Tolerogenic immunosuppression for organ transplantation.
BACKGROUND
Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants.


METHODS
82 patients awaiting kidney, liver, pancreas, or intestinal transplantation were pretreated with about 5 mg/kg of a broadly reacting rabbit antithymocyte globulin during several hours. Post-transplant immunosuppression was restricted to tacrolimus unless additional drugs were needed to treat breakthrough rejection. After 4 months, patients on tacrolimus monotherapy were considered for dose-spacing to every other day or longer intervals.


RESULTS
We frequently saw evidence of immune activation in graft biopsy samples, but unless this was associated with graft dysfunction or serious immune destruction, treatment usually was not intensified. Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13-18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13-18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11).


CONCLUSIONS
The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation.
Starzl
Thomas E
TE
Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. mangantl@msx.upmc.edu <mangantl@msx.upmc.edu>
Murase
Noriko
N
Abu-Elmagd
Kareem
K
Gray
Edward A
EA
Shapiro
Ron
R
Eghtesad
Bijan
B
Corry
Robert J
RJ
Jordan
Mark L
ML
Fontes
Paulo
P
Gayowski
Tim
T
Bond
Geoffrey
G
Scantlebury
Velma P
VP
Potdar
Santosh
S
Randhawa
Parmjeet
P
Wu
Tong
T
Zeevi
Adriana
A
Nalesnik
Michael A
MA
Woodward
Jennifer
J
Marcos
Amadeo
A
Trucco
Massimo
M
Demetris
Anthony J
AJ
Fung
John J
JJ
D000961:Antilymphocyte Serum / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007422:Intestines / Q000637:transplantation; D016030:Kidney Transplantation / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology; D018655:Lymphocyte Count; D008875:Middle Aged; D016035:Pancreas Transplantation / Q000276:immunology; D011300:Preoperative Care; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016559:Tacrolimus