Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade.
BACKGROUND
The applicability of islet transplantation as treatment for type 1 diabetes is limited by long-term graft dysfunction, immunosuppressive drug toxicity, need for multiple donors, and increased risk of allosensitization. We describe two immunosuppressive regimens based on the costimulation blocker belatacept (BELA) or the antileukocyte functional antigen-1 antibody efalizumab (EFA), which permit long-term islet allograft survival and address some of these concerns.


METHODS
Ten patients with type 1 diabetes with hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction and maintenance with sirolimus or mycophenolate and BELA (n=5) or EFA (n=5).


RESULTS
All five BELA-treated patients achieved independence after single transplants; one resumed partial insulin use 305 days after transplant but is now independent after a second transplant. All five patients treated with EFA achieved independence after one (3/5) or two (2/5) islet transplants and remained independent while on EFA (392-804 days). After EFA was discontinued because of withdrawal of the drug from the market, two patients resumed intermittent insulin use; the others remain independent. No patient in either group developed significant side effects related to the study drugs, and none have been sensitized to alloantigens. All have stable renal function.


CONCLUSIONS
These two novel immunosuppressive regimens are effective, well tolerated, and the first calcineurin inhibitor/steroid-sparing islet protocols resulting in long-term insulin independence. Although EFA is no longer available for clinical use, these early results demonstrate that a regimen using BELA may be an effective alternative to improve graft function and longevity while minimizing renal and β-cell toxicity.
Transplant Division, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143-0790, USA. andrew.posselt@ucsfmedctr.org
Andrew M
AM
Posselt
Gregory L
GL
Szot
Lynda A
LA
Frassetto
Umesh
U
Masharani
Mehdi
M
Tavakol
Raj
R
Amin
Joan
J
McElroy
Marissa D
MD
Ramos
Robert K
RK
Kerlan
Lawrence
L
Fong
Flavio
F
Vincenti
Jeffrey A
JA
Bluestone
Peter G
PG
Stock
D000069594:Abatacept; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001364:Awareness; D018845:CD11 Antigens / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D018796:Immunoconjugates / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000276:immunology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018845:CD11 Antigens; D007004:Hypoglycemic Agents; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007328:Insulin; D000069594:Abatacept; C472181:efalizumab