G. De Aloe

Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T‐cell lymphoma

Extracorporeal photochemotherapy (ECP) has been shown to be a potent activator of peripheral blood macrophages because it causes a marked release of macrophage‐dependent proinflammatory cytokines, and it is therefore currently considered to be a safe and non‐toxic immunomodulatory treatment. On this basis we studied the function of peripheral blood mononuclear cells (PBMC) in eight patients with early stage (Ib) cutaneous T‐cell lymphoma (CTCL), before and 1 year after ECP, together with their clinical and histological responses. In particular we evaluated in vitro phytohaemagglutinin (PHA)‐stimulated proliferation and production of interleukin‐4 (IL‐4) and interferon‐&ggr; (IFN‐&ggr;) as well as lipopolysaccharide (LPS)‐induced production of IL‐12. Before treatment we observed that PBMC of patients produced significantly higher levels of IL‐4 and lower levels of IFN‐&ggr; and IL‐12 than those of healthy control subjects. After 1 year of ECP, IL‐4, IFN‐&ggr; and IL‐12 production no longer differed from that of control subjects. Moreover, we observed a good clinical result matched by histological response. Our data confirm that early‐ stage CTCL patients show a predominantly type‐2 immune response that might be responsible for several immunological abnormalities found in this disease. We have demonstrated that ECP reverses the T‐helper type 1/T‐helper type 2 (Th1/Th2) imbalance and may therefore be considered an efficient biological response modifier.

Role of extracorporeal photochemotherapy in patients with refractory chronic graft-versus-host disease

Recent studies suggest that extracorporeal photochemotherapy (ECP) may be beneficial in patients with steroid‐refractory chronic graft‐versus‐host disease (cGvHD). However, it is not yet clear whether certain conditions, such as age, mode of onset of cGvHD etc., influence clinical response and whether certain affected organs are more sensitive to ECP than others. We analysed the main clinical and laboratory parameters related to evolution of the disease in 32 steroid‐refractory cGvHD patients, to identify any useful response predictors to ECP. ECP affected the course of the disease positively in 78% (25/32) of our cases.

Extracorporeal photochemotherapy induces apoptosis of infiltrating lymphoid cells in patients with mycosis fungoides in early stages. A quantitative histological study

Extracorporeal photochemotherapy (ExP) is a well‐tolerated new form of chemoimmunotherapy, which is considered to be effective for cutaneous T‐cell lymphoma (CTCL) and the treatment of choice for Sézary syndrome. Improvements have also been seen in patients with non‐erythrodermic mycosis fungoides (MF) in the early stages, even when tumour cells are not detectable in the peripheral blood. In this study, we used ExP as a monotherapy in seven patients who had early stage (Ib) MF, and who were no longer responsive to or had contraindications for other therapies. We observed a clinical improvement in the disease after 12 months of treatment: one patient showed a complete response, five a partial response, and one remained stable. In each patient we compared skin biopsies of large plaque lesions before and after the treatment. We undertook a histological evaluation of the infiltrate. The lymphoid cell proliferation and death rates were quantified using the following parameters: lymphoid cell density (LCD), Ki67+ lymphoid cell nuclei percentage (Ki67+ Lcn percentage), and apoptotic index (AI). Significant decreases in the lymphoid cell infiltrate and in cell proliferation, and a significant increase in AI were observed after therapy. The mean LCD decreased from 187 ± 33 to 34 ± 17·7, Ki67+ Lcn mean percentage decreased from 16·9 ± 3·9 to 4·9 ± 2·4, and the AI mean value increased from 0·05 ± 0·03 to 2·41 ± 1·54. Our results suggest a role for apoptosis in the improvement of the skin lesions and are in line with some reports on the mode of action of ExP. Although the way in which ExP works needs to be clarified further, it does seem to stimulate a CD8+ cell‐mediated anticlonotypic activity against circulating pathogenic clones. Furthermore, a release of tumour necrosis factor α (TNF‐α) by circulating monocytes has been demonstrated after ExP. Both are known to induce cell death by apoptosis.

Extracorporeal photopheresis affects co‐stimulatory molecule expression and interleukin‐10 production by dendritic cells in graft‐versus‐host disease patients

Graft‐versus‐host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. Extracorporeal photochemotherapy (ECP) has been introduced as an alternative treatment for GVHD refractory to conventional immunosuppressive treatment, although its mechanism of action is not yet clear. We investigated, in seven GVHD patients, the effects of ECP on dendritic cell maturation and cytokine production in an in vitro model that could mimic the potential in vivo effect of reinfusion of ECP‐treated peripheral blood mononuclear cells. The model was based on co‐culture of ECP‐treated lymphocytes with monocyte‐derived dendritic cells (DCs) of the same patient. We found that the co‐culture of ECP‐treated lymphocytes with immature DCs reduced CD54, CD40 and CD86 mean fluorescence intensity (MFI) significantly after lipopolysaccharide (LPS) stimulation, without affecting human leucocyte antigen D‐related and CD80 MFI. In the same co‐culture model, DCs produced increased amounts of interleukin (IL)‐10 when co‐cultured with ECP‐treated lymphocytes and stimulated with LPS, while IL‐12 and tumour necrosis factor‐α production were not affected. These results suggest that reinfusion of large numbers of autologous apoptotic lymphocytes is significant for the therapeutic outcome of ECP through down‐regulation of co‐stimulatory molecules on DCs, inducing non‐fully mature DCs with a low signal 2 and up‐regulation of IL‐10, which is an immunosuppressive cytokine.

