Pectins that Structurally Differ in the Distribution of Methyl-Esters Attenuate Citrobacter rodentium-Induced Colitis.

INTRODUCTION: Pectins have anti-inflammatory properties on intestinal immunity through direct interactions on Toll-like receptors (TLRs) in the small intestine or via stimulating microbiota-dependent effects in the large intestine. Both the degree of methyl-esterification (DM) and the distribution of methyl-esters (degree of blockiness; DB) of pectins contribute to this influence on immunity, but whether and how the DB impacts immunity through microbiota-dependent effects in the large intestine is unknown. Therefore, this study tests pectins that structurally differ in DB in a mouse model with Citrobacter rodentium induced colitis and studies the impact on the intestinal microbiota composition and associated attenuation of inflammation. METHODS AND RESULTS: Both low and high DB pectins induce a more rich and diverse microbiota composition. These pectins also lower the bacterial load of C. rodentium in cecal digesta. Through these effects, both low and high DB pectins attenuate C. rodentium induced colitis resulting in reduced intestinal damage, reduced numbers of Th1-cells, which are increased in case of C. rodentium induced colitis, and reduced levels of GATA3+ Tregs, which are related to tissue inflammation. CONCLUSION: Pectins prevent C. rodentium induced colonic inflammation by lowering the C. rodentium load in the caecum independently of the DB.

How we treat advanced stage cutaneous T-cell lymphoma - mycosis fungoides and Sézary syndrome.

T-cell lymphomas (TCLs) constitute a rare subset of non-Hodgkin lymphomas, with mycosis fungoides/Sézary syndrome (MF/SS) being the most common subtype of cutaneous TCLs (CTCLs). Considered an incurable but treatable disease, MF/SS management presents several challenges including diagnostic delays, debilitating effect on patients' quality of life, need for several lines of therapies, multidisciplinary care and cumulative drug toxicities limiting duration of use. The present review intends to provide an overview of the recent advances in our understanding of the biology of CTCL and how these are being leveraged to provide additional treatment options for management of advanced and recurrent disease. In addition, the discussion of the different modalities of treatment is summarised to further outline the importance of multidisciplinary care and early referral to CTCL centres.

ZIP8 exacerbates collagen-induced arthritis by increasing pathogenic T cell responses.

Zinc is a trace element that is essential for immune responses. Therefore, changes in cellular zinc levels in specific immune cells may influence inflammatory autoimmune diseases, such as rheumatoid arthritis (RA). However, the regulation of zinc mobilization in immune cells and its role in the pathogenesis of RA are not fully understood. Thus, we investigated the roles of zinc transporters in RA pathogenesis. We demonstrated that ZIP8 was specifically upregulated in CD4+ T cells that infiltrated the inflamed joint and that ZIP8 deficiency in CD4+ T cells abrogated collagen-induced arthritis. ZIP8 deficiency dramatically affected zinc influx in effector T cells and profoundly reduced T cell receptor (TCR)-mediated signaling, including NF-κB and MAPK signaling, which are pathways that are involved in T helper (Th) 17 cell differentiation. Taken together, our findings suggest that ZIP8 depletion in CD4+ T cells attenuates TCR signaling due to insufficient cellular zinc, thereby reducing the function of effector CD4+ T cells, including Th17 cells. Our results also suggest that targeting ZIP8 may be a useful strategy to inhibit RA development and pathogenesis.

Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function.

