Photopheresis affects the course of experimental allergic encephalomyelitis in Lewis rat.

BACKGROUND/PURPOSE: The mechanism responsible for the beneficial effects of extracorporeal photochemotherapy (ECP) remains unknown. In the rat model of experimental allergic encephalomyelitis (EAE), the transfer of encephalitogenic cells (EAE cells) induces transient passive EAE, followed by resistance to subsequent disease induction through immunization with central nervous system antigens (active EAE). METHODS: We tested whether ECP exerts its therapeutic effect by inducing an immune response targeted on circulating pathogenic T-lymphocytes, which results from their increased immunogenicity. We compared the potential of untreated versus ECP-treated encephalitogenic cells to transfer passive EAE and protect against active induction of the disease. The UVA irradiation conditions were derived from intensive ECP protocols used in human clinical studies. RESULTS: Animals receiving untreated cells showed clinical symptoms following cell transfer but not after subsequent immunisation, whereas those receiving ECP-treated cells remained healthy following cell transfer but experienced clinical symptoms after subsequent immunisation. However, these symptoms were less marked than in control naive rats. CONCLUSION: Under these ECP protocol conditions, ECP-treated cells have no greater active stimulatory potential for the recipient immune system than untreated cells, since they are less effective at triggering the response that causes the resistant state to active EAE. We suggest that intensive ECP protocol may have deleterious effects with a risk of relapses after treatment discontinuation. The search for the irradiation threshold that would inhibit the T-cell pathogenic properties, but retain their ability to educate the immune system, remains a major research challenge.

Extracorporeal photochemotherapy for secondary chronic progressive multiple sclerosis: a pilot study.

BACKGROUND/PURPOSE: Extracorporeal photochemotherapy (ECP) has been proposed for the treatment of various auto- and allo-immune reactions. However, a standard ECP regimen did not significantly alter the course of chronic progressive multiple sclerosis (MS). We tested whether an intensive ECP treatment can affect the course of secondary chronic progressive form of MS. METHODS: Five patients free of immunosuppression were included. Soluble 8-MOP was added ex vivo to a mononuclear cell suspension obtained in a cell separator. This cellular suspension was then irradiated using an UVA irradiator and re-infused into the patient. ECP was performed once a week for 6 weeks and then, depending on clinical evaluation, for a maximum of 6 months, with 2-year follow-up after treatment discontinuation. Scoring was performed with the Kurzke scale and EDSS by a single independent neurologist. RESULTS: One patient was excluded because of recurrent attacks at the very beginning of treatment. Four patients completed the study: one exhibited clinical improvement and three remained stable during the first 6 months of treatment. However, all experienced relapse or worsening of the disease after discontinuation of ECP treatment. CONCLUSION: Our intensive ECP treatment only transiently alters the course of the severe secondary chronic progressive form of MS, with rebound after treatment discontinuation.

Effect of protein A immunoadsorption in nephrotic syndrome of various etiologies.

Protein A immunoadsorption (IA) has proved effective in reducing proteinuria in patients with nephrotic syndrome after recurrence of focal and segmental glomerulosclerosis (FSGS) in kidney transplants. The effect of IA in nephrotic syndrome of other etiologies remains unknown. Nine patients with nephrotic syndrome secondary to membranous nephropathy (four cases), diabetes mellitus (one case), IgA nephropathy (two cases), and amyloidosis (two cases) had three to five IA of 2.5 plasma volumes over 4 to 8 d. Patients received no concomitant immunosuppressive treatment, and antihypertensive drugs were left unchanged. Proteinuria decreased from 12.64 +/- 5.49 to 3.35 +/- 2.2 g/24 h (mean +/- SD) in all patients after three to five IA. Hematocrit decreased from 37.32 to 32.64% (12.5% hemodilution) and serum albumin from 25.43 to 18.6 g/L (26.4% decrease). Proteinuria returned to baseline levels within 1 mo, as described in recurrent FSGS following transplantation. When serum albumin balance was controlled by albumin infusion after IA in two patients, comparable decreases in proteinuria were observed. Therefore, IA is effective in producing short-term reduction of proteinuria in nephrotic syndromes related not only to FSGS but also to membranous and IgA nephropathies, diabetes mellitus, and amyloidosis, which suggests that IA removes a nonspecific circulating hemodynamic-altering or permeability-increasing factor.

Treatment of graft-versus-host disease by extracorporeal photochemotherapy: a pilot study.

