Effects of Lymphangiogenesis Blockade On Cell Trafficking, Alloimmunity and Rejection After Skin or Heart Transplantation.

Abstract

Seminal studies from Billingham and others have demonstrated the key role of afferent lymphatics in the migration of donor passenger leukocytes to the recipient's lymph nodes after skin transplantation. In the present study, we tested the effect of mF4-31C, an anti-VEGFR3 antibody known to alter lymphangiogenesis, on the donor cell trafficking, T cell alloresponse and rejection after placement of skin or heart allografts. First, BALB/c mice were treated with mF4-31C (0.25 mg, i.p. at day 1, 3 and 5 post-Tx) or mF4-31C + MR1 (anti-CD40L mAb) and transplanted with a fully allogeneic B6-GFP skin graft. mF4-31C treatment resulted in an absence of donor passenger leukocytes in the recipient's draining lymph nodes (day 6 post-Tx), a reduction of the direct alloresponse and an abrogation of the indirect alloresponse by T cells but no prolongation of allograft survival (MST 10-12 days). Co-treatment with mF4-31C and MR1 abrogated both direct and indirect T cell alloresponses and significantly prolonged skin graft survival (MST > 40 days). Next, mF4-31 mAbs were tested for their ability to impact indirect alloimmunity and rejection of minor antigen-mismatched allografts. B6 mice were transplanted with B6-GFP skin or cardiac allografts and treated with mF4-31C, as described above. We observed a marked reduction of the indirect alloresponse by T cells as well as well as a prolongation of graft survival (> 25 days for both skin and heart transplants). Therefore, blockade of lymphangiogenesis represents a promising approach for the inhibition of indirect alloreactivity and may be used in combination with leukocyte costimulation blockade or conventional immunosuppression to prolong allograft survival.