It has been shown that proinflammatory and antiinflammatory cytokines correlate with disease activity in multiple sclerosis (MS). To establish whether such correlations depend on the disease stage, we assessed in a longitudinal fashion the expression of interleukin (IL)‐12 (p40 and p35), tumor necrosis factor‐α, interferon‐γ, and IL‐10 mRNA by competitive polymerase chain reaction in unstimulated peripheral blood mononuclear cells of relapsing–remitting (RR) and secondary progressive (SP) MS patients, in relation to monthly clinical and magnetic resonance imaging monitoring. MS patients had increased levels of IL‐12p40 and decreased levels of IL‐10 mRNA compared with controls; this difference was most pronounced in SP patients. Both RR and SP patients had increased levels of IL‐12p40 mRNA compared with controls during the development of active lesions. Moreover, in RR MS an increase was found before relapse. IL‐12p35 mRNA was decreased in both groups, and in relation to disease activity it showed a pattern different from IL‐12p40 mRNA. In RR MS, IL‐10 mRNA was low 4 weeks before magnetic resonance imaging activity and 6 weeks before relapse; a significant increase to normal levels was noted when active lesions became apparent. In contrast, SP patients showed low IL‐10 mRNA levels constitutively, suggesting that IL‐10 plays an important role in the control of disease progression. Ann Neurol 1999;45:695–703

Background-Chemokines play an important role in atherogenesis and in ischemic injury and repair; however, prospective data on individual chemokines in unstable angina pectoris (UAP) are scarce. Therefore, we assessed chemokine patterns in a prospective cohort of patients with UAP. Methods and Results-Plasma samples of 54 patients with Braunwald class IIIB UAP were examined at baseline for 11 chemokines and 5 inflammatory mediators via multiplex analysis. Levels of CC chemokine ligand (CCL)-5 (also known as RANTES [regulated on activation, normally T-cell expressed, and secreted]; 32.7 versus 23.1 ng/mL, Pϭ0.018) and CCL18 (also known as PARC [pulmonary and activation-regulated chemokine]; 104.4 versus 53.7 ng/mL, Pϭ0.011) were significantly elevated in patients with refractory ischemic symptoms versus stabilized patients. Temporal monitoring by ELISA of CCL5, CCL18, and soluble CD40 ligand (sCD40) levels revealed a drop in CCL5 and sCD40L levels in all UAP patients from day 2 onward (CCL5 12.1 ng/mL, PϽ0.001; sCD40L 1.35 ng/mL, PϽ0.05), whereas elevated CCL18 levels were sustained for at least 2 days, then were decreased at 180 days after inclusion (34.5 ng/mL, PϽ0.001). Peripheral blood mononuclear cells showed increased protein expression of chemokine receptors CCR3 and CCR5 in CD3 ϩ and CD14 ϩ cells at baseline compared with 180 days after inclusion, whereas mRNA levels were downregulated, which was attributable in part to a postischemic release of human neutrophil peptide-3-positive neutrophils and in part to negative feedback. Finally, elevated CCL5 and CCL18 levels predicted future cardiovascular adverse events, whereas C-reactive protein and sCD40L levels did not. Conclusions-We are the first to report that CCL18 and CCL5 are transiently raised during episodes of UAP, and peak levels of both chemokines are indicative of refractory symptoms. Because levels of both chemokines, as well as of cognate receptor expression by circulating peripheral blood mononuclear cells, are increased during cardiac ischemia, this may point to an involvement of CCL5/CCL18 in the pathophysiology of UAP and/or post-UAP responses.

In the search for proteins that might play a role in the pathogenesis of multiple sclerosis (MS), osteopontin (OPN) has been identified as the most prominent cytokine-encoding gene expressed within MS lesions. Here, we report significantly increased OPN protein levels in plasma of relapsing-remitting MS patients. In contrast, OPN protein levels in primary progressive and secondary progressive MS patients were similar to healthy control levels. Interestingly, active relapsing-remitting patients had higher OPN protein levels than patients without relapses.

