Clinical Immunology and Allergy
Understanding mechanisms of vaccination
Few medical inventions have affected and saved so many lives as vaccines against infectious diseases. The challenges we are facing today with developing effective vaccines to several of the world’s most serious infectious diseases (HIV-1/AIDS, malaria, tuberculosis) epidemics as well as designing therapeutic vaccines to tumors and/or allergies require a much more intimate understanding of the mechanisms dictating vaccine responses. Our group has had a long term focus on central questions in vaccinology related to how vaccine antigen, adjuvants and viral vaccine vectors influence innate immunity for the induction of strong T cell and B cell responses. A central element in our research is investigating dendritic cells (DCs). They provide the link between the innate response in the periphery and the development of T and B cells responses and their involvement is therefore likely critical to the success of a vaccine.
With a better understanding of how the immune system interacts with vaccines we would be better positioned to select formulations that can elicit stronger immunity, be used at lower doses or with fewer immunizations and are not associated with side effects. We have developed experimental in vitro systems using human primary blood and skin DCs. In addition, we characterize the immune responses in vivo after administration of selected vaccine formulations in animal models. Our strategy is to operate at a powerful infrastructure and leverage our expertise towards a translational research profile aided by our network of strong collaborators and availability to novel reagents and vaccine candidates on a clinical path.
Early in vivo events of vaccine-induced immune responses
When evaluating vaccines, it is common practice to focus on the ultimate outcomes – the elicitation of antibodies (abs) and T cell responses and protection from infection. What occurs between the administration of a vaccine (most often an intramuscular injection) and the development of an immune response is not clear. In this project we characterize and compare the early events after administration using well-defined and widely used antigen/adjuvant vaccine formulations in vivo at the site of injection (muscle) and try to define mechanisms as to why some adjuvants stimulate more powerful immune responses than others. In particular we focus on studying the benchmark adjuvant alum compared to oil-in water emulsion adjuvants and selected toll-like receptor ligands. Such data can make a significant contribution to the understanding of how vaccine-induced responses are developed and can be manipulated in order to improve immunity. This information could also help selecting the most suitable adjuvant to a given vaccine. We are also perfroming a similar investigation on the innate responses induced by recombinant adenoviral vaccine vectors after intramusclular injection. The project is sponsored by a Vinnova and EU Marie Curie grant as well as grant from Vetenskapsrådet to Karin Loré. Parts of the project are performed at the Vaccine Research Center, NIH, Bethesda, MD, USA. Main collaborators are NIH investigators Robert Seder, Richard Koup and Nancy Sullivan plus Novartis Vaccines investigators Derek O’hagan and Anja Seubert.
CD40 targeting as adjuvant for CD8+ T cell responses
The notion of using therapeutic cancer vaccination as a means of treatment has received increased interest over the years. However, a significant challenge is that most vaccines currently available (to infectious diseases) primarily work via elicitation of protective antibodies (Abs) while therapeutic cancer vaccines will need to induce strong cellular immune responses. We have recently found that using an agonistic anti-CD40 Ab (clone 341G2) as a vaccine adjuvant robustly enhanced DC function and induced several fold increase of CD8+ T cell responses. We therefore continue this investigation by focusing on mechanisms by which CD40 targeting can enhance cellular responses and whether there is potential to proceed with such strategy for therapeutic cancer vaccination. Altogether, such data can make a significant contribution to the understanding of how tumor-specific responses can be tailored to be more efficacious and for improving the design of future cancer vaccine formulations. The proposed project aims to both in vivo and an in vitro functionally characterize how CD40 targeting of DCs and other innate immune processes regulate cellular immunity. Main collaborators are Robert Seder, Vaccine Research Center, NIH and Ross Kedl, University of Colorado Denver.
