Therapeutic Granulocyte and Monocyte Apheresis (GMA) for Treatment Refractory Sarcoidosis: A Pilot Study of Clinical Effects and Possible Mechanisms of Action.
Sarcoidosis is a systemic, inflammatory disorder, which in a proportion of patients runs a chronic progressive course despite immunosuppressive treatment. Therapeutic granulocyte and monocyte apheresis (GMA) has been shown to be an effective treatment option for other systemic inflammatory disorders, but has not yet been investigated in sarcoidosis. The aim of this study was to evaluate the response to GMA in sarcoidosis. Seven patients with sarcoidosis refractory to standard immunosuppressive therapy received 10 GMA sessions. All patients underwent chest X-ray, spirometry, a Chronic Respiratory Disease Questionnaire (CRQ-SAS), blood tests and bronchoscopy with bronchoalveolar lavage (BAL) before treatment and at 2-4 weeks and 3 months (except bronchoscopy) after the last treatment session. Bronchoalveolar lavage fluid (BALF) cell differential counts were recorded and T cells from blood and BALF were analysed for markers of activity, differentiation and T regulatory function. Compared to baseline, five of seven patients reported an improvement in dyspnoea score. In BALF there was an increase in the percentage of macrophages and a decrease in the percentage of lymphocytes and CD4(+) /FoxP3(+) T cells. Furthermore, the decrease in BALF CD4(+) /FoxP3(+) T cells correlated significantly with an improvement in dyspnoea score. In peripheral blood there was a statistically significant increase in the percentage of CD4(+) /CD27(-) T cells and a trend towards an initial increase in the percentage of CD4(+) /FoxP3(+) T cells, followed by a statistically significant decrease. The effects of GMA on regulatory T cells are consistent with those observed in other inflammatory disorders and could potentially translate into a clinical benefit.
The expression profile of functional regulatory T cells, CD4+CD25high+/forkhead box protein P3+, in patients with ulcerative colitis during active and quiescent disease
K Kamikozuru 1, K Fukunaga, S Hirota, N Hida, Y Ohda, K Yoshida, Y Yokoyama, K Tozawa, K Kawa, M Iimuro, K Nagase, A R Saniabadi, S Nakamura, H Miwa, T Matsumoto Clin Exp Immunol 2009 May;156(2):320-7. doi: 10.1111/j.1365-2249.2009.03904.x. Epub 2009 Mar 9.
Regulatory T cells (T(reg)) have an essential role in maintaining immune tolerance in the gut. The functional CD4(+) T(reg) express the transcription factor forkhead box protein 3 (FoxP3) or a CD25(high) in humans. Further, depletion of elevated granulocytes/monocytes by extracorporeal adsorption (GMA) induces immunomodulation in patients with ulcerative colitis (UC). We investigated the impact of GMA on T(reg). Thirty-one UC patients, clinical activity index (CAI) 12.1 +/- 2.97, refractory to conventional medications including intravenous corticosteroid and 13 healthy controls (HC), were included. Patients received five GMA sessions over 5 weeks. Biopsies from the rectal mucosa and blood samples at baseline and post-GMA were immunostained with anti-CD4/FoxP3 and anti-CD4/CD25 antibodies for immunohistochemistry and flow cytometry. Following GMA, 22 of 31 patients achieved remission (CAI <or= 4, P < 0.01) and their endoscopic activity index decreased from 10.6 +/- 2.32 to 4.75 +/- 1.48 (P = 0.003). The circulating CD4(+)CD25(high+) T(reg) level was low and increased markedly in responders (P < 0.02). In the nine non-responders, the baseline CD4(+)CD25(high+) T(reg) level was about 50% of the level in the responders (P < 0.03) or in the HC (P < 0.01), and all nine had to undergo colectomy. Conversely, the number of CD4(+)/FoxP3(+) mucosal T(reg) in GMA responders decreased significantly after the fifth GMA session compared with the baseline level (P < 0.05). It is believed that the CD4(+) T(reg) has an essential role in the control of immune pathology in UC patients and a net influx of these cells from the circulation into the mucosa may proceed to suppress inflammation. GMA can impact the circulating as well as the mucosal levels of T(reg).
Demonstration of low-regulatory CD25High+CD4+ and high-pro-inflammatory CD28-CD4+ T-Cell subsets in patients with ulcerative colitis: modified by selective granulocyte and monocyte adsorption apheresis
Yoko Yokoyama 1, Ken Fukunaga, Yoshihiro Fukuda, Katsuyuki Tozawa, Koji Kamikozuru, Kunio Ohnishi, Takeshi Kusaka, Tadashi Kosaka, Nobuyuki Hida, Yoshio Ohda, Hiroto Miwa, Takayuki Matsumoto Dig Dis Sci 2007 Oct;52(10):2725-31. doi: 10.1007/s10620-006-9560-z. Epub 2007 Apr 3.
Low-CD25(High+)CD4(+), a subset of regulatory CD25(+)CD4(+) T cells and high-inflammatory CD28(-)CD4(+) T cells can exacerbate ulcerative colitis (UC). This study sought to investigate the frequency of CD25(High+)CD4(+) and CD28(-)CD4(+) T cells in patients with UC and the changes in these cells during Adacolumn granulocyte and monocyte adsorption apheresis (GMA). Subjects were 12 patients with active UC, 11 with quiescent UC, and 14 healthy volunteers (HVs). The mean clinical activity index was 15.7 +/- 2.2 in active UC and 4.5 +/- 1.1 in quiescent UC. Peripheral blood samples were stained with CD4, CD25, and CD28 antibodies for flow cytometry. Patients with active UC received GMA and blood samples were examined before and after the first GMA session. Patients with active UC (P < 0.04) or quiescent UC (P < 0.02) had a higher percentage of CD28(-)D4(+)T cells compared with HVs, while the percentage of CD28(+)CD4(+) T cells was lower in both UC groups compared with HVs (P = 0.03 and P < 0.02). Patients with active UC had a lower percentage of CD25(High+)CD4(+)T cells compared with quiescent UC patients (P < 0.001). A significant increase in CD25(High+)CD4(+) T cells was associated with GMA (P < 0.03). Low CD25(High+)CD4(+) and high CD28(-)CD4(+) are prominent features in UC. The increase in CD25(High+)CD4(+) T cells induced by GMA should contribute to improved immune function. Additional studies are warranted, since a low frequency of CD25(High+)CD4(+) (-) and a high frequency of CD28(-)CD4(+) (-) expressing T cells might be a predictor of clinical response to GMA.
In vivo modulation of leukocyte trafficking receptor following therapeutic purging of myeloid cells: implications for treatment of HIV infection and other immune disorders
Therapeutic purging of myeloid cells (monocytes and granulocytes) (MYP) has been proposed as a treatment of severe inﬂammatoryconditions like ulcerative colitis and rheumatoid arthritis. Although direct purging of inﬂammatory cells contributes to its efﬁcacy, the precise mechanism of action is still unclear. We have tested MYP in a pilot study on 12 patients with chronic HIV infection, of whom 6 underwent MYP. Three/6 MYP patients and none of the controls displayed a strong and long-lasting decrease of cells expressing CXCR3,a major chemokine receptor responsible for trafﬁcking of inﬂammatory cells. In these three patients, the number of circulating CD4 T cells increased during treatment. The data provide a rational for the use of MYP as a therapeutic tool acting via the modulation of immune cell trafﬁcking
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