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.