Effect of Triple Costimulation Blockade on Islet Allograft Survival in Sensitized Mice

Abstract

Background Islet allograft rejection in sensitized recipients is difficult to control by costimulation blockade using anti-CD154 and cytotoxic T-lymphocyte antigen-4 immunoglobulin (CTLA4Ig). Because leukocyte function antigen (LFA) 1 is highly expressed on memory T cells, adding an LFA-1 blockade may inhibit memory T-cell activities. We examined the effects on islet allograft survival of triple costimulation blockade in presensitized recipient mice. Methods C57BL/6 mice were sensitized by transplantation under the kidney capsule or intraperitoneal injection of Balb/c islets. Four weeks after transplantation, sensitization was confirmed by flow-cytometric detection of alloreactive antibodies. Diabetes was induced by a single intravenous injection of streptozotocin. Recipients were transplanted with 200 Balb/c islets under the right kidney capsule. Graft function was assessed by daily blood glucose and body weight records. Transplanted animals were divided into 3 treatment groups: group 1, control antibody; group 2, anti-CD154 and CTLA-4 Ig double therapy; group 3, anti-CD154, CTLA4Ig, and anti–LFA-1 triple therapy. Injections were administered every second day from day – 2 to day 8. Results Naïve mice rejected islet allografts between days 7 and 29 (mean 16 ± 6 d; n = 5), sensitized mice in group 1 between days 0 and 14 (mean 7 ± 5 d; n = 8), in group 2 between days 4 and 16 (mean 8 ± 4 d; n = 7), and in group 3 between days 4 and 26 (mean 11 ± 7 d; n = 10). Conclusion Triple costimulation blockade with anti-CD154, CTLA4Ig, and anti–LFA-1 was not sufficient to improve islet allograft survival in sensitized recipients.

Rat islets are not rejected by anti‐islet antibodies in mice treated with costimulation blockade

“…in sensitized recipients is not primarily an Ab-mediated rejection, but is likely to be mediated by primed/memory T cells as previously reported [31,33,34]. As such, and to avoid the diabetogenic immunosuppressive drugs used in clinical islet transplantation today, traditional inhibitors of costimulation should be combined with new biologics targeting other molecules delivering costimulatory signals.…”

“…In contrast, when neonatal porcine islets from GTKO pigs lacking αGal were transplanted into diabetic rhesus macaques, more animals reached insulin independence than if islets from wild‐type pigs were grafted suggesting a role for anti‐Gal in the rejection . Because sensitized recipients become resistant to costimulation blockade , we decided to delineate the role of Abs in this resistance. Immune serum, from mice sensitized against Lewis rat islets, or serum from naïve mice was injected intraperitoneal in naïve mice at the time of rat islet transplantation.…”

“…In the latter case, it was combined with conventional immunosuppression. Even though long-term islet allo-and xenograft survival can be accomplished in na€ ıve mice, sensitized recipients become resistant to costimulation blockade [26,[31][32][33][34]. This is particularly relevant in islet transplantation procedures, in which repeated transplantation may be necessary to reach a sufficient number of engrafted cells and insulin independence [2][3][4].…”

Inhibition of Recall Responses through Complementary Therapies Targeting CD8+T-Cell- and Alloantibody-Dependent Allocytotoxicity in Sensitized Transplant Recipients

“…Diab et al found that anti-LFA-1 mAb, in combination with CTLA4-Ig and CD154 blockade, was not sufficient to enhance islet allograft survival in sensitized wild-type recipients (18). In this study, wild-type mice were sensitized by islet transplantation under the kidney capsule.…”

Immune Rejection after Pancreatic Islet Cell Transplantation: In Vivo Dual Contrast-enhanced MR Imaging in a Mouse Model

“…Early losses of islet cell function and mass are primarily driven by the damage sustained during the isolation procedure, ischemia reperfusion-like injury, and other nonspecific inflammatory phenomena (2). Other causes of loss of function include allogeneic rejection, recurrence of autoimmunity, and immunosuppressive drug toxicity (3)(4)(5).…”