Extracorporeal elimination of TNF-alpha-producing CD14(dull)CD16(+) monocytes in leukocytapheresis therapy for ulcerative colitis.
BACKGROUND
In recent years leukocytapheresis using a leukocyte removal filter (known as lymphocytapheresis, LCAP) has been applied to the treatment of various autoimmune diseases including ulcerative colitis (UC). In the present study we aimed to clarify how LCAP therapy modifies inflammatory responses by modulating circulating TNF-alpha-producing monocytes.


METHODS
Mononuclear cells were obtained from blood before and after the first treatment, and the expression profiles of various immune cells (naive versus. memory, regulatory CD4(+)CD25(bright) versus non-regulatory CD4(+)CD25(-) T cells, and CD14(+)CD16(-) versus CD14(dull)CD16(+) monocytes) were assessed. To evaluate immunological differences between CD14(+)CD16(-) and CD14(dull)CD16(+) monocytes, the expression of TNF-alpha, IL-6, IL-12, IL-10, IL-18, surface toll-like receptor 2 (TLR2), TLR4, and other activation markers including HLA-DR, CD80 and CD86, as well as cytokine profiles, were analyzed.


RESULTS
LCAP treatment selectively removed CD14(dull)CD16(+) monocytes, which preferentially produce TNF-alpha and IL-12 and express HLA-DR, CD80, CD86, and TLR2, compared with the major fraction of CD14(+)CD16(-) monocytes, which conversely produce a higher amount of IL-10. In addition, the CD4(+)CD45RO(+)CD62L(-)/CD4(+)CD45RO(+)CD62L(+) ratio was significantly lower after LCAP therapy. However, the CD4(+)CD25(bright)/total CD4(+) ratio did not change.


CONCLUSIONS
The present findings revealed the real target of proinflammatory CD14(dull)CD16(+) monocytes removed during LCAP treatment of UC and that LCAP might be used as an extracorporeal anti-TNF-alpha therapy, expanding the clinical applications of this procedure to include the treatment of Crohn's disease.
Kanai
Takanori
T
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Makita
Shin
S
Kawamura
Takahiro
T
Nemoto
Yasuhiro
Y
Kubota
Daisuke
D
Nagayama
Kazuyoshi
K
Totsuka
Teruji
T
Watanabe
Mamoru
M
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D007937:Leukapheresis; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008297:Male; D017452:Receptors, IgG / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology
D018950:Lipopolysaccharide Receptors; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha