Shigaku Ikeda 1, Hidetoshi Takahashi 2, Yasushi Suga 3, Hikaru Eto 4, Takafumi Etoh 5, Keiko Okuma 6, Kazuo Takahashi 7, Takeshi Kanbara 8, Mariko Seishima 9, Akimichi Morita 10, Yasutomo Imai 11, Takuro Kanekura 12
Therapeutic depletion of myeloid lineage leukocytes in patients with generalized pustular psoriasis indicates a major role for neutrophils in the immunopathogenesis of psoriasis
J Am Acad Dermatol 2013 Apr;68(4):609-617. doi: 10.1016/j.jaad.2012.09.037. Epub 2013 Jan 17.
Background: Generalized pustular psoriasis (GPP) is a chronic autoimmune disease characterized by fever, erythema, and neutrophilic pustules over large areas of the skin. GPP does not respond well to pharmacologic intervention. Objective: We sought to assess efficacy of selectively depleting the myeloid lineage leukocytes in patients with GPP. Methods: Fifteen patients with persistent moderate to severe GPP despite conventional therapy were included. Eligible patients had more than 10% of their skin area covered by pustules. Treatment with oral etretinate, cyclosporine, methotrexate, prednisolone, and topical prednisolone/vitamin D3 was continued if had been initiated well in advance of study entry. Five sessions of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn (JIMRO Co Ltd, Takasaki, Japan) were administered (1 session/wk over 5 weeks) to selectively deplete Fcγ receptor and complement receptor bearing leukocytes. Efficacy was assessed by measuring the skin areas covered by pustules at baseline and 2 weeks after the last GMA session. Results: One patient did not complete the first GMA session. Based on the GPP severity scores relative to entry, the overall scores improved (n = 14, P = .0027), and the area of erythroderma (P = .0042), pustules (P = .0031), and edema (P = .0014) decreased. Likewise, Dermatology Life Quality Index improved (P = .0016), reflecting better daily function and quality of life. Twelve patients were judged as responders (85.7%), and 10 patients maintained the clinical response for 10 weeks after the last GMA session without any change in medication. Limitations: This study was unblinded and without a placebo arm. Conclusion: GMA in this clinical setting was safe and effective, suggested a major role for granulocytes/monocytes in the immunopathogenesis of GPP.
Down-modulation of toll-like receptor 2 expression on granulocytes and suppression of interleukin-8 production due to in vitro treatment with cellulose acetate beads
The Adacolumn, which is filled with cellulose acetate beads (CA beads), has been used as a medical device for inflammatory diseases. The CA beads selectively adsorb granulocytes and monocytes and remove them from the peripheral blood. The anti-inflammatory effects of the Adacolumn are possibly caused by removal of these cells but also due to the functional changes in the processed cells. In this study, we investigated the effects of CA beads treatment on modulation of the expression of innate immunity receptors such as the Toll-like receptor (TLR) family and production of an inflammatory cytokine, interleukin-8 (IL-8). Changes in the expressions of TLR1, 2, 4 and 6 in peripheral leukocytes exposed to CA beads were examined by flow cytometry. TLR2 expression on the surface of granulocytes exposed to CA beads was decreased, but the amount of intracellular TLR2 was increased, possibly by internalization. These changes were not observed in monocytes or lymphocytes. Peptidoglycan (PGN) treatment produced similar changes in TLR2 on granulocytes. We also measured the amounts of IL-8 in cultured blood treated with lipopolysaccharide (LPS) and PGN, which are known TLR agonists. PGN-induced IL-8 production was lower in CA beads-treated leukocytes than that in non-treated leukocytes, but LPS did not induce these changes. Based on these findings, we conclude that the down-modulation of TLR2 and suppression of IL-8 production on granulocytes by CA beads, may play an important role in the anti-inflammatory effects of the Adacolumn.
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