Extracorporeal photochemotherapy in the treatment of eosinophilic fasciitis

Background Eosinophilic fasciitis (EF) is a rare connective tissue disorder characterized clinically by symmetrical swelling, induration and thickening of the skin and histologically by thickening of the fascia with chronic inflammatory infiltrate containing eosinophils. The disease is classified in the spectrum morphea/systemic sclerosis and treated with systemic steroids and other immunosuppressant drugs.

Clinical Evaluation of the Trophic Effect of Polydeoxyribonucleotide (PDRN) in Patients Undergoing Skin Explants. A Pilot Study

SUMMARY Objective: The purpose of this double-blind, randomised, placebo-controlled study was to assess the effects of intramuscular and subcutaneous PDRN in favouring the wound-healing process in donor sites of grafts. Methods: 26 adult patients of both sexes (15 males and 11 females; mean age: 68.2 ± 16.1 years) subjected to skin explants due to plastic surgery were eligible to participate in this double-blind, placebo-controlled study. Patients were randomly allocated into the PDRN group (14 subjects) or the placebo group (12 subjects). PDRN (5625 mg/vial) or placebo were administered by the intramuscular route once daily, associated with a subcutaneous administration of the same dosage form (2 vials every 3 days) for 10 consecutive days. The primary end point for efficacy was the evolution of wound healing in donor sites, which was evaluated measuring wound surface area and then calculating percentage re-epithelialisation. Secondary end points were local subjective symptoms, such as pain and itching, and objective signs such as perilesional erythema and blisters. Signs and symptoms were quantified through an analogue scale. Results: At day 7 of the treatment period, the difference in percentage of re-epithelialisation was statistically significant (p < 0.008) in; favour of the PDRN group. At the end of the observational period, between-group comparison demonstrated that patients treated: with PDRN had a more prompt trophic effect. No adverse events were reported during the trial. Conclusions: The findings of our study demonstrated that PDRN is able to modify positively the repair processes in donor sites of autologous skin grafts. This could improve the clinical outcome and decrease the need for additional therapies or hospital stay.

Extracorporeal Photochemotherapy Induces a Significant Increase in CD36+ Circulating Monocytes in Patients with Mycosis fungoides

BACKGROUND In patients with Sezary syndrome undergoing extracorporeal photochemotherapy it is currently thought that photodamage of a congruent number of pathogenic circulating T cells is a necessary condition for a specific anticlonal response to be induced against these cells by the immune system. However other mechanisms of action, such as the induction of release by photoirradiated monocytes of some cytokines, are thought to cooperate in the induction of a therapeutic response. OBJECTIVE We investigated the effects of extracorporeal photochemotherapy on peripheral blood mononuclear cells in seven stage Ib cutaneous T cell lymphoma patients. METHOD Samples of peripheral blood were taken before starting extracorporeal photochemotherapy (baseline), and before the 3rd and 6th cycle of treatment, and then incubated with specific monoclonal antibodies. RESULTS The results showed a significant increase of CD8+ and CD36+ and a significant decrease of CD25+ in all the treated patients. CONCLUSION Our results show that extracorporeal photochemotherapy is able to induce an increase of CD36+ cell in peripheral blood of patients with mycosis fungoides in its early stages. This subset of monocytes could be involved in the complex mechanism of action of extracorporeal photochemotherapy.

Extracorporeal photopheresis affects interleukin (IL)-10 and IL-12 production by monocytes in patients with chronic graft-versus-host disease.

Background  Chronic graft‐versus‐host disease (cGVHD) is a major complication of allogeneic bone marrow transplantation. Extracorporeal photopheresis (ECP) has recently been introduced as an alternative treatment for cases of cGVHD refractory to conventional immunosuppressive treatment, but its mechanism of action is not yet clear.

Floppy eyelid syndrome associated with obstructive sleep apnoea

Floppy eyelid syndrome (FES), initially reported by Culbertson and Ostler in 1981, is a rare disorder of unknown aetiology, often described in association with other systemic conditions, manifesting as an easily everted, floppy upper eyelid, upper papillary conjunctivitis and nonspecific irritative symptoms. We report a 45-year-old obese woman with intense conjunctival hyperaemia and papillary hypertrophy whose left upper eyelid was pulpy and easily everted (Fig. 1). Biopsy showed thickening of the epithelium with a mild chronic lymphocytic tarsal infiltrate (Fig. 2). Giemsa-orcein staining revealed a marked decrease in the tarsal elastic network with fragmentation and loss of elastic fibres. Ultrastructural study confirmed changes in tarsal elastin, which appeared disorganized and focally disrupted, with a reduced

Conjunctival edema and alopecia of the external third of the eyebrows in a patient with Meige syndrome.

Abstract · Purpose: To describe a patient with Meige syndrome in whom we observed the coexistence of hereditary lymphedema of the lower legs, conjunctival edema and alopecia of the lateral third of the eyebrows. · Methods: Case report. · Results: Histological examination of the conjunctival and skin specimens showed dermal edema and a slight reduction in the number of severely ectatic lymphatics in the reticular dermis. The vessel were identified as lymphatics on the basis of immunohistochemical evidence of discontinuity and/or absence of basement membrane. · Conclusions: Clinical and histological findings suggest that the etiopathogenesis of the edema in Meige syndrome is related to a structural ectatic defect of lymphatics. This anomaly seems to involve both skin and other sites, such as conjunctival mucosa.