Linda Klavinskis, PhD FRCPath
Senior Lecturer Immunobiology.
Group Leader, Viral immunology.
Chair, the Medical Research Club
Member of the Postgraduate Research Progress Committee
SSM Co-ordinator ‘Prospects and Challenges in HIV vaccine development’
Lectures on the following courses: Intercalated BSc in Infectious Diseases and Immunobiology; modules in Molecular Immunology, Cell and Tissue Pathology and HIV/AIDS; BSc undergraduate modules in: Viruses and Disease, Immunology of human disease, MSc in Immunology, MSc in Medical Immunology. Personal tutor; Yr 1 and Yr 2 MBBS students, and Intercalated BSc students.
Tel: +44 (0) 20 7188 0151
Fax: +44 (0) 20 7188 3385
Dendritic cells are central to immune regulation because of their roles in inducing protective immunity against pathogens while maintaining tolerance to self antigens. Fundamental to their immune regulatory role is their capacity to integrate qualitatively distinct signals from their environment that de facto inhibit or promote pro-inflammatory immune responses, which may result in vastly different outcomes for the host, ranging from tolerogenic or regulatory responses to protective adaptive Th1, Th2 or Th17 responses. Our laboratory is interested in both understanding and exploiting basic mechanisms by which dendritic cells control innate and adaptive immunity in the context of developing effective adjuvants for clinical use, and vaccines for infectious diseases such as HIV and Influenza A virus..
Within this broad context, our current interests include:
1. Exploring HIV-1 vaccine elicited CD8 T lymphocyte epitope immunondominance with the goal of inducing a broader protective T cell response. We are investigating how the diversity, magnitude and quality of CD8 T cell responses can be enhanced by combinatorial modification and re-arrangement of epitopes within the antigen.
2.Understanding the mechanisms underlying T-cell immunity to influenza virus in order to inform improved vaccine design. These studies also include exploiting vaccine targeting to dendritic cell subsets with the aim of eliciting heterotypic protective T cell immunity to influenza virus.
3.Improving vaccine delivery by a novel transcutaneous vaccine delivery platform. We have developed a simple ‘dissolvable’ microneedle array delivery system, where the vaccine is fabricated within the microneedle matrix, that preserves the immunogenicity of the vaccine antigens and elicits potent systemic and mucosal immune responses equipotent to that induced by conventional injection routes.
Our goals are to exploit this technology by undertaking translational studies in the clinic and also investigate further the role of dendritic cell subsets and stress signals in contributing to the potency of this vaccination platform.
4. Targeted delivery of polymer coated adenoviral vectored vaccines to dendritic cells. We are developing a ‘stealth’ vaccine vector based upon Ad type 5. We are using novel polymers coupled to specific dendritic cell ligands so as to avoid pre-existing immunity to Ad5 and to specifically target the vector to dendritic cell subtypes.
5. Defining the immune potentiating and modulating activity of a novel microbial derived adjuvant identified in our laboratory. We are taking both molecular profiling techniques and cellular approaches, to understand the signaling networks modulated by the novel derived adjuvant in dendritic cells. Our goals are to exploit this adjuvant to (i) enhance CD8 T cell responses against infectious disease and tumour antigens and (ii) re-direct detrimental Th2 responses in allergic disease.
6.Investigating the immunology of the intestine, using ex vivo organ culture systems to address (i) what are the basic features of immune cells in the human healthy intestinal mucosa and (ii) how do cells of the intestinal immune system handle potential pathogens and vaccines and (Iii) how can we enhance this process to enable the design of effective mucosal vaccines.
Bachy V, Hervouet C, Becker PD, Chorro L, Carlin LM, Herath S, Papagatsias T, Barbaroux JB, Oh SJ, Benlahrech A, Athanasopoulos T, Dickson G, Patterson S, Kwon SY, Geissmann F, Klavinskis LS. (2013). Langerin negative dendritic cells promote potent CD8+ T-cell priming by skin delivery of live adenovirus vaccine microneedle arrays. Proc. Natl. Acad. Sci. U S A. 2013 19; 110(8):3041-6
Article highlighted by PNAS (June 18 2013) in their News Feature’ Under the skin of intradermal vaccines’. PNAS. 110 (25), 10049-10051 .
