T and B Cell Composition and Cytokine Producing Capacity Before and After Bariatric Surgery.

Morbid obesity is associated with a chronic state of low-grade inflammation, which may lead to accelerated differentiation of T and B cells. These differentiated immune cells are strongly cytotoxic and have an increased pro-inflammatory cytokine producing capacity. Furthermore, the anti-inflammatory function of the T and B cells decreases. The aim of this study was to evaluate the effect of morbid obesity on the subset profile and cytokine producing capacity of T and B cells. Subsequently, we assessed whether bariatric surgery affected the subset profile and cytokine producing capacity of these cells. We determined the proportion of T and B cell subsets and their cytokine producing capacity in peripheral blood collected from 23 morbidly obese patients before and three months after bariatric surgery using flow-cytometry. We compared this with the results of 25 lean controls. Both CD4+ and CD8+ T cells showed a more differentiated subset profile in morbidly obese patients as compared to lean controls, which was not recovered three months after bariatric surgery. The B cell composition of morbidly obese patients after bariatric surgery adjusted towards the profile of lean controls. However, the IL-2 and IFN-γ producing capacity of CD8+ T cells and the IL-2, IFN-γ, TNF-α and IL-10 producing capacity of B cells was not restored three months after bariatric surgery. In conclusion, the data suggest that the immune system has the capacity to recover from the detrimental effects of morbid obesity within three months after bariatric surgery in terms of cell composition; however, this was not seen in terms of cytokine producing capacity. The full restoration of the immune system after bariatric surgery may thus take longer.

Effects of bariatric surgery on telomere length and T-cell aging.

BACKGROUND: Obesity adversely affects health and is associated with subclinical systemic inflammation and features of accelerated aging, including the T-cell immune system. The presence of metabolic syndrome (MetS) may accelerate, while bariatric surgery might reverse these phenomena. To examine the effects of MetS and bariatric surgery on T-cell aging, we measured relative telomere length (RTL) and T-cell differentiation status in obese patients before and after bariatric surgery. METHODS: WHO II/III classified obese patients scheduled for bariatric surgery were included: 41 without MetS and 67 with MetS. RTL and T-cell differentiation status were measured in circulating CD4+ and CD8+ T cells via flow cytometry. T-cell characteristics were compared between patients with and without MetS prior to and at 3, 6, and 12 months after surgery considering effects of age, cytomegalovirus-serostatus, and weight loss. RESULTS: Thymic output, represented by numbers of CD31-expressing naive T cells, showed an age-related decline in patients with MetS. MetS significantly enhanced CD8+ T-cell differentiation. Patients with MetS had significant lower CD4+ RTL than patients without MetS. Within the first 6 months after bariatric surgery, RTL increased in CD4+ T cells after which it decreased at month 12. A decline in both thymic output and more differentiated T cells was seen following bariatric surgery, more pronounced in the MetS group and showing an association with percentage of body weight loss. CONCLUSIONS: In obese patients, MetS results in attrition of RTL and accelerated T-cell differentiation. Bariatric surgery temporarily reverses these effects. These data suggest that MetS is a risk factor for accelerated aging of T cells and that MetS should be a more prominent factor in the decision making for eligibility for bariatric surgery.

CD4+ CD28null T cells are not alloreactive unless stimulated by interleukin-15.

