Islet Transplantation in Type 1 Diabetic Patients Using Calcineurin Inhibitor-Free Immunosuppressive Protocols Based on T-Cell Adhesion or Costimulation Blockade

Abstract

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 myco-phenolate 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.

Update on Islet Transplantation

“…Two compounds have currently been approved for use: abatacept (CTLA4Ig) and belatacept (LEA29Y), which block T-cell interaction with CD80/ CD86 on antigen-presenting cells. The group at UCSF has reported promising results with belatacept costimulation blockade in combination with thymoglobulin (thymo)-based therapy (Posselt et al 2010b). This protocol allowed a calcineurin-inhibitor-free maintenance therapy strategy and even permitted single-donor engraftment success.…”

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away

“…Substitution of tacrolimus with belatacept in combination with sirolimus or MMF, as the maintenance therapy, and ATG, as the induction immunosuppressant, has been tested in clinical islet transplantation. All five patients treated with this protocol achieved insulin independence after a single transplant (171). In another study, successful substitution of tacrolimus with efalizumab, an anti-leukocyte function-associated antigen-1 (LFA-1) antibody, was reported for maintenance of an immunosuppressant regimen of islet transplant patients.…”

“…Review M Khosravi-Maharlooei, E Hajizadeh-Saffar and others (171,172). B7H4 is a co-inhibitory molecule of the B7 family expressed on APCs that interacts with CD28 on T cells.…”

What’s New, What’s Hot in Solid Organ Transplantation? Summary of the American Transplant Congress 2011

“…LFA-1/ICAM, an adhesion pathway involved in T-cell activation and the immunological synapse, has recently been explored as a potential target to facilitate allograft survival blocking inflammatory cell trafficking in successful phase II studies in the kidney (22) and islets (23). The in vitro effects of blockade were explored by a number of laboratories presented at this meeting.…”