The ability of CD4+ T cells from CBA/Rij mice to produce interleukin (IL) 2 after stimulation with anti-CD3, concanavalin A, or the combination of phorbol 12-myristate 13-acetate and ionomycin declines during aging. This phenomenon was accompanied by an increased production of IL 4 and interferon-gamma. These age-related changes in lymphokine production correlated with the decrease in the percentage of CD45RBhi CD4+ T cells from about 80% in 2-month-old to about 40% in 27-month-old mice. This phenotypic shift was responsible for the decline in IL 2 production, because in young and in old mice CD45RBhi CD4+ T cells were more potent IL 2 producers than CD45RBlo cells. Moreover, old CD45RBhi CD4+ T cells produced less IL 2 than their young counterparts. Proliferative responses by T cells from old mice were lower than those of young mice, regardless whether the cultures were supplemented with IL 2, IL 4 or both lymphokines. As far as CD4+ T cells were concerned, this hyporesponsiveness was found in the CD45RBlo as well as in the CD45RBhi CD4+ T cell population.

It is well known that immune reactivity declines with age. Recently, we demonstrated that the age-related decrease in IL-2 production by CD4+ T cells was accompanied by an increased production of IL-4 and interferon-γ,(IFN-γ). This age-related shift in the profile of lymphokine production was related to phenotypic changes within the CD4+ T-cell subset, that is, a decrease in the percentage of CD45RB++ CD4+ T cells and an increase in the percentage of Pgp-1+ CD4+ T cells. To study whether these age-related changes were due to previous antigenic exposure, we performed a phenotypic and functional analysis on splenic CD4+ T cells isolated from individual, germ-free (GF), specific pathogen-free (SPF), and clean conventional (CC) mice. Interestingly, the total number of splenic CD4+ T cells in GF mice was twofold lower as compared to age-matched SPF or CC mice, regardless whether mice were analyzed at young (10 weeks) or at advanced age (13-14 months). Unexpectedly, the phenotypic composition of the CD4+ T-cell subset was comparable in the GF, SPF, and CC mice as determined by the expression of CD45RB and Pgp-1, indicating that CD4+ T cells with a naive phenotype (CD45RB++ Pgp-1 –) were not enriched in GF mice. Moreover, at an age of 13–14 months, CD4+ T cells from GF mice frequently produced more IL-4 and IFN-γ, than their CC counterparts. These lymphokine data showed, therefore, that a relatively high proportion of CD4 T cells with a memory phenotype can also be defined in GF mice on the basis of their function. The contamination of GF mice with a colonization resistant factor (CRF flora) resulted in twofold higher numbers of splenic CD4+ T cells. Surprisingly, not only CD4+ T cells with a memory phenotype (CD45RB–/+ Pgp-1++) had expanded, but also CD4+ T cells with a naive (CD45RB++ Pgp-1–) phenotype. Our results, therefore, strongly suggest that the expansion of naive CD4+ T cells in the periphery is mediated by the intestinal microflora.

Antigen-presenting cells are thought to modulate the development of Th1 and Th2 cells by the secretion of interleukin-10 (IL-10) and IL-12. Because glucocorticoids (GC) favor the development of Th2 responses, we determined whether dexamethasone (DEX) and hydrocortisone (HC) have differential effects on lipopolysaccharide-induced IL-10 and IL-12 production in whole-blood cultures. Significant inhibition of IL-12(p40) and IL-12(p70) was found with 10−8 mol/L and 10−9 mol/L DEX respectively, whereas IL-10 was relatively insensitive or even stimulated. Accordingly, the expression of IL-12(p40) and IL-12(p35) mRNA was more sensitive to DEX than IL-10 mRNA. The glucocorticoid receptor (GR) antagonist RU486 enhanced IL-12 production and largely abrogated the inhibition of IL-12 by GC, indicating that this suppression was mainly GR-mediated. High concentrations of RU486 were inhibitory for IL-10, suggesting that GC may exert a positive effect on IL-10. In the presence of neutralizing anti–IL-10 antibodies, DEX was still capable of IL-12 suppression whereas RU486 still enhanced IL-12 production, indicating that GC do not modulate IL-12 via IL-10 exclusively. Taken together these results indicate that GC may favor Th2 development by differential regulation of IL-10 and IL-12.

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