Proinflammatory, cytotoxic CD4+ CD28null T cells can be substantially expanded in patients with end-stage renal disease. These cells have been associated with the risk for rejection, but their alloreactive potential is unknown. CD4+ CD28null T cells were stimulated with HLA-mismatched antigen presenting cells in the absence/presence of exogenous cytokines. Alloreactive potential was evaluated based on proliferation, degranulation, cytotoxicity, and cytokine production. Further, their suppressive capacity was assessed by measuring inhibition of proliferating alloreactive CD28+ T cells. CD4+ CD28null T cells contained alloreactive (CD137+ ) T cells but did not proliferate in response to allogeneic stimulation, unless interleukin (IL)-15 was added. However, they could proliferate on stimulation with cytomegalovirus antigen without exogenous cytokines. IL-15 increased the frequency of proliferating alloreactive CD4+ CD28null T cells to 30.5% without inducing CD28 expression (P < .05). After allogeneic stimulation together with IL-15 and IL-21, frequency of degranulating CD107a+ CD4+ CD28null T cells increased significantly from 0.6% to 5.8% (P < .001). Granzyme B and perforin positivity remained similar, but production of interferon-γ and tumor necrosis factor-α increased by the combination of IL-15 and IL-21 (P < .001 and P < .05, respectively). Finally, CD4+ CD28null T cells did not show significant suppression. Thus, CD4+ CD28null T cells represent a population with absent alloreactivity unless IL-15 is present.

Co-inhibitory profile and cytotoxicity of CD57+ PD-1- T cells in end-stage renal disease patients.

Blockade of the CD80/86-CD28 pathway by belatacept after kidney transplantation is associated with an increased risk of rejection compared with standard, calcineurin inhibitor (CNI)-based therapy. CD28- T cells, which express CD57, are not susceptible to belatacept treatment. High numbers of CD4+ CD57+ programmed death 1 (PD-1)- T cells pretransplantation have been associated with a higher chance of rejection, although conflicting data have been reported. To investigate the working mechanism behind this possible higher chance of rejection, we studied the expression of co-inhibitory molecules (CD223, CD244 and PD-1), proliferative capacity and cytotoxic potential of fluorescence activated cell sorted (FACS) CD4+ CD57+ PD-1- and CD8+ CD57+ PD-1- T cells, and their CD57- control populations, after alloantigen stimulation. The effect of belatacept on the cytotoxic capacity of pretransplantation peripheral blood mononuclear cells from 20 patients who received belatacept post-transplantation was also tested. Expression of co-inhibitory molecule CD223 increased by approximately 10-fold after allogeneic stimulation in all four T cell subsets. Proliferation and up-regulation of CD244 and PD-1 was observed for CD4+ CD57- PD-1- T cells after allogeneic stimulation, but no up-regulation of these markers occurred on CD8+ T cells or CD4+ CD57+ PD-1- T cells. However, CD4+ CD57+ PD-1- T cells and, to a lesser extent, CD8+ CD57+ PD-1- T cells displayed higher cytotoxicity as indicated by granzyme B expression. Belatacept inhibited the cytotoxic potential of CD4+ CD57+ PD-1- T cells (median of inhibition 31%, P < 0·01) and CD8+ CD57+ PD-1- T cells (median of inhibition 10%, P < 0·05). In conclusion, alloantigen-activated CD4+ CD57+ PD-1- T cells exhibited a less proliferative but more cytotoxic profile than their CD57- counterparts. Their cytotoxic capacity can be inhibited partly by belatacept and was not associated with development of rejection after kidney transplantation.

Pretransplant Numbers of CD16+ Monocytes as a Novel Biomarker to Predict Acute Rejection After Kidney Transplantation: A Pilot Study.

Acute rejection is one of the major immunological determinants of kidney graft function and survival. Early biomarkers to predict rejection are lacking. Emerging evidence reveals a crucial role for the monocyte/macrophage lineage cells in the pathogenesis of rejection. We hypothesized that higher pretransplant numbers of proinflammatory CD16+ monocytes can predict rejection. The study cohort consisted of 104 kidney transplant recipients (58 with no rejection and 46 with biopsy-proven rejection) and 33 healthy persons. Posttransplant median follow-up time was 14.7 mo (interquartile range 0.3-34 mo). Pretransplantation blood samples were analyzed by flow cytometry for monocyte immunophenotypes. Groups were compared by Cox regression models for the occurrence of acute rejection. We documented a significantly increased absolute number of pretransplant CD16+ monocytes in patients who developed biopsy-proven rejection after transplantation compared with those with no rejection (hazard ratio [HR] 1.60, 95% CI 1.28-2.00, p < 0.001) and healthy persons (HR 1.47, 95% CI 1.18-1.82, p < 0.001). In parallel, significantly fewer absolute numbers of CD16- monocytes were observed at pretransplant time points in rejectors versus nonrejectors (HR 0.74, 95% CI 0.58-0.94, p < 0,014). A higher pretransplant number of CD16+ monocytes is significantly associated with a higher risk of acute rejection after kidney transplantation.