Adult T-cell leukemia/lymphoma (ATLL) patients have an extremely poor prognosis, partly due to their immunosuppressive state. The majority of ATLL patients have leukemic cells with phenotype similar to Tregs, prompting suggestions that ATLL cells themselves have immunosuppressive functions. In this study, we detected CD39 expression on ATLL cells, particularly frequent on aggressive subtypes. CD39 and CD73 convert extracellular adenosine triphosphate (ATP) into adenosine, a key player in Tregs' immunosuppression. In vitro culture, both CD39+ ATLL cells and normal Tregs converted rapidly extracellular ATP to AMP, which was disturbed by CD39 inhibitors, and was negated in the CD39 knockout MJ cell line. The proliferation of cocultured CD4+/CD8+ normal T cells was suppressed by CD39+ MJ cells, but not by CD39 knockout MJ cells. Supplemented ATP was exhausted by an EG7-OVA T-cell line with stable CD39 induction, but not by mock. When these cell lines were subcutaneously transplanted into murine flanks, Poly(I:C) peritoneal administration reduced tumor size to 1/3 in mock-transplanted tumors, but not in CD39 induced tumors. Overall, we found that ATLL cells express CD39 at a high rate, and our results suggest that this helps ATLL cells escape antitumor immunity through the extracellular ATPDase-Adenosine cascade. These findings will guide future clinical strategies for ATLL treatment.

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity.

Co-inhibitory receptors are important regulators of T-cell function that define the balance between tolerance and autoimmunity. The immune regulatory function of co-inhibitory receptors, including CTLA-4, PD-1, TIM-3, TIGIT, and LAG-3, was first discovered in the setting of autoimmune disease models, in which their blockade or deficiency resulted in induction or exacerbation of the disease. Later on, co-inhibitory receptors on lymphocytes have also been found to influence outcomes in tumor and chronic viral infection settings. These receptors suppress T-cell function in the tumor microenvironment (TME), thereby making the T cells dysfunctional. Based on this observation, blockade of co-inhibitory receptors (also known as checkpoint molecules) has emerged as a successful treatment option for a number of human cancers. However, severe autoimmune-like side effects limit the use of therapeutics that block individual or combinations of co-inhibitory receptors for cancer treatment. In this review we provide an overview of the role of co-inhibitory receptors in autoimmunity and anti-tumor immunity. We then discuss current approaches and future directions to leverage our knowledge of co-inhibitory receptors to target them in tumor immunity without inducing autoimmunity.

Short-term changes in frequencies of circulating leukocytes associated with narrowband UVB phototherapy in people with clinically isolated syndrome.

Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). Low environmental exposure to UV radiation is implicated in risk of developing MS, and therefore, narrowband UVB phototherapy might delay progression to MS in people with CIS. Twenty individuals with CIS were recruited, and half were randomised to receive 24 sessions of narrowband UVB phototherapy over a period of 8 weeks. Here, the effects of narrowband UVB phototherapy on the frequencies of circulating immune cells and immunoglobulin levels after phototherapy are reported. Peripheral blood samples for all participants were collected at baseline, and 1, 2, 3, 6 and 12 months after enrolment. An extensive panel of leukocyte populations, including subsets of T cells, B cells, monocytes, dendritic cells, and natural killer cells were examined in phototherapy-treated and control participants, and immunoglobulin levels measured in serum. There were significant short-term increases in the frequency of naïve B cells, intermediate monocytes, and fraction III FoxP3+ T regulatory cells, and decreases in switched memory B cells and classical monocytes in phototherapy-treated individuals. Since B cells are increasingly targeted by MS therapies, the effects of narrowband UVB phototherapy in people with MS should be investigated further.

The PD-1/PD-Ls pathway is up-regulated during the suppression of experimental autoimmune encephalomyelitis treated by Astragalus polysaccharides.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of CNS. Astragalus polysaccharides (APS), the main active extract from astragalus membranaceus which is a kind of traditional Chinese medicinal herb, is associated with a variety of immunomodulatory activities. We have evaluated the therapeutic effects of APS in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). It was found that APS could effectively alleviate EAE through inhibiting MOG35-55-specific T cell proliferation and reducing the expression of proinflammatory cytokines, which is mediated by up-regulating the expression of PD-1/PD-Ls signaling pathway. Our results demonstrated that EAE could be suppressed significantly by APS administration. It indicated that APS might be a potential of developing innovative drug for the therapy of MS.

Galectin-9 Induced by Dietary Probiotic Mixture Regulates Immune Balance to Reduce Atopic Dermatitis Symptoms in Mice.

