Research Group Heussler (Malaria I) - Bernhard-Nocht-Institut für ...

Medical Microbiology Section
Role of regulatory T Cells in Onchocerciasis
Zusammenfassung
In den Endemiegebieten unterscheidet man
hauptsächlich die generalisierte Form und die Sowda-Form
von Onchozerkose. Die Immunantwort der
Patienten mit generalisierter Form ist durch die Produktion
der potentiell immunsuppressiven Zytokine
IL-10 und TGF-ß1 charakterisiert. Verschiedene Mechanismen
können solcher Immunsuppression zugrunde
liegen. Neuerdings sind T-Zell-Subgruppen
beschrieben worden, die eine inflammatorische Immunantwort
unterdrücken können, und die durch
die Zytokine IL-10 und TGF-ß1 gekennzeichnet sind.
Das Ziel dieses Projekts war es herauszufinden, ob
solche T-Zell-Populationen auch die mit Onchozerkose
einhergehende Immunsuppression verursachen
könnten. Aus Onchozerkomen (Knoten, die
Wurm enthalten) wurden T-Zellen isoliert und kloniert.
Die Analyse dieser T-Zell-Klone hat gezeigt,
dass es sich um T - regulatorische Zellen mit hoher
Produktion der Zytokine IL-10 und TGF-ß-1 handelt,
die die Mehrheit der Onchocerca volvulus spezifischen
CD4+ Zellen sowohl im Blut (PBMCs) als
auch in Knoten bilden. Diese O.v spezifischen Tr-1
TCC unterdrückten die Proliferation anderer Th1
und Th2 Zellen und exprimierten stark CTLA-4, ein
immunmodulatorisches Molekül, auf ihrer Oberfläche.
Diese Ergebnisse weisen darauf hin, dass in
der Onchozerkose eine Regulation einer anderweitig
auto-aggresiven Immunantwort mit Hilfe von T regulatorischen
Zellen stattfindet.
Summary
It is well known that patients with the generalised form
of onchocerciasis are hyporesponsive to O. volvulus
antigen. The hyperreactive onchocerciasis (so-called
sowda) in contrast, is characterized by a mixture of Th1
and Th2-type pro-inflammatory cytokine responses.
New subsets of T cells, so-called T regulatory cells,
Table I. Cytokine production by onchocercoma-derived TCC*
62
have been described by us which showed suppressor
functions in vitro and in vivo and are characterized by a
predominant production of IL-10 and/or TGF-ß1 cytokines.
The aim of the study was to find out whether
such suppressive T-cell subsets were responsible for
the immunosuppression seen in patients with generalized
onchocerciasis. For this reason we generated O.
volvulus (O.v) specific T cell clones (TCC) from onchocercoma
cells isolated from patients with generalised
disease. We obtained T regulatory 1 cells from
these patients, producing no IL-2 nor IL-4 but substantial
amounts of IL-10 aside from IL-5 and some IFN-γ.
These cells displayed elevated amounts of CTLA-4 after
stimulation and are able to inhibit other T cells in a
mixed culture system, in contrast to Th1 and Th2
clones. This suggests that in a chronic infection like onchocerciasis,
where effector mechanisms involve both
Th1/Th2 responses, downregulation is mediated by another
non-Th1, non-Th2 type of response, termed Tr1.
Introduction
The infection with the filarial nematode Onchocerca
volvulus (O.v) can induce two polar forms of disease:
the hypo-responsive generalized form and the hyper-reactive
sowda form. The first is characterized by high microfilarial
load and presents little pathology compared
to the second, where infected individuals have a strong
Th2 response that leads to effective killing of mf, but at
the expense of severe lymphadenitis and dermatitis.
The still unresolved question is how, in the generalized
form, the adult worms manage to live up to 15 years in
the human body and to produce between 5 and 10 million
microfilariae (mf) during that time. Previous results
showed that the hypo-responsive patients have high levels
of the T-cell derived suppressive cytokines IL-10 and
TGFbeta-1 as measured in peripheral blood mononuclear
cells (PBMCs). The project was aimed at searching
the mechanisms that keep the immune reaction at
bay in the generalized onchocerciasis and to find out
whether specific T-cell subsets were involved.
IL-2 IL-5 IL-10 IFN-gamma
Positive TCC 7 85 106 14
Total number
of clones
130 99 130 99
*cytokines were measured after anti-CD3 and anti CD-28 stimulation