Potent Alloimmune Modulation By Efalizumab in Islet Transplantation.

Abstract

Background:We have treated islet transplant recipients with thymoglobulin induction and maintenance immunosuppression consisted of sirolimus or mycophenolate along with either efalizumab to block LFA-1. Dosing of sirolimus or mycophenolate was adjusted when efalizumab was withdrawn from the market. The immunological impact of Elalizumab was compared to belatacept in this study. Methods: Peripheral blood mononuclear cells were collected and cryopreserved beginning at enrollment before transplantation. Donor spleens were banked at the time of transplant. Percentages of regulatory T cells (Tregs) were determined using fl ow cytometry. Proliferative responses of CD4, CD8, and Tregs were measured in vitro using a CFSE dilution assay. Results: All patients on efalizumab showed dramatic increase of percentage of Tregs from 5 to 10% among CD4 + T cells pre-transplant to peaks of 15 to 67% between 1 and 3 months post transplant. Treg percentages remained elevated while patients were on the regimen. T cell proliferation to donor and polyclonal stimulations was markedly reduced in patients on efalizumab and returned to pre-transplant levels 5 months after the cessation of efalizumab (Figure 1). In contrast, percentages of Tregs and T cell proliferative responses remained stable in patients on the belatacept. Efalizumab led to profound changes of patients' immunological make-up when compared to belatacept. Particularly, one of the most severely immunosuppressed efalizumab patient experienced recurrent infections that necessitated complete withdrawal of immunosuppression. Her anti-donor and polyclonal responses rebounded from non-detectable levels to her pre-transplant baseline after efalizumab withdrawal. Remarkably, she has remained insulin independent despite receiving no immunosuppression in the past 16 months.