Lymph node and circulating T cell characteristics are strongly correlated in end-stage renal disease patients, but highly differentiated T cells reside within the circulation.

Ageing is associated with changes in the peripheral T cell immune system, which can be influenced significantly by latent cytomegalovirus (CMV) infection. To what extent changes in circulating T cell populations correlate with T cell composition of the lymph node (LN) is unclear, but is crucial for a comprehensive understanding of the T cell system. T cells from peripheral blood (PB) and LN of end-stage renal disease patients were analysed for frequency of recent thymic emigrants using CD31 expression and T cell receptor excision circle content, relative telomere length and expression of differentiation markers. Compared with PB, LN contained relatively more CD4+ than CD8+ T cells (P < 0·001). The percentage of naive and central memory CD4+ and CD8+ T cells and thymic output parameters showed a strong linear correlation between PB and LN. Highly differentiated CD28null T cells, being CD27- , CD57+ or programmed death 1 (PD-1+ ), were found almost exclusively in the circulation but not in LN. An age-related decline in naive CD4+ and CD8+ T cell frequency was observed (P = 0·035 and P = 0·002, respectively) within LN, concomitant with an increase in central memory CD8+ T cells (P = 0·033). Latent CMV infection increased dramatically the frequency of circulating terminally differentiated T cells, but did not alter T cell composition and ageing parameters of LN significantly. Overall T cell composition and measures of thymic function in PB and LN are correlated strongly. However, highly differentiated CD28null T cells, which may comprise a large part of circulating T cells in CMV-seropositive individuals, are found almost exclusively within the circulation.

Latency for cytomegalovirus impacts T cell ageing significantly in elderly end-stage renal disease patients.

The number of elderly patients with end-stage renal disease (ESRD) has increased significantly during the last decade. Elderly ESRD patients are vulnerable to infectious complications because of an aged immune system. Additional immunological ageing effects may be derived from the uraemic environment and cytomegalovirus (CMV) latency. Elderly patients may be affected by these factors in particular, but data in this age group are limited. To assess the degree of immunological ageing and proliferative capacity of T lymphocytes, 49 elderly ESRD patients (defined as aged ≥ 65 years) on the renal transplantation waiting list were recruited and compared to 44 elderly healthy individuals (HI), matched for age and CMV serostatus. CMV latency was associated with more highly differentiated CD4+ and CD8+ T cells in both elderly HI and patients. Elderly CMV seropositive ESRD patients showed a substantial reduction in the number of naive CD4+ and CD8+ T cells compared with age- and CMV serostatus-matched HI. Elderly ESRD patients also showed significantly decreased numbers of central memory CD4+ and CD8+ T cells compared with HI, independently of CMV serostatus. In addition, thymic output and relative telomere length of both CD4+ and CD8+ T cells were decreased in CMV seropositive ESRD patients compared with HI. The proliferative capacity of T cells was similar for patients and HI. Elderly ESRD patients have an advanced aged T cell compartment when compared to age-matched healthy controls, which is driven mainly by CMV latency.

Uremia-Associated Premature Aging of T Cells Does Not Predict Infectious Complications After Renal Transplantation.

