Clinical Viro-Immunology
Leukocyte dynamics in health and disease: mathematical analysis of experimental data
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José Borghans
Our major line of research encompasses the study of leukocyte dynamics. For decades immunologists have tried to estimate the typical proliferation and death rates of diverse leukocyte populations. Even though these rates are often regarded textbook immunology, estimates easily vary by more than 100-fold. Nevertheless, these turnover rates are a key factor in our understanding of many immunological processes in health and disease. Moreover, we are trying to reveal how human diseases like HIV infection, and therapeutic interventions such as haematopoietic stem-cell transplantation, affect lymphocyte kinetics, but as long as there is controversy about the lymphocyte kinetics in healthy individuals, such questions remain hard to address. Thanks to recent experimental advances, including the application of stable-isotope labelling to measure cells that undergo proliferation, the time is now ripe to determine these rates of leukocyte turnover. However, proper interpretation of the experimental data hinges upon the use of mathematical models; without such models, labelling curves remain merely descriptive and do not yield the quantitative turnover parameters that are needed.
Unfortunately, there is still a large gap between immunologists and mathematicians, which hampers a potentially fruitful synergy between the two fields of research. I have recently been awarded a VIDI-grant from the Netherlands Organization for Scientific Research (NWO) to bridge this gap, and to develop a truly interdisciplinary line of research where experiments are interpreted using mathematical models, which in turn suggest new experiments. This interdisciplinary approach is used to determine the typical rates of cell death and proliferation of different leukocyte populations in healthy subjects, to study how these rates change with age, and to study the contribution of the thymus to the maintenance of the peripheral T-cell pool. Similar studies in patients should reveal how the population dynamics of various leukocyte populations change when the immune system is disturbed by infections such as HIV, or by haematopoietic stem cell transplantation.
A second line of research addresses the role of cytotoxic T-lymphocyte responses and human leukocyte antigen (HLA) molecules in HIV-disease progression. Some HLA types have been associated with delayed HIV-disease progression, while others are clearly associated with rapid progression. We investigate two alternative hypotheses that could explain these associations. The first hypothesis is that common HLA types are no longer protective because HIV has evolved to escape presentation by these HLA molecules. The second hypothesis states that protective HLA molecules present epitopes from constrained HIV-1 regions for which escape mutations reduce the fitness of the virus. In line with the latter hypothesis, our bio-informatic analyses have pointed out that certain HLA molecules provide better protection to HIV disease progression than others because of intrinsic differences in their tendency to bind peptides from the HIV-p24 protein.
Julia Drylewicz, Postdoc
Liset Westera, PhD student
Vera van Hoeven, PhD student
Hilde Spits, PhD student
Anouk Schuren, Masters' student
Former Group Members:
Tendai Mugwagwa, PhD student
Rogier van Gent, PhD student
Nienke Vrisekoop, PhD student
Ingrid Schellens, PhD student
Maintenance of peripheral naive T cells: a mouse-man divide
Den Braber I*, Mugwagwa T*, Vrisekoop N*, Westera L, Mögling R, De Boer AB, Willems N, Schrijver EHR, Spierenburg G, Gaiser K, Mul E, Otto SA, Ruiter AFC, Ackermans MT, Miedema F, Borghans JA*, De Boer RJ*, Tesselaar K*
Immunity (in press)
Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration?van Gent R, Schadenberg AW, Otto SA, Nievelstein RA, Sieswerda GT, Haas F, Miedema F, Tesselaar K, Jansen NJ, Borghans JA.
Blood. 2011 Jul 21;118(3):627-34. Epub 2011 May 31
Loss of HIV-1-derived cytotoxic T lymphocyte epitopes restricted by protective HLA-B alleles during the HIV-1 epidemic.
Schellens IM, Navis M, van Deutekom HW, Boeser-Nunnink B, Berkhout B, Kootstra N, Miedema F, Keşmir C, Schuitemaker H, van Baarle D, Borghans JA.
AIDS. 2011 Sep 10;25(14):1691-1700.
Lymphocyte kinetics in health and disease
Asquith B, Borghans JAM, Ganusov VV & Macallan DC (2009)
Trends in Immunology 30, 182-189.
Restoration of the CD4 T cell compartment after long-term highly active antiretroviral therapy without phenotypical signs of accelerated immunological aging.
Vrisekoop N, Van Gent R, De Boer AB, Otto SA, Borleffs JCC, Steingrover R, Prins JM, Kuijpers TW, Wolfs TFW, Geelen SPM, Vulto I, Lansdorp P, Tesselaar K, Borghans JAM & Miedema F (2008)
J. Immunol. 181, 1573-1581.
An unanticipated lack of consensus cytotoxic T lymphocyte epitopes in HIV-1 databases: The contribution of prediction programs.
Schellens IMM, Keşmir C, Miedema F, Van Baarle D & Borghans JAM (2008)
AIDS 22, 33-37.
Sparse production but preferential incorporation of recently produced naive T cells in the human peripheral pool.
Vrisekoop N, Den Braber I, De Boer AB, Ruiter AFC, Ackermans MT, Van der Crabben SN, Schrijver EHR, Spierenburg G, Sauerwein HP, Hazenberg MD, De Boer RJ, Miedema F, Borghans JAM & Tesselaar K (2008)
Proc. Natl. Acad. Sci. USA 105, 6115-6120.
HLA alleles associated with slow progression to AIDS truly prefer to present HIV-1 p24Borghans JAM, Molgaard A, De Boer RJ & Keşmir C (2007)
PLoS ONE 2, e920.
Quantification of T-cell dynamics: From telomeres to DNA labelling.
Borghans JAM & De Boer RJ (2007)
Imm. Rev. 216, 35-47.
Early determinants of long-term T-cell reconstitution after hematopoietic stem cell transplantation for severe combined immunodeficiencyBorghans JAM, Bredius RG, Hazenberg MD, Roelofs H, Jol-van der Zijde EC, Heidt J, Otto SA, Kuijpers TW, Fibbe WE, Vossen JM, Miedema F & van Tol MJ (2006)
Blood 108, 763-9.
T cell homeostasis: Thymus regeneration and peripheral T cell restoration in mice with a reduced fraction of competent precursors.
Almeida AR, Borghans JAM & Freitas AA (2001)
J. Exp. Med. 194, 591-600.
2008-2013 Aspasia grant
Netherlands Organization for Scientific Research (NWO)
2008-2013 VIDI grant
Netherlands Organization for Scientific Research (NWO)
Leukocyte dynamics in health and disease: mathematical analysis of experimental data.
2008-2012 Meervoud grant
Netherlands Organization for Scientific Research (NWO)
Studying lymphocyte dynamics by mathematical modelling of experimental data.
2009-2013 Grant for a PhD student
Landsteiner Foundation for Blood Transfusion Research
Leukocyte dynamics in healthy and stem-cell transplanted individuals.
2010-2014 Grant for a PhD student
AIDS Foundation Netherlands
Unraveling the contribution of cytotoxic T-lymphocytes to the delay of HIV-disease progression
2010-2014 Grant for a PhD student
Netherlands Asthma Foundation (NAF)
The lifespan of human neutrophils, eosinophils and basophils under homeostatic and allergic
asthmatic conditions in vivo
2010-2011 Seeding Grant
Infection & Immunity Center Utrecht
The lifespan of human neutrophils, eosinophils and basophils under homeostatic and allergic
asthmatic conditions in vivo
This work is performed in strong collaboration with Kiki Tesselaar and Rob de Boer