Background: Induction of T cell immune response c-DNA (TIRC7) is restricted to activated lymphocytes. Modulation of TIRC7 signalling prevents immune activation specifically at the site of inflammation while preserving immune competency of peripheral lymphocytes. The efficacy of a novel high affinity, chimeric antibody against human TIRC7 was investigated to prevent allograft rejection after transplantation in combination and comparison to a calcineurin inhibitor, FK506.

Method: Rat splenocytes were stimulated with either mitogen or IL2 in presence or absence of anti-TIRC7 antibody (anti-TIRC7 mAb) or control mAb to analyze cross-reactivity. Synergistic effects of anti-TIRC7 mAb with Tacrolimus (Tac) were tested in a strong histoincompatible donor/recipient combination (DA to Lewis). Kidney transplant recipients were treated either with Tac 0.2mg/kg or 0.5mg/kg or anti-TIRC7 mAb 2mg/day in combination with Tac (0.2mg/kg, days 0-7). Low dose FK506 was combined with the anti-TIRC7 mAb to prevent immunogenecity. Serum and spleens were procured by day 7 and for FACS to analyze lymphocyte subsets. Free anti-TIRC7 mAb concentration and allograft reaction was assessed in serum collected at days 1, 4 and 7 after transplantation. Anti-TIRC7 mAb kinetics was analyzed after a single dose administration to rats in serum collected on days 1,2,6,9,14 and 30.

Results: Anti-TIRC7 antibody in combination with low dose FK506 prolonged graft survival up to 80 days (mean 46d). Graft survival was inferior with Tac treatment only (max. 55d; mean 24d). Immunogenicity was absent after antibody application. Free antibody concentrations were 200 and 50ug/ml on days 1 and 30, respectively. No clinical side-effects was observed in anti-TIRC7 treated animals with unchanged periphereal lymphocyte counts in the peripheral blood. Elevated intragraft TIRC7 expression was observed in biopsies of allografts undergoing rejection.

Conclusion: The results suggest a pharmacodynamic synergism between the anti-TIRC7 mAb and FK506. No anti-drug antibody reaction was observed indicating no immunogenecity relevant epitops are presented to induce immune activation. Targeting of TIRC7 may provide a highly specific, novel approach for modulation of immune response restricted solely to tissue infiltrating lymphocytes in transplantation.

CITATION INFORMATION: Tullius S., Kumamoto Y., Nalan U. Anti-TIRC7 Antibody Acts Synergistically with Tacrolimus in Promoting Graft Survival in a Rat Kidney Transplant Model Am J Transplant. 2017;17 (suppl 3).

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