Patients with end-stage renal disease have prematurely aged T cell systems. We tested whether T cell aging parameters were associated with the risk of infections after renal transplantation (RTx). We studied 188 patients over 1 year. Peripheral T cells were analyzed before and at 3 and 6 mo after RTx for frequency of recent thymic emigrants, relative telomere length and differentiation status. These parameters were related to the occurrence of opportunistic and serious infections. Overall, 84 patients developed an infection. In this group, 50 developed an opportunistic infection and 53 developed a serious infection. T cell aging parameters assessed before RTx were not associated with infection risk. The memory T cells showed a decrease within the first 3 mo in both groups (p < 0.001). The CD4(+) memory T cells increased between 3 and 6 mo within the infection group (p = 0.015). The number of CD8(+) memory T cells increased in both groups (p < 0.001) but reached baseline levels only in the infection group. In the infection group, the CD8(+) CD28(null) T cell percentage increased between 3 and 6 mo (p = 0.024), tending to be higher than at baseline (p = 0.061). These differences in post-RTx dynamics resulted from infections. Parameters of uremia-associated premature aging of peripheral T cells do not predict posttransplant infections.

Primary Cytomegalovirus Infection Significantly Impacts Circulating T Cells in Kidney Transplant Recipients.

Cytomegalovirus (CMV) infection profoundly affects the T cell compartment and is associated with alterations in T cell aging parameters and generation of cytotoxic CD4(+) CD28null T cells. Hence, the effect of a primary CMV infection post-kidney transplantation (KT) on the peripheral T cell compartment was examined. As aging parameters, we determined the T cell differentiation status, T cell receptor excision circle (TREC) content, CD31(+) naïve T cell numbers and relative telomere length (RTL) pre-KT and 12 months post-KT. CMV-seronegative KT recipients, receiving a kidney from a CMV-seropositive donor (D+/R-) were compared to D+/R+ KT recipients. Eleven out of the 22 D+/R- KT recipients had CMV viremia post-KT. They developed CMV-specific CD4(+) and CD8(+) T cells and their T cell compartment shifted towards a more differentiated memory phenotype with expansion of CD4(+) CD28null and CD8(+) CD28null cells. One year post-KT, the CD8(+) T cell count was almost doubled compared to nonviremic D+/R- and D+/R+ KT recipients. In addition, the RTL of the CD8(+) T cell was significantly lower and both the TREC content and CD31(+) naïve T cell numbers significantly decreased. Moreover, primary CMV infection was associated with a negative impact on glomerular filtration rate. In conclusion, primary CMV infection has a substantial impact on the number and phenotype of peripheral T cells and may negatively affect renal allograft function.

CMV Primary Infection Is Associated With Donor-Specific T Cell Hyporesponsiveness and Fewer Late Acute Rejections After Liver Transplantation.

Viral infections, including cytomegalovirus (CMV), abrogate transplantation tolerance in animal models. Whether this also occurs in humans remains elusive. We investigated how CMV affects T cells and rejection episodes after liver transplantation (LT). Phenotype and alloreactivity of peripheral and allograft-infiltrating T cells from LT patients with different CMV status were analyzed by flow cytometry. The association of CMV status with early and late acute rejection was retrospectively analyzed in a cohort of 639 LT patients. CMV-positivity was associated with expansion of peripheral effector memory T cell subsets after LT. Patients with CMV primary infection showed donor-specific CD8(+) T cell hyporesponsiveness. While terminally differentiated effector memory cells comprised the majority of peripheral donor-specific CD8(+) T cells in CMV primary infection patients, they were rarely present in liver allografts. Retrospective analysis showed that R(-) D(+) serostatus was an independent protective factor for late acute rejection by multivariate Cox regression analysis (hazard ratio [HR] = 0.18, 95% CI = 0.04-0.86, p = 0.015). Additionally, CMV primary infection patients showed the highest Vδ1/Vδ2 γδ T cell ratio, which has been shown to be associated with operational tolerance after LT. In conclusion, our data suggest that CMV primary infection may promote tolerance to liver allografts, and CMV status should be considered when tapering or withdrawing immunosuppression.

