Effects of different immunosuppressive regimens on regulatory T-cells in noninflamed colon of liver transplant recipients.
BACKGROUND
Regulatory T-cells (Treg) are natural suppressors of autoimmunity. Previous studies indicate that immunosuppressive drugs, especially calcineurin-inhibitors, may interfere with Treg homeostasis. Inflammatory bowel disease (IBD) can relapse or develop de novo after liver transplantation. IBD is associated with a relative deficiency of Treg. The aim of this study was to determine the effect of long-term immunosuppression on the presence of Treg in the noninflamed colonic mucosa of liver transplant recipients.


METHODS
Colonic biopsies of normal mucosa of 36 liver transplant recipients on different types of immunosuppression and 11 controls were studied. Treg marker Foxp3 and Treg products transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) were studied by quantitative polymerase chain reaction (Q-PCR) and immunohistochemistry. TGF-beta-induced Smad-protein 3 and 7 were studied by Q-PCR.


RESULTS
No significant differences between controls and patients were observed in IL-10, TGF-beta, and Smad expression. Mucosal Foxp3 mRNA levels and Foxp3+CD3+ cells were significantly reduced in transplant recipients using prednisone/azathioprine/tacrolimus compared with controls but no direct relationship between Foxp3 expression and 1 specific drug was detected.


CONCLUSIONS
These results challenge the hypothesis that calcineurin-induced reduction of Treg or TGF-beta expression predisposes nontransplanted tissue to inflammation, but indicate that combined immunosuppression hampers Treg development in the intestine.
Verdonk
R C
RC
Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands.
Haagsma
E B
EB
Jonker
M R
MR
Bok
L I H
LI
Zandvoort
J H
JH
Kleibeuker
J H
JH
Faber
K N
KN
Dijkstra
G
G
D000328:Adult; D000368:Aged; D015551:Autoimmunity / Q000187:drug effects; D001706:Biopsy; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics; D051906:Smad7 Protein / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D051900:Smad3 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D012313:RNA