Probiotics can be an effective treatment for atopic dermatitis (AD), while their mechanism of action is still unclear. Here, we induced AD in mice with 2,4-dinitrochlorobenzene and administrated YK4, a probiotic mixture consisting of Lactobacillus acidophilus CBT LA1, L. plantarum CBT LP3, Bifidobacterium breve CBT BR3, and B. lactis CBT BL3. Then, we have validated the underlying mechanism for the alleviation of AD by YK4 from the intestinal and systematic immunological perspectives. Administration of YK4 in AD mice alleviated the symptoms of AD by suppressing the expression of skin thymic stromal lymphopoietin and serum immunoglobulin E eliciting excessive T-helper (Th) 2 cell-mediated responses. YK4 inhibited Th2 cell population through induce the proportion of Th1 cells in spleen and Treg cells in Peyer's patches and mesenteric lymph node (mLN). CD103+ dendritic cells (DCs) in mLN and the spleen were significantly increased in AD mice administered with YK4 when compared to AD mice. Furthermore, galectin-9 was significantly increased in the gut of AD mice administered with YK4. In vitro experiments were performed using bone marrow-derived DCs (BMDC) and CD4+ T cells to confirm the immune mechanisms of YK4 and galectin-9. The expression of CD44, a receptor of galectin-9, together with programmed death-ligand 1 was significantly upregulated in BMDCs following treatment with YK4. IL-10 and IL-12 were upregulated when BMDCs were treated with YK4. Cytokines together with co-receptors from DCs play a major role in the differentiation and activation of CD4+ T cells. Proliferation of Tregs and Th1 cell activation were enhanced when CD4+T cells were co-cultured with YK4-treated BMDCs. Galectin-9 appeared to contribute at least partially to the proliferation of Tregs. The results further suggested that DCs treated with YK4 induced the differentiation of naïve T cells toward Th1 and Tregs. At the same time, YK4 alleviated AD symptoms by inhibiting Th2 response. Thus, the present study suggested a potential role of YK4 as an effective immunomodulatory agent in AD patients.

Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism.

Chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic bone marrow transplantation (BMT). The discovery of novel therapeutics is dependent on assessment in preclinical murine models of cGVHD. Rho-associated kinase 2 (ROCK2) recently was shown to be implicated in regulation of interleukin-21 (IL-21) and IL-17 secretion in mice and humans. Here, we report that the selective ROCK2 inhibitor KD025 effectively ameliorates cGVHD in multiple models: a full major histocompatibility complex (MHC) mismatch model of multiorgan system cGVHD with bronchiolitis obliterans syndrome and a minor MHC mismatch model of sclerodermatous GVHD. Treatment with KD025 resulted in normalization of pathogenic pulmonary function, which correlates with a marked reduction of antibody and collagen deposition in the lungs of treated mice to levels comparable to non-cGVHD controls. Spleens of mice treated with KD025 had decreased frequency of T follicular helper cells and increased frequency of T follicular regulatory cells, accompanied by a reduction in signal transducer and activator of transcription 3 (STAT3) and concurrent increase in STAT5 phosphorylation. The critical role of STAT3 in this cGVHD model was confirmed by data showing that mice transplanted with inducible STAT3-deficient T cells had pulmonary function comparable to the healthy negative controls. The therapeutic potential of targeted ROCK2 inhibition in the clinic was solidified further by human data demonstrating the KD025 inhibits the secretion of IL-21, IL-17, and interferon γ along with decreasing phosphorylated STAT3 and reduced protein expression of interferon regulatory factor 4 and B-cell lymphoma 6 (BCL6) in human peripheral blood mononuclear cells purified from active cGVHD patients. Together these data highlight the potential of targeted ROCK2 inhibition for clinical cGVHD therapy.

Methanolic extract of Origanum vulgare ameliorates type 1 diabetes through antioxidant, anti-inflammatory and anti-apoptotic activity.

