Immune monitoring of islet allograft recipients treated with a limited course of efalizumab

G. Szot¹, K. Melli¹, L. Frassetto², U. Masharani², L. Fong², P. Stock¹, A. Posselt¹, Q. Tang^1
1 University of California, San Francisco, Department of Surgery, San Francisco, USA; ² University of California, San Francisco, Department of Medicine, San Francisco, USA

Objective: We previously reported on long-term islet allograft function in recipients treated with a calcineurin inhibitor-free protocol using the anti LFA-1 antibody efalizumab (EFA). Here we examine the immunologic basis for continued graft function.

Methods: 5 type 1 diabetic patients with hypoglycemic unawareness and normal renal function received intraportal islet transplants. Immunosuppression consisted thymoglobulin induction, maintenance sirolimus (trough 3-6ng/ml) and EFA. EFA was weaned and stopped in all patients 13-27 months after transplant and maintenance immunosuppression was modified to include mycophenolate. Regulatory T cell (Treg) frequencies were determined by flow cytometric analysis of CD4+FoxP3+ cells among peripheral blood mononuclear cells. CD4, CD8, and Treg responses to donor and 3rd party stimulators were determined using a CFSE-based MLR assay. Anti-CD3/anti-CD28 antibody-stimulated responses were also monitored.

Results: All patients achieved insulin independence after transplant and remained independent while on EFA. After EFA discontinuation, 2 patients resumed intermittent insulin use; the others remain independent (>24 - 44 months post-transplant). No patient had significant EFA-related side effects. Treg frequencies were elevated in all patients while on EFA and returned to baseline within 6 months after EFA discontinuation. In 3/4 patients, CD4, CD8, and Treg responses to donor, 3rd party, and anti- CD3/CD28 stimulation were markedly reduced while on EFA and remained suppressed for at least 6 months after EFA discontinuation. One patient, showed minimal CD4 responses pre-transplant and had small increases in responses to donor, 3rd party and anti-CD3/CD28 after transplant while on EFA and after EFA cessation. Additional analyses of cytokine secretion and anti-viral responses are underway to fully evaluate the general impact of EFA.

Conclusion: These results demonstrate that EFA treatment promotes Treg generation but also has profound and long-lasting effects on T cell proliferative responses. These characteristics may contribute to the preservation of islet function despite low-dose immunosuppression after EFA cessation.