P. Dejong et al., SELECTIVE STIMULATION OF T-HELPER-2 CYTOKINE RESPONSES BY THE ANTI-PSORIASIS AGENT MONOMETHYLFUMARATE, European Journal of Immunology, 26(9), 1996, pp. 2067-2074
Type 2 cytokines are thought to have a protective role in psoriasis vu
lgaris by dampening the activity of T helper 1 (Th1) lymphocytes. The
aim of the present study was to determine the effect of monomethylfuma
rate (MMF), the most active metabolite of the new anti-psoriatic drug
Fumaderm(R), on the production of cytokines and the development of Th
subsets. MMF was found to enhance interleukin (IL)-4 and IL-5 producti
on by CD2/CD8 monoclonal antibody-stimulated peripheral blood mononucl
ear cells (PBMC) in a dose-dependent manner. Maximal effects of MMF we
re found at a concentration of 200 mu M and resulted in tenfold enhanc
ed levels of IL-4 and IL-5 production. MMF did not affect the levels o
f IL-2 production, interferon (IFN)-gamma production or proliferative
T cell responses in these cultures. Similar effects of MMF were observ
ed in cultures of purified peripheral blood T cells indicating that th
is compound can act directly on T cells. MMF did not influence cytokin
e production by purified CD4(+)CD45RA(+) (unprimed) T cells, but great
ly enhanced IL-4 and IL-5 production without affecting IFN-gamma produ
ction by purified CD4(+)CD45R0(+) (primed) T cells. Furthermore, MMF a
lso augmented IL-4 and IL-5 production in established Th1/Th0 clones t
hat were stimulated with CD2/CD28 monoclonal antibody. Finally, when P
BMC were challenged with Mycobacterium tuberculosis that typically ind
uces Th1 recall responses with strong IFN-gamma secretion, MMF again a
ppeared to induce high levels of IL-4 and IL-5 secretion while IFN-gam
ma production was unaffected. These results may be relevant for the de
velopment of therapeutic regimens designed to correct inappropriate Th
1 subset development in immunopathologic conditions.