Type 1 diabetes (T1D), an autoimmune inflammatory disorder, develops as a consequence of pancreatic ß-cell destruction and results in hyperglycaemia. Since current T1D therapy mainly involves insulin replacement, the aim of the present study was to evaluate the therapeutic potential of Origanum vulgare L. ssp. hirtum (Greek oregano) leaf extract rich in biophenols for the treatment of T1D. The phytochemical profile of methanolic oregano extract (MOE) and aqueous oregano extract (AOE) was determined by liquid chromatography/electrospray ion-trap tandem MS (LC/DAD/ESI-MSn), while their main compounds were quantified by HPLC with diode array detection. After establishing their potent in vitro antioxidant activity, the extracts were administered to C57BL/6 mice treated with multiple low doses of streptozotocin for diabetes induction. While prophylactic AOE therapy had no impact on diabetes induction, MOE reduced diabetes incidence and preserved normal insulin secretion. In addition, MOE scavenged reactive oxygen and nitrogen species and, therefore, alleviated the need for the up-regulation of antioxidant enzymes. MOE treatment specifically attenuated the pro-inflammatory response mediated by T helper 17 cells and enhanced anti-inflammatory T helper 2 and T regulatory cells through the impact on specific signalling pathways and transcription factors. Importantly, MOE preserved ß-cells from in vitro apoptosis via blockade of caspase 3. Finally, rosmarinic acid, a predominant compound in MOE, exhibited only partial protection from diabetes induction. In conclusion, acting as an antioxidant, immunomodulator and in an anti-apoptotic manner, MOE protected mice from diabetes development. Seemingly, there is more than one compound responsible for the beneficial effect of MOE.

High dietary intake of vitamin C suppresses age-related thymic atrophy and contributes to the maintenance of immune cells in vitamin C-deficient senescence marker protein-30 knockout mice.

Vitamin C (VC) is an essential nutrient for humans and certain other animals. It has antioxidant properties and has been reported to ameliorate oxidative damage to lipids, DNA and proteins. However, the effects of VC on immune function are poorly understood, especially the influence of long-term high-dose VC intake on the number and function of immune cells. In the present study, to evaluate the immune effects of VC, VC-deficient senescence marker protein-30 knockout (SMP30KO) mice were fed a diet containing the recommended level of VC (20 mg/kg per d; 0·02 % VC) or a high level of VC (200 mg/kg per d; 0·2 % VC) for 1 year. The plasma VC concentration of the 0·02 % group was the same as that of age-matched C57BL/6 mice after 1 year of feeding; however, plasma VC concentration and thymus weight were significantly higher in the 0·2 % VC group than in the 0·02 % VC group. The total counts of leucocytes, lymphocytes, granulocytes and monocytes in the peripheral blood, as well as the number of splenocytes and thymocytes, were all significantly higher in the 0·2 % VC group than in the 0·02 % VC group. In addition, the number of naive T cells in peripheral blood lymphocytes, the number of memory T-cell populations in splenocytes, and the number of cluster of differentiation (CD)4⁺CD8⁺ or CD4⁺CD8⁻ or CD4⁻CD8⁺ T cells in thymocytes were all markedly higher in the 0·2 % VC group than in the 0·02 % VC group after 1 year of dietary treatment. These results suggest that a long-term high-dose intake of VC is effective in the maintenance of immune cells, partly through the suppression of age-related thymic involution in VC-deficient SMP30KO mice.

Curcuma longa attenuates carbon tetrachloride-induced oxidative stress in T-lymphocyte subpopulations.

A comparison of crude curcuminoid extract and purified curcumin was made to evaluate the immunoprotective effect of Curcuma longa (turmeric) Zingiberaceae. Carbon tetrachloride (CCl4) induced selective cytolytic effects among immature (PNA(+)) thymocytes and peripheral helper (CD4(+)) T lymphocytes in the spleen were paralleled by a significant reduction in CD25, CD71, and Con A receptor expression. Treatment with curcumanoid crude extract, at two different doses, showed a significant restoration of lymphocyte viability and CD25, CD71, and Con A receptor expression in both immature (PNA+) thymocytes and splenic helper (CD4(+)) T lymphocytes. Turmeric crude extract, at both low and high dose, was found to be more efficient as compared to purified curcumin, suggesting synergistic effect of curcumin with other components of the crude extract.

Small intestinal intraepithelial TCRγδ+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis.