Follicular T helper cells and humoral reactivity in kidney transplant patients.

Memory B cells play a pivotal role in alloreactivity in kidney transplantation. Follicular T helper (Tfh) cells play an important role in the differentiation of B cells into immunoglobulin-producing plasmablasts [through interleukin (IL)-21]. It is unclear to what extent this T cell subset regulates humoral alloreactivity in kidney transplant patients, therefore we investigated the absolute numbers and function of peripheral Tfh cells (CD4(POS) CXCR5(POS) T cells) in patients before and after transplantation. In addition, we studied their relationship with the presence of donor-specific anti-human leucocyte antigen (HLA) antibodies (DSA), and the presence of Tfh cells in rejection biopsies. After transplantation peripheral Tfh cell numbers remained stable, while their IL-21-producing capacity decreased under immunosuppression. When isolated after transplantation, peripheral Tfh cells still had the capacity to induce B cell differentiation and immunoglobulin production, which could be inhibited by an IL-21-receptor-antagonist. After transplantation the quantity of Tfh cells was the highest in patients with pre-existent DSA. In kidney biopsies taken during rejection, Tfh cells co-localized with B cells and immunoglobulins in follicular-like structures. Our data on Tfh cells in kidney transplantation demonstrate that Tfh cells may mediate humoral alloreactivity, which is also seen in the immunosuppressed milieu.

Mesenchymal stem cells control alloreactive CD8(+) CD28(-) T cells.

CD28/B7 co-stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients. However, cells lacking CD28 are not susceptible to belatacept treatment. As CD8(+) CD28(-) T-cells have cytotoxic and pathogenic properties, we investigated whether mesenchymal stem cells (MSC) are effective in controlling these cells. In mixed lymphocyte reactions (MLR), MSC and belatacept inhibited peripheral blood mononuclear cell (PBMC) proliferation in a dose-dependent manner. MSC at MSC/effector cell ratios of 1:160 and 1:2·5 reduced proliferation by 38·8 and 92·2%, respectively. Belatacept concentrations of 0·1 µg/ml and 10 µg/ml suppressed proliferation by 20·7 and 80·6%, respectively. Both treatments in combination did not inhibit each other's function. Allostimulated CD8(+) CD28(-) T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α. While belatacept did not affect the proliferation of CD8(+) CD28(-) T cells, MSC reduced the percentage of CD28(-) T cells in the proliferating CD8(+) T cell fraction by 45·9% (P = 0·009). CD8(+) CD28(-) T cells as effector cells in MLR in the presence of CD4(+) T cell help gained CD28 expression, an effect independent of MSC. In contrast, allostimulated CD28(+) T cells did not lose CD28 expression in MLR-MSC co-culture, suggesting that MSC control pre-existing CD28(-) T cells and not newly induced CD28(-) T cells. In conclusion, alloreactive CD8(+) CD28(-) T cells that remain unaffected by belatacept treatment are inhibited by MSC. This study indicates the potential of an MSC-belatacept combination therapy to control alloreactivity.

Cytomegalovirus contributes partly to uraemia-associated premature immunological ageing of the T cell compartment.

Cytomegalovirus (CMV) infection has been implicated in accelerated T cell ageing. End-stage renal disease (ESRD) patients have a severely immunologically aged T cell compartment but also a high prevalence of CMV infection. We investigated whether CMV infection contributes to T cell ageing in ESRD patients. We determined the thymic output by the T cell receptor excision circle (TREC) content and percentage of CD31+ naïve T cells. The proliferative history of the T cell compartment by determination of the relative telomere length (RTL) and the T cell differentiation status was determined by immunophenotyping. It appeared that CMV infection did not affect thymic output but reduced RTL of CD8+ T cells in ESRD patients. Moreover, increased T cell differentiation was observed with higher percentages of CD57+ and CD28null CD4+ and CD8+ memory T cells. These CD28null T cells had significantly shorter telomeres compared to CD28+ T cells. Therefore we concluded that CMV infection does not affect the decreased thymic output but increases T cell differentiation as observed in ESRD-related premature T cell ageing.

Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells.

Detection and isolation of viable alloreactive T cells at the single-cell level requires a cell surface marker induced specifically upon T cell receptor activation. In this study, a member of the tumour necrosis factor receptor (TNFR)-family, CD137 (4-1BB) was investigated for its potential to identify the total pool of circulating alloreactive T cells. Optimal conditions for sensitive and specific detection of allogeneic-induced CD137 expression on circulating T cells were established. Thereafter, CD137(+) alloreactive T cells were phenotypically and functionally characterized by multi-parameter flow cytometry. Alloantigen-induced CD137 expression identified both alloreactive CD8(+) T cells (mean ± standard error of the mean: 0·21 ± 0·07%) and alloreactive CD4(+) T cells (0·21 ± 0·05%). CD137(+) alloreactive T cells were detected in different T cell subsets, including naive T cells, but were found preferentially in CD28(+) T cells and not in the terminally differentiated T cell subset. Upon allogeneic (re-)stimulation, the cytokine-producing as well as proliferative capacity of T cells resided mainly within the CD137-expressing fraction. About 10% of the CD137(+) alloreactive T cells produced any combination of interferon (IFN)-γ, interleukin (IL)-2 and TNF-α. Polyfunctional alloreactive T cells, defined by multiple cytokine expression, were observed infrequently. In conclusion, activation-induced CD137 expression is a fast assay allowing for detection and functional analysis of the total alloreactive T cell compartment at the single-cell level by multi-parameter flow cytometry.

Human adipose-tissue derived mesenchymal stem cells induce functional de-novo regulatory T cells with methylated FOXP3 gene DNA.

Due to their immunomodulatory properties, mesenchymal stem cells (MSC) are interesting candidates for cellular therapy for autoimmune disorders, graft-versus-host disease and allograft rejection. MSC inhibit the proliferation of effector T cells and induce T cells with a regulatory phenotype. So far it is unknown whether human MSC-induced CD4(+) CD25(+) CD127(-) forkhead box P3 (FoxP3)(+) T cells are functional and whether they originate from effector T cells or represent expanded natural regulatory T cells (nT(reg)). Perirenal adipose-tissue derived MSC (ASC) obtained from kidney donors induced a 2·1-fold increase in the percentage of CD25(+) CD127(-) FoxP3(+) cells within the CD4(+) T cell population from allostimulated CD25(-/dim) cells. Interleukin (IL)-2 receptor blocking prevented this induction. The ASC-induced T cells (iT(reg)) inhibited effector cell proliferation as effectively as nT(reg). The vast majority of cells within the iT(reg) fraction had a methylated FOXP3 gene T(reg)-specific demethylated region (TSDR) indicating that they were not of nT(reg) origin. In conclusion, ASC induce T(reg) from effector T cells. These iT(reg) have immunosuppressive capacities comparable to those of nT(reg). Their induction is IL-2 pathway-dependent. The dual effect of MSC of inhibiting immune cell proliferation while generating de-novo immunosuppressive cells emphasizes their potential as cellular immunotherapeutic agent.

Effects of monomethylfumarate on dendritic cell differentiation.

