Affects of immunosuppression on circulating dendritic cells: an adjunct to therapeutic drug monitoring after heart transplantation.
OBJECTIVE
Recent evidence emerges dendritic cells (DCs) as pharmacological targets of immunosuppressive drugs. Therefore, in this study we monitored DCs in peripheral blood to compare the effects of calcineurin inhibitors (CNI: cyclosporine, tacrolimus) and mammalian target of rapamycin inhibitors (sirolimus, SRL, everolimus, ERL) basis-immunosuppressive therapies in human heart transplanted (HTx) recipients.


METHODS
We compared HTx recipients which were converted from either CNI to ERL (severe renal dysfunction, n=8), or from SRL to ERL (approval of ERL for HTx, n=8) with 20 healthy human controls. Twenty four after the last CNI or SRL dose recipients were treated with ERL/BID on days 1-3. Peripheral blood was collected at trough in the morning before and on day 4 after conversion. Percentages of positive myeloid and plasmacytoid DC (m and pDC) subsets in peripheral blood were analysed by flow cytometry. The status of maturation was further characterised by flow cytometry analysis of % expression of CD83 and % expression of various intracellular cytokines (IL-1beta, TNF-alpha, IL-8, IL-12), respectively.


RESULTS
HTx recipients had higher % positive mDCs regardless the immunosuppressive therapy compared to controls (p<0.05). Whereas, % positive pDCs were only significantly lower in recipients converted from CNI to ERL compared to controls (p<0.05). The data consolidate the finding that the subset ratio pDCs/mDCs was lower in recipients compared to controls. But after conversion from CNI or SRL to ERL the ratio increased towards pDCs. Percentages of expression of CD83 on mDCs were not different among the recipient groups and controls. Recipients with CNI and SRL had higher % expression of IL-12 and lower % expression of IL-1beta compared to controls (p<0.05). However, after conversion to ERL % expression of both IL-12 and IL-1beta returned to control values in both groups.


CONCLUSIONS
The results showed that analysis of immunosuppression of circulating DCs in peripheral blood may be an adjunct to therapeutic drug monitoring to optimize immunosuppressive therapy after HTx.
Barten
Markus J
MJ
University of Leipzig, Department of Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany. bartenm@medizin.uni-leipzig.de <bartenm@medizin.uni-leipzig.de>
Garbade
Jens
J
Bittner
Hartmuth B
HB
Fiedler
Martin
M
Dhein
Stefan
S
Thiery
Joachim
J
Mohr
Friedrich W
FW
Gummert
Jan F
JF
D015703:Antigens, CD / Q000378:metabolism; D002452:Cell Count; D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016903:Drug Monitoring / Q000379:methods; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D018664:Interleukin-12 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D016559:Tacrolimus / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000097802:CD83 Antigen
D015703:Antigens, CD; D016572:Cyclosporine; D000068338:Everolimus; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D018664:Interleukin-12; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D020123:Sirolimus; D016559:Tacrolimus; D000097802:CD83 Antigen