The role of dendritic cells and neutrophils in the induction of vaccine-specific immunity
The project focuses on questions in vaccine development related to specific targeting of 1) protein antigens and 2) adjuvant components to distinct subsets of primary human dendritic cells (DCs), monocytes and neutrophils in order to improve antigen delivery and activation of such cells for the induction of strong adaptive immunity. DCs are essential for stimulation of primary antigen-specific CD4+ T helper cells which in turn are critical for regulating both cellular and humoral immune responses. However, as our in vivo data show that neutrophils are the most abundant cell type that is recruited to the site of vaccine injection, this project is also focused on whether these cells have an important role in the generation of vaccine responses. Understanding the functional patterns of the various innate immune subtypes and and activation signals to optimize vaccine-induced responses is central. An important originality of our studies is that we use physiologically relevant systems including freshly isolated cell subsets from human blood and skin and not in vitro-derived surrogates. This project is sponsored by research grants from Vetenskapsrådet as well as the Swedish Society of Medicine to Karin Loré. Main collaborators are Professor Anna Norrby-Teglund and Assistant professor Anna Smed Sörensen, KI.
Approaches to enhance and broaden B cell responses against HIV-1 Env
The main goal of this proposal is to design and evaluate improved HIV-1 envelope glycoprotein (Env) immunogens to enhance and broaden B cell responses and neutralizing antibodies against HIV-1. We will investigate the impact of the high affinity interaction between Env and primate CD4, which may compromise exposure of the conserved CD4 binding site during vaccination. Since CD4 is a signaling receptor, Env interactions with CD4-expressing primary cells during immunization may affect the function of such cells and this will be addressed. To meet these goals CD4-binding defective soluble Env trimers will be generated and evaluated in vitro and in vivo. We will use new methodology to investigate the evolution of Env-specific memory B cell and plasma cell responses in non-human primates to gain new insights into the quality of B cell responses elicited by state-of-the-art Env immunogens. This project is sponsored by a grant from Swedish International Development Cooperation Agency (SIDA) to Associate Professor Gunilla Karlsson-Hedestam, MTC/KI and Karin Loré. Main collaborators are Gunilla Karlsson-Hedestam and and Investigators Richard T. Wyatt, Scripps Research Institute, IAVI, La Jolla, CA and John Mascola, Vaccine Research Center, NIH, Bethesda, MD.
Defects in human dendritic cell subsets during HIV-1 infection
The ultimate question to be addressed in this study is whether dendritic cells (DCs), which are central in their function to regulate immune responses, are depleted and/or dysfunctional in HIV-1+ individuals. Specifically, we are studying recruitment in situ of distinct human DC subsets to the skin shortly after intradermal antigen exposure. As a model to examine the functional pattern of DCs in a local immune response in the skin, we are utilizing skin punch biopsies taken after PPD (purified protein derivate) or saline injections in clinically well-defined healthy seronegative and HIV-1+ cohorts with documented positive PPD reactions.
Specific questions are:
Do various DC subsets infiltrate the skin after PPD delivery?
Are there marked differences between HIV-1+ and healthy individuals in terms of magnitude of recruitment and phenotypes of DCs in the skin after PPD injection?
Are DC-related effector functions e.g. production of pro-inflammatory cytokines and IFN-a in response to PPD injection deficient in HIV-1 infection?
This project is sponsored by a grant from Läkare mot AIDS forskningsfond to Karin Loré. Main collaborators are Professor Jan Andersson, KI and Professor Robert J. Wilkinson, Clinical Infectious Diseases Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa and MRC National Institute for Medical Research and, Imperial College, London, UK.
Sandgren K, Smed-Sörensen A, Forsell M, Soldemo M, Adams W, Liang F, Perbeck L, Koup RA, Wyatt RT, Karlsson Hedestam GB, Loré K. Human plasmacytoid dendritic cells efficiently capture HIV-1 envelope glycoproteins via CD4 for antigen presentation. J. Immunol. 2013 Jul;191(1):60-9.
Liang F, Bond E, Sandgren K, Smed-Sörensen A, Rangaka M, Lange C, Koup RA, McComsey GA, Lederman MM, Wilkinson RJ, Andersson J, Loré K. Dendritic cell recruitment in response to skin antigen tests in HIV-1-infected individuals correlates with the level of T-cell infiltration. AIDS 2013 Apr;27(7):1071-80.
