Combined Costimulation Blockade Prevents Rejection of Allogeneic Islets in Mice

Abstract

There is a need for immunosuppressive protocols in islet transplantation that are neither nephrotoxic nor diabetogenic. We have examined blockade of the CD28‐B7, CD40‐CD40L and ICAM‐LFA‐1 pathways in a model of allogeneic islet transplantation in mice to determine the efficacy of this blockade in prolongation of graft survival. Histological evidences of inflammation and function were evaluated in grafts that had been functioning for 100 days. Treatment with a combination of all three drugs, or with CTLA4Ig and anti‐CD40L, administered four times during the first six postoperative days, resulted in an excellent graft survival. All animals had a graft survival of >100 days (i.e. indefinitely). Mice treated with CTLA4Ig and anti‐CD40L all showed well‐preserved islets without signs of degeneration or destruction. There were no signs of rejection, as evidenced by the absence of infiltrating lymphocytes. This group had the least amount of rejection/inflammation changes according to ranking of all grafts. In conclusion, a short induction treatment with anti‐CD40L and CTLA4Ig totally prevents rejection and preserves the allogeneic islets transplanted to mice. The addition of anti‐LFA‐1 did not confer any benefit.

Xenoreactive CD4+ memory T cells resist inhibition by anti‐CD44 mAb and reject islet grafts via a Th2‐dependent pathway

“…The sections were then incubated with biotin‐conjugated goat anti‐rat IgG after pre‐diluted strepavidin‐HRP was added, and the slides were exposed to diaminobenzidine (DAB). The amount of islet degeneration/destruction was assessed semiquantitatively as follows: 0 = no degeneration, 1 = ≤1 apoptosis/100 islets, 2 = ≤ 2 apoptosis/100 islets, 3 = one focus of islet destruction and 4 = ≥ 2 foci of islet destruction [20].…”

Monoclonal Antibody Treatment to Prolong the Secondary Cardiac Allograft Survival in Alloantigen-primed Mice

“…The role of anti‐CD154 in preventing organ transplant rejection is well known [11]. The lymphocyte function–associated antigen 1 (LFA‐1)/intercellular adhesion molecule‐1 (ICAM‐1) pathway plays an important role in the activation and proliferation of naïve T cells, especially CD8 + T cells [12, 13], and the combination of anti‐LFA‐1 and anti‐CD154 induces tolerance of primary allografts in mice [14, 15]. It has been reported that the OX40/OX40L pathway plays a critical role in the activation and proliferation of CD4 + memory T cells [16, 17].…”

“…anti-CD154 induces tolerance of primary allografts in mice [14,15]. It has been reported that the OX40 ⁄ OX40L pathway plays a critical role in the activation and proliferation of CD4 + memory T cells [16,17].…”

A new approach for treatment of type 1 diabetes: Phytotherapy and phytopharmacology of regulatory T cells

“…Compound (Cpd) K, as a ginseng metabolite, is a synthesized analog of highly unsaturated fatty acids of Isatis tinctoria L. (27,36). The therapeutic effect of Cpd K in diabetic mice shows that Cpd K significantly prolongs islet allograft survival with minimal adverse effects after 10 days.…”