Short-Term Treatment of VCAM-1-Targeting Antibody Induces Immunological Tolerance Against Allogeneic Islet Grafts

Abstract

Background: Blocking adhesion domain of VCAM-1 prevents trafficking of immune cells into the inflammatory sites, and thereby prolongs longterm survival of allogeneic islet grafts in mice. In this study, we developed novel antibody targeting the sixth non-adhesive immunoglobulin-like domain of VCAM-1 and evaluated its efficacy with allogeneic-islet transplantation model. Methods: Chimeric rabbit/human VCAM-1 antibody (anti-VCAM-1-D6) targeting Ig-like domain six of VCAM-1 was generated using phage display technology. Balb/c islets were transplanted underneath of the kidney capsule of diabetic C57BL/6 mouse with the transient anti-VCAM-1-D6 (100ug/day on day -1, 0,1,2,3,4,5,6,7 after transplantation) treatment. Antigen-specific tolerance induction was confirmed by second-party transplantation of Balb/c islets or tail skin. Results: Short-term treatment of anti-VCAM-1-D6 antibody led to the long-term survival of islet allografts in 5 out of 5 mice. Donor-specific-IL-2, IFN-r, Granzyme B- secreting cell population significantly decreased in VACM-1-D6 treated-mouse in ELISPOT analysis. In the grafts, peri-islet infiltrates of leukocytes were observed with intact insulin-positive beta cells in long-term survived mice. Importantly, secondary-islet allograft, but not secondary-skin graft, was survived without evident graft rejection for more than 80 days, meaning tissue-specific tolerance was induced by the short-term treatment of anti-VCAM-1 antibody. Conclusion: Developing VCAM-1 targeting antibody may be a promising therapeutic modality in inducing antigen-specific tolerance in allogeneic islet transplantation.