Type 2 cytokines are thought to have a protective role in psoriasis vulgaris by dampening the activity of T helper 1 (Th1) lymphocytes. The aim of the present study was to determine the effect of monomethylfumarate (MMF), the most active metabolite of the new anti-psoriatic drug Fumaderm, on the production of cytokines and the development of Th subsets. MMF was found to enhance interleukin (IL)-4 and IL-5 production by CD2/CD8 monoclonal antibody-stimulated peripheral blood mononuclear cells (PBMC) in a dose-dependent manner. Maximal effects of MMF were found at a concentration of 200 microM and resulted in tenfold enhanced levels of IL-4 and IL-5 production. MMF did not affect the levels of IL-2 production, interferon (IFN)-gamma production or proliferative T cell responses in these cultures. Similar effects of MMF were observed in cultures of purified peripheral blood T cells indicating that this compound can act directly on T cells. MMF did not influence cytokine production by purified CD4+CD45RA+ (unprimed) T cells, but greatly enhanced IL-4 and IL-5 production without affecting IFN-gamma production by purified CD4+CD45RO+ (primed) T cells. Furthermore, MMF also augmented IL-4 and IL-5 production in established Th1/Th0 clones that were stimulated with CD2/CD28 monoclonal antibody. Finally, when PBMC were challenged with Mycobacterium tuberculosis that typically induces Th1 recall responses with strong IFN-gamma secretion, MMF again appeared to induce high levels of IL-4 and IL-5 secretion while IFN-gamma production was unaffected. These results may be relevant for the development of therapeutic regimens designed to correct inappropriate Th1 subset development in immunopathologic conditions.

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Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritisMaurice, M.M.; Lankester, A.C.; Bezemer, A.C.; Geertsma, M.F.; Tak, P.P.; Breedveld, F.C.; van Lier, R.A.W.; Verweij, C.L.

ABSTRACT. We studied the major determinants of opSystemic infection due to Streptococcus pneumoniae is a serisonophagocytosis against Streptococcus pneumoniae sero-ous disease in the neonatal period. In many infants the infection types 14 and 19 in paired cord/maternal sera from 27 runs a fulminant course with a fatal outcome in 50%. The healthy term and 24 preterm infants in an attempt to gain incidence of neonatal pneumococcal septicemia, however, is low. more insight in the susceptibility of newborns to pneumo-S. pneumoniae causes approximately 5% of all neonatal septicoccal infection. For both pneumococcal serotypes studied, cemia~ (1). Results of epidemiologic studies suggest that the opsonic activity in neonatal sera varied greatly, but was majority of infants with neonatal pneumococcal septicemia acmoderately to profoundly deficient when compared to quire the microorganisms either by the ascending route or during pahed maternal sera, both in preterm (34.5 and 34.9% of passage through the birth canal. The rarity of neonatal pneuthe activity in maternal serum, for serotypes 14 and 19, mococcal disease is probably due to the low incidence of camage respectively, p < 0.001 for both) and in term serum (43.5 of pneumococci in the genital tract (2-4). and 52.7% of the activity in maternal serum, for serotypesTo gain better insight in the apparent susceptibility of the 14 and 19, respectively, p < 0.001 for both). The opsonic newborn to pneumococcal septicemia, we determined the efideficiency in preterm sera could be ascribed to a diminished ciency of opsonophagocytosis of pneumococci in paired cord/ level of the major opsonins for pneumococci, i.e. comple-maternal sera of healthy term and premature neonates. This ment factor C3 deposited on the bacterial surface (69.5 process is one of the major host-defense mechanisms against and 66.2% of C3 deposition in maternal serum on serotypes such bacteria in man.14 and 19, respectively, p < 0.01 for both) and specific anticapsular IgG antibodies (48.5 and 14.1 % of maternal MATERIALS AND METHODS levels for serotypes 14 and 19, respectively, p < 0.001 for both). However, the opsonic defect in serum from term Sera. Serum was collected from the umbilical cord directly infants could not be explained in a similar way, because postnatally or by venipuncture within 48 h of birth from 27 C3 deposition and specific anticapsular IgG levels were healthy term neonates (mean gestational age 40 wk, range 37-equal to the values found in the paired maternal sera. 42 wk; mean birth wt 3447 g, range 2750-4250 g), 20 preterm Therefore, we conclude that the opsonic defect in newborn neonates (mean gestational age 33 wk, range 28-36 wk; mean serum for pneumococci cannot be solely explained by a birth wt 2064 g, range 1200-3400 g), and four immature neonates deficiency in the major opsonins for these bacteria. A (mean gestational age 26 wk, range 25-26 wk; mean birth wt dysfunction in these opsonins seems to be a more likely 1022 g, range 755-1330 g). These newborns were hospitalized in expl...