Adams W, Berenson R, Karlsson Hedestam G, Lieber A, Koup R, Loré K. Attenuation of CD4+ T-cell function by human adenovirus type 35 is mediated by the knob protein. J. Gen. Virol. 2012 Jun;93(Pt 6):1339-44.
Bond E, Liang F, Sandgren K, Smed-Sörensen A, Bergman P, Brighenti S, Adams WC, Betemariam SA, Rangaka MX, Lange C, Wilkinson RJ, Andersson J, Loré K. Plasmacytoid dendritic cells infiltrate the skin in positive tuberculin skin test indurations. J. Invest. Dermatol. 2012 Jan;132(1):114-23.
Smed-Sörensen A, Loré K. Dendritic cells at the interface of innate and adaptive immunity to HIV-1. Curr Opin HIV AIDS 2011 Sep;6(5):405-10.
Gujer C, Sandgren KJ, Douagi I, Adams WC, Sundling C, Smed-Sörensen A, Seder RA, Karlsson Hedestam GB, Loré K. IFN-α produced by human plasmacytoid dendritic cells enhances T cell-dependent naïve B cell differentiation. J. Leukoc. Biol. 2011 Jun;89(6):811-21.
Adams WC, Gujer C, McInerney G, Gall JG, Petrovas C, Karlsson Hedestam GB, Koup RA, Loré K. Adenovirus type-35 vectors block human CD4+ T-cell activation via CD46 ligation. Proc. Natl. Acad. Sci. U.S.A. 2011 May;108(18):7499-504.
Sundling C, O’Dell S, Douagi I, Forsell MN, Mörner A, Loré K, Mascola JR, Wyatt RT, Karlsson Hedestam GB. Immunization with wild-type or CD4-binding-defective HIV-1 Env trimers reduces viremia equivalently following heterologous challenge with simian-human immunodeficiency virus. J. Virol. 2010 Sep;84(18):9086-95.
Sundling C, Forsell M, O’Dell S, Feng Y, Chakrabarti B, Rao S, Loré K, Mascola JR, Wyatt RT, Douagi I, Karlsson Hedestam GB. Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates. J. Exp. Med. 2010 Aug;207(9):2003-17.
Douagi I, Forsell MN, Sundling C, O’Dell S, Feng Y, Dosenovic P, Li Y, Seder R, Loré K, Mascola JR, Wyatt RT, Karlsson Hedestam GB. Influence of novel CD4 binding-defective HIV-1 envelope glycoprotein immunogens on neutralizing antibody and T-cell responses in nonhuman primates. J. Virol. 2010 Feb;84(4):1683-95.
Loré K, Karlsson Hedestam G. Novel adjuvants for B cell immune responses. Curr Opin HIV AIDS 2009 Sep;4(5):441-6.
Bond E, Adams WC, Smed-Sörensen A, Sandgren KJ, Perbeck L, Hofmann A, Andersson J, Loré K. Techniques for time-efficient isolation of human skin dendritic cell subsets and assessment of their antigen uptake capacity. J. Immunol. Methods 2009 Aug;348(1-2):42-56.
Adams WC, Bond E, Havenga MJ, Holterman L, Goudsmit J, Karlsson Hedestam GB, Koup RA, Loré K. Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus-adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN. J. Gen. Virol. 2009 Jul;90(Pt 7):1600-10.
Douagi I, Gujer C, Sundling C, Adams WC, Smed-Sörensen A, Seder RA, Karlsson Hedestam GB, Loré K. Human B cell responses to TLR ligands are differentially modulated by myeloid and plasmacytoid dendritic cells. J. Immunol. 2009 Feb;182(4):1991-2001.
Loré K, Adams WC, Havenga MJ, Precopio ML, Holterman L, Goudsmit J, Koup RA. Myeloid and plasmacytoid dendritic cells are susceptible to recombinant adenovirus vectors and stimulate polyfunctional memory T cell responses. J. Immunol. 2007 Aug;179(3):1721-9.