Thoma C, Bachy V, Seaton P, Green N, Greaves D, Klavinskis L, Seymour L, Morrison J. (2013). Adenovirus serotype 11 causes less long-term intraperitoneal inflammation than serotype 5, implications for ova rian cancer therapy. Vi rology. 447 (1-2):74-83
Smyth LA, Hervouet C, Hayday T, Becker PD, Ellis R, Lechler RI, Lombardi G, Klavinskis LS. (2012). Acquisition of MHC: peptide complexes by dendritic cells contributes to the generation of anti-viral CD8+T cell immunity in vivo. J Immunol. 2 012 Sep 1;189(5):2274- 82
Spencer J, Klavinskis LS, Fraser LD. 2012. The human intestinal IgA response: burning questions. Front Immunol. 2012;3:108. Epub 2012 May 11.
Soderquest K, Walzer T, Zafirova B, Klavinskis LS, Vivier E, Lord GM, Martín-Fontecha A. 2011. Cutting edge: CD8+ T cell priming in the absence of NK cells leads to enhanced memory responses. J Immunol. 2011 Mar 15;186(6):3304-8
Harandi AM, Medaglini D, Shattock RJ et al ; Working Group convened by EUROPRISE. 2010. Vaccine adjuvants: a priority for vaccine research. Vaccine ;28(12):2363-6
Benlahrech A, Harris J, Meiser A, Papagatsias T, Hornig J, Hayes P, Lieber A, Athanasopoulos T, Bachy V, Csomor E, Daniels R, Fisher K, Gotch F, Seymour L, Logan K, Barbagallo R, Klavinskis L, Dickson G, Patterson S. (2009). Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1. Proc Natl. Acad Sci U S A. 24;106(47):19940-5.
Cerovic V, Barnes ACG, Jenkins C, Milling S, MacPherson G and Klavinskis L. S. (Feb 2009). Hyporesponsiveness of intestinal dendritic cells to TLR stimulation is limited to TLR4. J. Immunol. 15: 182(4): 2405 – 15.
Article highlighted in Nature (Research News) June 18th 2009 “An infection biologist points out an outstanding issue in mucosal immunology."
Benlahrech A; Donaghy H; Rozis G; Goodier M; Klavinskis L; Gotch F; Patterson S. (Jan 2009). Human NK Cell Up-regulation of CD69, HLA-DR, Interferon gamma Secretion and Cytotoxic Activity by Plasmacytoid Dendritic Cells is Regulated through Overlapping but Different Pathways. SENSORS-BASEL. 9:386-403
Smyth LA, Harker N, Turnbull W, El-Doueik H, Klavinskis L, Kioussis D, Lombardi G, Lechler R.(2008). The relative efficiency of acquisition of MHC: peptide complexes and cross-presentation depends on dendritic cell type. J Immunol. 2008 Sep 1;181(5):3212-20.
Barnes AG, Cerovic V, Hobson P and Klavinskis L.S. 2007. Bacillus subtilis spores: a novel microparticle adjuvant which can instruct a balanced Th1 and Th2 immune response to specific antigen. Eur. J. Immunol. 37(6): 1538-1547.
Peters BS, Janko W, Vardas E, Panayotakopoulos G, Fast P, Schmidt C, Gilmour J, Bogoshi M, Dally L, Klavinskis L, Farah B, Tarragona T, Bart PA, McMichael AJ, Pantaleo G, Hanke T and Bwayo J. 2007. Studies of a prophylactic HIV-1 vaccine candidate based on modified vaccinia virus Ankara (MVA) with and without DNA priming: effects of dosage and route on safety and immunogenicity. Vaccine. 25(11):2120-7.
Yrlid U, Cerovic V, Milling S, Jenkins C, Klavinskis L. S. and MacPherson G. 2006. Plasmacytoid dendritic cells do not migrate in intestinal or hepatic lymph. J. Immunol. 177(9): 6115-21.
Yrlid U, Cerovic V, Milling S, Jenkins C, Klavinskis L. S. and MacPherson G. 2006. A distinct subset of dendritic cells responds selectively to oral TLR7/8 stimulation. Eur. J. Immunol. 36 (10): 2639-48.
Klavinskis L. S. Chapter 45. Nucleic Acid Vaccines. 2006. Topley and Wilsons Microbiology and Microbial Infections - Immunology 10th Edition, Ed. Stefan H E Kaufmann, Michael W Steward , Edward Arnold
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