Frank Miedema

Clinical (Viro-) Immunology

@ Frank Miedema
 

Research interest

• T cell dynamics and homeostasis in children and adults 
• The role of HIV-specific cellular immunity in particular HLA class restricted T cell responses in the pathogenesis of HIV infection

T cell dynamics and homeostasis in health and disease
A long standing line of research is directed towards the pathogenic mechanism by which HIV-1 infection causes depletion of CD4+ T cells, immune deficiency and ultimately AIDS. We have proposed that chronic immune activation may be the driving force for CD4+ T cell depletion characteristic of HIV-infection, because the naive CD4+ T cell pool is lost through activation, and is not easily replenished (Hazenberg et al, Nat Immunol 2000).

We study diverse molecular and cellular parameters that may be useful to follow T-cell production and death rates in healthy and lymphopenic individuals, including telomere length, T-cell receptor excision circles (TRECs), CD31 expression on CD4+ T cells and measures for T cell division and life span such as Ki67 expression and in vivo labelling of dividing T cells using deuterated water. The fundamental questions that we address are related to the contribution of thymic output and peripheral naïve and memory T-cell proliferation in children and adults.

Protective effects of HLA- B57 in HIV infection
We and others have identified strong associations between HLA-B35 and A24 and rapid HIV disease progression and between HLA-B27 and B57 and slow progression. We hypothesize that this HLA-restricted CTL-imposed attenuation could be the major explanation for HLA-disease associations in HIV infection and study this in a well-defined group of monogamous homosexual couples and mother-child pairs with proven sexual or parental transmission of HIV-1 and in participants from the Amsterdam Cohort Studies with rare HLA types.

Key publications

Grand Challenges in the immunology of HIV and AIDS
Miedema, F.
Frontiers in HIV and AIDS 2011

Abundance of early functional HIV-specific CD8+ T cells does not predict AIDS-free survival time.
Schellens IM, Borghans JA, Jansen CA, De Cuyper IM, Geskus RB, van Baarle D, Miedema F.
PLoS ONE. 2008 Jul 23;3(7) :e2745

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 JC, Steingrover R, Prins JM, Kuijpers TW, Wolfs TF, Geelen SP, Vulto I, Lansdorp P, Tesselaar K, Borghans JA, Miedema F.
J Immunol. 2008 Jul 15; 181(2): 1573-81

Growth hormone resurrects adult human thymus during HIV-1 infection
Tesselaar K, Miedema F.
J Clin Invest. 2008 Mar; 118(3) :844-7

HIV-specific CD4+ T cells and viremia: who's in control?
Jansen CA, van Baarle D, Miedema F.
Trends Immunol. 2006 Mar;27(3) :119-24

Prognostic value of HIV-1 Gag-specific CD4+ T-cell responses for progression to AIDS analyzed in a prospective cohort study.
Jansen CA, De Cuyper IM, Hooibrink B, van der Bij AK, van Baarle D, Miedema F.
Blood. 2006 Feb 15;107(4) :1427-33

Thymic output: a bad TREC record. 
Hazenberg MD, Borghans JA, de Boer RJ and Miedema F. 2003
Nat Immunol. Feb;4(2):97-9 

T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events.
Hazenberg MD, Otto SA, de Pauw ES, Roelofs H, Fibbe WE, Hamann D and Miedema F. 2002
Blood. May 1;99(9):3449-53