BACKGROUND: Fumaric acid esters (FAE) are effective against psoriasis vulgaris and monomethylfumarate (MMF) is believed to be the most bioactive metabolite of this medication. Earlier we found that the beneficial effects of FAE medication are accompanied by a downregulation of type 1 cytokine production by T-helper (Th) lymphocytes, which are important as they maintain a type 1 cytokine [interferon (IFN)-gamma, interleukin (IL)-2] environment in the skin lesions of psoriasis vulgaris patients and once maximal beneficial effects are obtained type 2 cytokine production is also decreased. In vitro MMF selectively induced type 2 cytokine production by primed Th lymphocytes, whereas type 1 cytokine production by and profileration of T lymphocytes were unaffected. OBJECTIVES: As dendritic cells (DCs) present in these skin lesions play a key role in the activation of Th lymphocytes, we investigated the effects of MMF on monocyte-derived DC differentiation. METHODS: Monocytes were differentiated into immature (i) DCs by cytokines with or without MMF. To establish whether these cells were differentiated into iDCs, we analysed the expression of cell surface molecules on these cells and the capacity to capture antigens using flow cytometry. Next, we determined whether these MMF-incubated (MMF-)iDCs could be matured by lipopolysaccharide (LPS) and whether MMF affected this responsiveness as well. For this purpose we measured cytokine production by these LPS-stimulated cells (MMF-DCs) using enzyme-linked immunosorbent assays as well as their ability to activate naive Th lymphocytes. RESULTS: The presence of MMF during the differentiation of monocytes into iDCs resulted in cells that retained low levels of CD14 and hardly expressed CD1a. Upon maturation, these MMF-iDCs upregulated CD83 and costimulatory molecules and HLA-DR on their surface, indicating that these cells respond to LPS, albeit less than control iDCs. In addition, in response to LPS, MMF-iDCs did not decrease the capacity to capture antigens when compared with control iDCs. MMF-DCs hardly produced IL-12p70 and IL-10 and low levels of tumour necrosis factor (TNF)-alpha, whereas IL-8 produced by MMF-DCs and control DCs did not differ. Moreover, MMF-DCs were less able to induce IFN-gamma production by naive Th lymphocytes compared with control DCs. The production of IL-4 and IL-10 by naive Th lymphocytes cocultured with MMF-DCs did not differ from that by T cells cocultured with control DCs. CONCLUSIONS: MMF inhibited the monocyte-derived DC differentiation resulting in cells that cannot be appropriately matured to DCs. Consequently, these MMF-DCs are less effective than control DCs in stimulating type 1 cytokine, but not type 2 cytokine production, in Th lymphocytes. This general immunomodulatory effect may in part explain the beneficial effects of FAE therapy in psoriasis.

Beneficial effects of fumarate therapy in psoriasis vulgaris patients coincide with downregulation of type 1 cytokines.

BACKGROUND: Fumarates have been shown to be effective in psoriasis vulgaris. OBJECTIVES: To find out whether successful therapy is associated with modulation of cytokines. METHODS: We determined interferon (IFN)-gamma, interleukin (IL)-4 and IL-10 secretion capacities of peripheral blood mononuclear cells (PBMC) after phytohaemagglutinin stimulation, and IL-12p70 and IL-10 secretion capacities of PBMC after endotoxin stimulation in psoriasis vulgaris patients during treatment with fumarates. In a cohort study, 12 patients (five men, median age 50 years; seven women, median age 46 years) with psoriasis vulgaris were followed during 24 months of fumarate treatment. In addition, we followed 14 healthy controls (six men, median age 31 years; eight women, median age 29 years) without skin diseases during 12 months to investigate possible changes in the cytokine secretion capacity of PBMC as a result of seasonal changes. Disease activity in patients was determined by Psoriasis Area and Severity Index (PASI) score. Blood was collected for measurement by enzyme-linked immunosorbent assay of cytokine levels after stimulation of PBMC. RESULTS: Within 6 months of fumarate treatment, the mean +/- SD PASI score had decreased to 22 +/- 9% of its initial value. These beneficial effects coincided with lymphocytopenia and a significant (P < 0.05) downregulation of IFN-gamma expression by circulating blood cells, followed by a significant downregulation of IL-4 expression. Notably, production of the cytokine synthesis inhibitor IL-10 by PBMC was unchanged. CONCLUSIONS: The beneficial effects of fumarates may be attributed to their downregulatory action on type 1 cytokines.