BACKGROUND: Graft-versus-host disease (GVHD) is a major complication after bone marrow transplantation, which may be refractory to immunosuppressive drugs. As preliminary case reports suggested that extracorporeal photochemotherapy (ECP) using a Therakos device might be beneficial, we conducted a pilot study to assess the efficacy and safety of a new ECP method that does not require administration of 8-methoxypsoralen (8-MOP) to the patient. METHODS: ECP was performed three times a week for 3 weeks and then tapered according to the patient's course. Soluble 8-MOP was added ex vivo to an enriched mononuclear cell suspension obtained by a cell separator. This cellular suspension was then ultraviolet A irradiated and reinfused into the patient. Evaluation was performed using specific objective tests depending on clinical conditions. RESULTS: The two patients in the study with acute GVHD and severe liver dysfunction resistant to steroid pulse showed no improvement with ECP treatment. The five patients with chronic GVHD (c-GVHD) had the following clinical features: three patients had myositis and two patients had severe cutaneous c-GVHD, including one patient with sclerodermoid lesions, one with bronchiolitis obliterans, one with bronchitis, and one with liver involvement. Immunosuppressive drugs were either prohibited or ineffective. The number of procedures for each patient ranged from 13 to 30. Cytapheresis required the use of a double-lumen catheter (4/5) or an arteriovenous fistula (1/5). No side effects were related to 8-MOP or ultraviolet A irradiation. Four of five patients improved after ECP; one patient with bronchiolitis obliterans, a fibrotic condition, remained stable. CONCLUSIONS: ECP treatment may be helpful for the treatment of severe c-GVHD and the avoidance of increased immunosuppression.

Anti-neutrophil cytoplasm antibodies in patients with ACR criteria for polyarteritis nodosa: help for systemic vasculitis classification?

The american college of rheumatology (ACR) proposed in 1990 revised clinical criteria for systemic vasculitis classification to define homogeneous group of patients for clinical trials. However, microscopic polyarteritis (MPA) was not clearly identified from polyarteritis nodosa (PAN). Since anti-neutrophil cytoplasm antibodies (ANCA) are markers of disease activity of small vessel vasculitides including MPA, we tested the clinical significance of ANCA in 24 patients with PAN according to the ACR 1990 criteria. Two of 24 patients had ANCA, as defined by indirect immunofluorescence on normal human neutrophils, antigen-specific ELISA and Western blot analysis. However, they exhibited histologically proven small vessel but not medium vessel vasculitis. Furthermore, they had neither artery microaneurysms nor large organ injury consequent upon large vessel occlusion. Although they satisfied ACR criteria for PAN, they probably were misclassified and should be considered as MPA. We conclude that: (i) ANCA are not found in patients with classical PAN in the absence of MPA features; (ii) caution should be exercised when defining PAN according to the ACR 1990 criteria; (iii) ANCA may help systemic vasculitis classification.

Topographical dissociation of BCL-2 messenger RNA and protein expression in human lymphoid tissues.

Immunohistochemistry and in situ hybridization with a synthetic oligonucleotide probe were used to compare the topographical distribution of BCL-2 proto-oncogenic protein with that of its messenger RNA (mRNA) in normal lymphoid tissues, follicular lymphomas, and lymphoma-derived cell lines. In normal lymph nodes, BCL-2 protein was most abundant in the small lymphocytes of primary lymphoid follicles and the mantle zones of secondary follicles, virtually absent within germinal centers, and of variable abundance in many interfollicular cells. In contrast, the distribution of BCL-2 mRNA was roughly reciprocal to that of the protein with intense hybridization signal in germinal centers and almost none in mantle zones. Discordant BCL-2 RNA and protein levels were also observed in tonsillar epithelial cells and cortical thymocytes. Concordant and abundant expression of BCL-2 mRNA and protein was detected in biopsy tissues and cell lines from t(14;18)-carrying lymphomas. The contrasting distributions of BCL-2 protein and RNA in normal lymphoid tissues suggest that translational and posttranslational control mechanisms play a significant role in regulating BCL-2 protein levels in germinal center cells, epithelial cells, and cortical thymocytes. Concordant BCL-2 mRNA and protein levels in follicular lymphomas suggest that translational control mechanisms may be disrupted as part of the sequence of genetic changes that transforms normal lymphoid cells into neoplastic follicular lymphoma cells.