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

Medical Microbiology Section
Zusammenfassung
T-Zellen spielen eine entscheidende Rolle bei der
Bekämpfung der Malaria und sind sowohl an der
Kontrolle der Leberstadien, als auch an der Kontrolle
der Blutstadien beteiligt. Eine Aktivierung von T-Zellen
während der Leberphase induziert keine Pathologie,
wodurch diese Phase in der Regel ohne Symptome
verläuft. Im Gegensatz dazu wird die Blutphase
von der charakteristischen Symptomatik der
Malaria und der damit verbundenen Pathologie begleitet.
Eine Schlüsselstellung bei der Pathogenese
nehmen dabei T-Zellen ein. Insbesondere Th1-Zellen
und die damit assoziierten Zytokine IFN-γ und TNF-α
scheinen ursächlich an der Pathologie der schweren
Malaria beteiligt zu sein. Aus früheren Arbeiten wissen
wir, dass CTLA-4 (CD152) an der Kontrolle der
T-Zellen beteiligt ist. Dieses Molekül ist ein negativer
Regulator auf der Oberfläche von aktivierten T-Zellen
und wird im Verlauf der Malaria induziert. Eine
Blockade dieses Moleküls in einem Mausmodell der
Malaria führt zwar zu einer verstärkten Aktivierung
von T-Zellen, aber induziert gleichzeitig eine Pathologie
in verschiedenen Organen. Unsere Untersuchungen
haben gezeigt, dass die Expression von CTLA-4
zu einer Kontrolle von T-Zellen in verschiedene Geweben
führen kann und dadurch das Ausmaß der
Entzündung kontrolliert wird.
CTLA-4 dependent regulation
of T cells during Malaria
52
Summary
T cells were shown to play an important role in the control
of malaria during the liver stage as well as during
the blood stage of the disease. An activation of T cells
during the liver phase is not associated with any symptoms,
whereas an activation of T cells during the blood
stage contribute to the typical symptoms of malaria.
T cells were shown to play a key role in the development
of pathology. Especially Th1 cells and their characteristic
cytokines IFN-γ and TNF-α were shown to be
involved in pathology. Recently it was shown that CTLA-
4 (CD152) could regulate the function of T cells. This
molecule expressed on the surface of activated T cells
and its expression is induced during malaria. A blockade
of this molecule leads to an increased activation of
T cells but was also accompanied by a severe pathology
in various organs. Our studies have shown that an
expression of CTLA-4 leads to a control of T cells in peripheral
tissues and thus providing a mechanism by
which inflammation could be controlled.
Introduction
T cells play a key role in the control of various
pathogens by either providing direct effector molecules
or by regulating other branches of the immune system.
However the immune response has to be tightly regulated
to prevent pathology. Recently, co-stimulatory
molecules that deliver negative signals to T cells were
described. CTLA-4 (CD152) has a sequence homology
to CD 28 but is only expressed on activated T cells.
Several studies have shown that CTLA-4 plays an essential
inhibitory role and is involved in the induction of
peripheral tolerance. Studies at the Bernhard Nocht Institute
have shown that during human malaria CTLA-4 is
Figure 1: Serum levels of liver-enzymes in P. berghei infected mice at day 8 after infection. (A) P. berghei infected displayed an increased
level of liver-enzymes that further increased dramatically upon blockade of CTLA-4 by a monoclonal antibody against CTLA-4. (B) P.
berghei infected mice that are deficient for pro-inflammatory cytokines are resistant for liver-pathology induced by CTLA-4 blockade.