BACKGROUND: Gastrointestinal barrier immaturity predisposes preterm infants to necrotizing enterocolitis (NEC). Intraepithelial lymphocytes (IEL) bearing the unconventional T cell receptor (TCR) γδ (γδ IEL) maintain intestinal integrity and prevent bacterial translocation in part through production of interleukin (IL) 17. OBJECTIVE: We sought to study the development of γδ IEL in the ileum of human infants and examine their role in NEC pathogenesis. We defined the ontogeny of γδ IEL proportions in murine and human intestine and subjected tcrδ-/- mice to experimental gut injury. In addition, we used polychromatic flow cytometry to calculate percentages of viable IEL (defined as CD3+ CD8+ CD103+ lymphocytes) and the fraction of γδ IEL in surgically resected tissue from infants with NEC and gestational age matched non-NEC surgical controls. RESULTS: In human preterm infants, the proportion of IEL was reduced by 66% in 11 NEC ileum resections compared to 30 non-NEC controls (p<0.001). While γδ IEL dominated over conventional αß IEL early in gestation in mice and in humans, γδ IEL were preferential decreased in the ileum of surgical NEC patients compared to non-NEC controls (50% reduction, p<0.05). Loss of IEL in human NEC was associated with downregulation of the Th17 transcription factor retinoic acid-related orphan nuclear hormone receptor C (RORC, p<0.001). TCRδ-deficient mice showed increased severity of experimental gut injury (p<0.05) with higher TNFα expression but downregulation of IL17A. CONCLUSION: Complimentary mouse and human data suggest a role of γδ IEL in IL17 production and intestinal barrier production early in life. Specific loss of the γδ IEL fraction may contribute to NEC pathogenesis. Nutritional or pharmacological interventions to support γδ IEL maintenance in the developing small intestine could serve as novel strategies for NEC prevention.

Effects of dietary selenium on histopathological changes and T cells of spleen in broilers exposed to aflatoxin B1.

Aflatoxin B1 (AFB1), which causes hepatocellular carcinoma and immune-suppression, is commonly found in feedstuffs. To evaluate the ability of selenium (Se) to counteract the deleterious effects of AFB1, two hundred 1-day-old male avian broilers, divided into five groups, were fed with basal diet (control group), 0.3 mg/kg AFB1 (AFB1 group), 0.3 mg/kg AFB1+0.2 mg/kg Se (+Se group I), 0.3 mg/kg AFB1+0.4 mg/kg Se (+Se group II) and 0.3 mg/kg AFB1+0.6 mg/kg Se (+Se group III), respectively. Compared with control group, the relative weight of spleen in the AFB1 group was decreased at 21 days of age. The relative weight of spleen in the three +Se groups was higher than that in the AFB1 group. By pathological observation, the major spleen lesions included congestion in red pulp and vacuoles appeared in the lymphatic nodules and periarterial lymphatic sheath in the AFB1 group. In +Se groups II and III, the incidence of major splenic lesions was decreased. The percentages of CD3+, CD3+CD4+ and CD3+CD8+ T cells in the AFB1 group were lower than those in control group from 7 to 21 days of age, while there was a marked increase in the three +Se groups compared to the AFB1 group. The results indicated that sodium selenite could improve the cellular immune function impaired by AFB1 through increasing the relative weight of spleen and percentages of splenic T cell subsets, and alleviating histopathological spleen damage.

CCR1 inhibition ameliorates the progression of lupus nephritis in NZB/W mice.

Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a progressive loss of renal function. Such dysfunction is associated with leukocyte infiltration in the glomerular and tubulointerstitial compartments in both human and experimental lupus nephritis. In this study, we investigated the role of the Ccr1 chemokine receptor in this infiltration process during the progression of nephritis in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. We found that peripheral T cells, mononuclear phagocytes, and neutrophils, but not B cells, from nephritic NZB/W mice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/W mice. Short-term treatment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macrophages. Longer Ccr1 blockade decreased kidney accumulation of effector/memory CD4(+) T cells, Ly6C(+) monocytes, and both M1 and M2 macrophages; reduced tubulointerstitial and glomerular injuries; delayed fatal proteinuria; and prolonged animal lifespan. In contrast, renal humoral immunity was unaffected in BL5923-treated mice, which reflected the unchanged numbers of infiltrated B cells in the kidneys. Altogether, these findings define a pivotal role for Ccr1 in the recruitment of T and mononuclear phagocyte cells to inflamed kidneys of NZB/W mice, which in turn contribute to the progression of renal injury.

