Defining optimal immunosuppression for islet transplantation based on reduced diabetogenicity in canine islet autografts.
BACKGROUND
The recent results of clinical islet transplantation have improved substantially with the introduction of a more potent but less diabetogenic immunosuppressant protocol. The successful development of this protocol was based in part on the outcomes of studies reported herein, addressing the diabetogenic potential of a series of immunosuppressant agents used alone or in combination in a canine islet autograft model. Although it is recognized that failure to achieve long-term insulin independence in human islet allotransplantation has been multifactorial, with low engraftment mass, acute or chronic rejection, autoimmune recurrence, loss of islet-acinar integrity, heterotopic site, denervation, and insulin resistance all being implicated to varying degrees, avoidance of diabetogenic immunosuppression has been pivotal to the enhanced outcomes of clinical islet transplantation. We here explore the effects of clinically relevant doses of cyclosporine or tacrolimus when given alone or in combination with glucocorticoids on long-term canine islet autograft function.


METHODS
Dogs (n=8) underwent total pancreatectomy, islet isolation, and intrasplenic autotransplantation and were normoglycemic with stable long-term graft function 3 months to 8 years posttransplant. The frequently sampled intravenous glucose tolerance test (FSIGT) was performed predrug (baseline), at 1 month of therapy (on drug), and again 1 month after withdrawal of therapy (postdrug).


RESULTS
Monotherapy treatments with low- or high-dose prednisone, Neoral, or tacrolimus had minimal impact on islet autograft function. The combination of Neoral and prednisone led to a marked impairment in glucose decay (25% decline from 1.77+/-0.2 to 1.24+/-0.2, P<0.05), without significant change in insulin responsiveness or glucose effectiveness. However, insulin sensitivity was markedly impaired while on therapy (7.10+/-1.2 to 3.10+/-0.5, P<0.01). Importantly, glucose decay and insulin sensitivity failed to return to baseline after withdrawal of therapy. The combination of tacrolimus and glucocorticoids led to permanent and irreversible diabetes in all recipients (n=6, P<0.001). Similar treatment of healthy control dogs led to a 44% decrease in glucose decay (P<0.01).


CONCLUSIONS
Immunosuppression must be specifically tailored for islet transplantation and be glucocorticoid free if insulin independence is to be sustained clinically.
Shapiro
A M James
AM
Surgical-Medical Research Institute, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. amjs@islet.ca
Geng Hao
Er
E
Lakey
Jonathan R T
JR
Finegood
Diane T
DT
Rajotte
Ray V
RV
Kneteman
Norman M
NM
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000209:etiology / Q000517:prevention & control*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use; D007165:Immunosuppression Therapy / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000187:drug effects / Q000503:physiopathology; D016381:Islets of Langerhans Transplantation; D016559:Tacrolimus / Q000627:therapeutic use; D013997:Time Factors; D014182:Transplantation, Autologous
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus