Heightened Expression of CD39 by Regulatory T Lymphocytes Is Associated with Therapeutic Remission in Inflammatory Bowel Disease.
BACKGROUND
To evaluate whether changes in expression of CD39 by regulatory T lymphocytes (Treg) impact treatment response in inflammatory bowel disease. To then define the biological role of expression of CD39 on Treg in an animal model of colitis.


METHODS
A prospective study of consecutive patients commencing anti-tumor necrosis factor therapy with infliximab (IFX) or adalimumab (ADA), who were then followed for 12 months. Treatment responses were defined both symptomatically and by endoscopy showing mucosal healing. Peripheral blood Tregs were quantified by flow cytometry. Functional importance of CD39 expression by Treg was determined in an adoptive T-cell transfer model of colitis.


RESULTS
Forty-seven patients (ulcerative colitis, n = 22; Crohn's disease, n = 25) were recruited; 16 patients were complete responders and 13 nonresponders to anti-tumor necrosis factor. CD39 expression by Treg was lower in active inflammatory bowel disease and increased significantly after treatment in responders (CD39Treg/total Treg; 8% at baseline to 22.5% at late time point, P < 0.001). Responders were more likely to have therapeutic drug levels and in multivariate analysis therapeutic drug levels were associated with higher expression of CD39 by FoxP3 Treg and lower frequencies of interleukin 17A expressing cells. Tregs with genetic deletion of CD39 exhibit decrements in potential to suppress intestinal inflammation in a murine (CD45RB) T-cell transfer model of colitis in vivo, when compared with wild-type Treg.


CONCLUSIONS
Increased expression of CD39 by peripheral blood Treg is observed in the setting of clinical and endoscopic remission in inflammatory bowel disease. Deficiency of CD39 expression by Treg can be linked to inability to suppress experimental colitis.
*Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin and School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; †Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands; and ‡Division of Gastroenterology, Beth Israel Deaconess Medical School and Harvard Medical School, Boston, Massachusetts.
David J
DJ
Gibson
Louise
L
Elliott
Edel
E
McDermott
Miriam
M
Tosetto
Denise
D
Keegan
Kathryn
K
Byrne
Sean T
ST
Martin
Theo
T
Rispens
Garret
G
Cullen
Hugh E
HE
Mulcahy
Adam S
AS
Cheifetz
Alan C
AC
Moss
Simon C
SC
Robson
Glen A
GA
Doherty
Elizabeth J
EJ
Ryan
D000068879:Adalimumab / Q000627:therapeutic use; D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000097:blood*; D001081:Apyrase / Q000097:blood*; D003093:Colitis, Ulcerative / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D000069285:Infliximab / Q000627:therapeutic use; D020381:Interleukin-17 / Q000097:blood; D008297:Male; D051379:Mice; D008875:Middle Aged; D011446:Prospective Studies; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D005765:Gastrointestinal Agents; C508717:IL17A protein, human; D007155:Immunologic Factors; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D001081:Apyrase; C067869:CD39 antigen; D000068879:Adalimumab