Characterisation of CD154+ T cells following ex vivo allergen stimulation illustrates distinct T cell responses to seasonal and perennial allergens in allergic and non-allergic individuals.

BACKGROUND: Allergic sensitisation has been ascribed to a dysregulated relationship between allergen-specific Th1, Th2 and regulatory T cells. We sought to utilise our short-term CD154 detection method to further analyse the relationship between these T cell subsets and investigate differences between seasonal and perennial allergens. Using peripheral blood samples from grass-allergic, cat-allergic and healthy non-atopic subjects, we compared the frequencies and phenotype of CD154-positive T helper cells following stimulation with seasonal (grass) and perennial (cat dander) allergens. RESULTS: We identified a higher frequency of CD154+ T cells in grass-allergic individuals compared to healthy controls; this difference was not evident following stimulation with cat allergen. Activated Th1, Th2 and Tr1-like cells, that co-express IFNγ, IL4 and IL10, respectively, were identified in varying proportions in grass-allergic, cat-allergic and non-allergic individuals. We confirmed a close correlation between Th1, Th2 and Tr1-like cell frequency in non-allergic volunteers, such that the three parameters increased together to maintain a low Th2: Th1 ratio. This relationship was dysregulated in grass-allergic individuals with no correlation between the T cell subsets and a higher Th2: Th1 ratio. We confirmed previous reports of a late-differentiated T cell phenotype in response to seasonal allergens compared to early-differentiated T cell responses to perennial allergens. CONCLUSIONS: The findings confirm our existing work illustrating an important balance between Th1, Th2 and Tr1-like responses to allergens in health, where Th2 responses are frequently observed, but balanced by Th1 and regulatory responses. We confirm previous tetramer-based reports of phenotypic differences in T cells responding to seasonal and perennial allergens.

Protective role of sodium selenite on histopathological lesions, decreased T-cell subsets and increased apoptosis of thymus in broilers intoxicated with aflatoxin B1.

For evaluating the ability of selenium (Se) in counteracting the adverse effects of aflatoxin B1 (AFB1), two hundred 1-day-old male Avian broilers, divided into five groups, were fed with basal diet (control group), 0.3 mg/kg AFB1 (AFB1 group), 0.3 mg/kg AFB1+0.2 mg/kg Se (+Se group I), 0.3mg/kg AFB1+0.4 mg/kg Se (+Se group II) and 0.3mg/kg AFB1+0.6 mg/kg Se (+Se group III), respectively. Compared with control group, the decreased relative weight of thymus and percentages of mature thymocytes, congestion in medulla and much debris in cortex of thymus, and the increased apoptotic thymocytes were observed in AFB1 group. However, supplied dietary sodium selenite could increase the relative weight of thymus and percentages of mature thymocytes, and alleviate histopathological lesions. Compared with AFB1 group, the percentages of apoptotic thymocytes detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method and flow cytometry method in three +Se groups were decreased, the expression of Caspase-3 and Bax, through quantitative real-time PCR and immunohistochemical method, in three +Se groups were decreased, while the expression of Bcl-2 was increased. The results indicate that sodium selenite supplied in the diet, through a mechanism of apoptosis regulation, may ameliorated AFB1-induced lesions of thymus and accordingly improve the impaired cellular immune function.

In vivo vitiligo induction and therapy model: double-blind, randomized clinical trial.

In this study, we developed an in vivo vitiligo induction model to explore the underlying mechanisms leading to Koebner's phenomenon and to evaluate the efficacy of therapeutic strategies. The model consisted of 12 pigmented test regions on the back of generalized vitiligo patients that were exposed to three Koebner induction methods: cryotherapy, 755 nm laser therapy, and epidermal abrasion. In addition, four cream treatments (pimecrolimus, tacrolimus, steroid and placebo) were randomly applied. Koebnerization was efficiently induced by all three induction methods. In general, cryotherapy was the best method of Koebner induction, followed by 755 nm laser therapy and epidermal abrasion. Reproducible results were obtained, which showed enhanced depigmented surface areas and higher amounts of T lymphocytes in placebo-treated test zones compared to active treated areas. Tacrolimus and local steroids were better inhibitors of Koebner's process (P < 0.05) compared to pimecrolimus. Our in vivo vitiligo induction model is very informative to investigate vitiligo induction and to determine the efficacy of topical treatments in vitiligo. This proof of concept confirms the efficient comparison of head-to-head therapeutic strategies intra-individually in a standardized, specific and better timed way.

Vitamin D-mediated immune regulation in multiple sclerosis.

Although Vitamin D is best known as a modulator of calcium homeostasis, it also has immune modulating potential. A protective effect of Vitamin D on Multiple Sclerosis (MS) is supported by the reduced risk associated with sun exposure and use of Vitamin D supplements. Moreover, high circulating levels of Vitamin D have been associated with lower risk of MS. To gain more insight into putative regulatory mechanisms of Vitamin D in MS pathogenesis, we studied 132 Hispanic patients with clinically definite MS, 58 with relapsing remitting MS (RR MS) during remission, 34 RR MS patients during relapse, and 40 primary progressive MS cases (PP MS). Sixty healthy individuals matched with respect to place of residence, race/ethnicity, age and gender served as controls. Levels of 25(OH) Vitamin D and 1,25(OH)(2) Vitamin D, measured by ELISA were significantly lower in RR MS patients than in controls. In addition, levels in patients suffering relapses were lower than during remissions. By contrast, PP MS patients showed similar values to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specific T cells was significantly inhibited by 1,25(OH)(2) Vitamin D. Moreover, activated Vitamin D enhanced the development of IL-10 producing cells, and reduced the number of IL-6 and IL-17 secreting cells. Notably, VDR expression was induced by 1,25(OH)(2) Vitamin D in both activated and resting cells. Interestingly, T cells were able to metabolize 25(OH) Vitamin D into biologically active 1,25(OH)(2) Vitamin D, since T cells express 1α-hydroxylase constitutively. Finally, 1,25(OH)(2) Vitamin D also increased the expression and biological activity of IDO, triggering significant increase in the number of CD4+CD25+ T regulatory cells. Collectively, these findings suggest that 1,25(OH)(2) VitaminD plays an important role in T cell homeostasis during the course of MS, suggesting correction of its deficiency may be useful during treatment of the disease.

[Interstitial mycosis fungoid: a rare variant of mycosis fungoids. Two cases]. / Le MF interstitiel : une variante rare de mycosis fongoïde.

Mycosis fungoids can present with various clinical and histological features, with only a few of them being recognized as distinct entities in the current WHO and EORTC classifications. Histologically, mycosis fungoids (MF) usually show a superficial perivascular or band-like lymphocytic infiltrate with epidermotropism. We here report two cases of a rare histological variant of MF, called interstitial in the literature. Our first patient, a 71-year-old male, had a previously diagnosed MF, which clinically evolved towards nodules, showing histologically an interstitial lymphocytic infiltrate without epidermotropism and without large cell transformation. The second patient was a 64-year-old female with widespread plaques and nodules. Histologically, a dense dermal interstitial infiltrate was observed, with foci of epidermotropism, without large cell transformation. At relapse after treatment, she presented with plaques, papules and nodules, histologically showing a slight interstitial lymphocytic infiltrate that resembled granuloma annulare or inflammatory morphea. In both patients, clinical aspect suggested MF and a dominant T-cell clone was found in lesional skin. Nodules in MF are not always the hallmark of large cell transformation, but may correspond to unusual interstitial lesions. Diagnosis of such rare variant may be difficult and requires a good clinical pathological correlation together with the search for foci of epidermotropism on skin biopsy and for a dominant cutaneous T-cell clone.