitations to lecture at the International Meetings of the Institute of Human Virology in Baltimore, Maryland; 2014, 2015, 2016, 2017. 3. Member of the Scientific Committee of the Institute of Virology of the University of Maryland, (2007 to 2012). 4. Member of the Steering Committee of the Gates Foundation Collaboration for AIDS Vaccine Research (CAVD, 2006 to 2011). 5. External Scientific Advisor to the Gates Foundation (2007-2011). 6. He was invited by the Chinese Academy of Sciences to adjudicate on the present vaccine studies and advise on future vaccine investigations at the Guangzhou Institute of Biomedicine and Health (2015). He was the only non-Chinese scientist of the appointed committee of 10 scientists assessing about 25 presentations by Chinese medical scientists. This was followed by detailed recommendation on future vaccine studies. 7. He was invited as “The Honoured Guest” to present the Plenary Lecture and chair the 21st World Congress on “Vaccines, Vaccination & Immunization“at Vienna, Austria in 2017. 8. He was invited to present a paper at the 9th Blizzard Institute HIV Symposium 2017 on “A novel mechanism of memory stem cells in HIV infection”.
Intellectual Property-Patents (King's College London)
Two patent applications have been filed relating to compositions, methods and uses of prophylactic and therapeutic KCL vaccines in the prevention and treatment of HIV-1 infections in women and men. Covered in the claims, among others, are: 1. Various vaccine compositions primarily comprising: An HIV envelope glycoprotein and immunogenic fragments or immunogenic derivatives thereof, conjugated to a heat shock protein; CC chemokine receptor type 5 (CCR5) protein and immunogenic fragments or immunogenic derivatives thereof; plus either one of two enhancing agents that are currently used in clinical practice. 2. Also covered are methods of providing prophylaxis in HIV infections, as well as methods of treating HIV infections. Patent filings were made to the UK Intellectual Property Office (UKIPO) and were allotted a filing date of 9 November 2018. We are projecting an earliest expiry for these patent filings in the 2038 timeframe.
Publicty
The London Times published within one month in 2017 two of Prof Lehner's letters formally from King's College London. One was entitled ‘Controlled Aid’ and the 2nd was ‘Higg’s Bosom Value’.
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Professor of Basic and Applied Immunology
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Professor Thomas Lehner
Centre for Host-Microbiome Interactions
Floor 17, Tower Wing
Guy's Hospital