In the United States, approximately 2.4 million burn injuries are reported per year. Many patients with major burns involving at least 25% of their total body surface die. The transplantation of large patches of skin would save their lives. However, allogeneic skin grafts are invariably rejected in an acute fashion. Seminal studies performed in the 1960's by Barker and Billingham have demonstrated the key role of afferent lymphatic vessels in the rejection of skin allografts. However, this feature of skin grafts has bee difficult to exploit in an effort to achieve tolerance to these transplants. Recently, a series of agents, capable of disrupting the process of lymphangiogenesis, have been developed to prevent cancer cell metastasis. These agents (anti-VEGFR3 antibody, mF4-31C and a5ss1 integrin inhibitor, JSM6427) have been shown to prevent lymphangiogenesis for 3 weeks in vivo with no side effects. Preliminary studies using these agents have proven their efficacy in corneal and islet transplantation. Most importantly, we have obtained preliminary data showing that blocking lymphangiogenesis using mF4-31C mAbs prevents donor passenger leukocyte trafficking, reduced the anti-donor immune response and prolonged alloskin graft survival for up to 50 days (while non-treated mice rejected their grafts after 10 days). We hypothesize that treatment of recipients (systemic or topical) with anti-VEGFR3 antibody, mF4-31C and a5ss1 integrin inhibitor, JSM6427 at the time of skin transplantation with will disrupt the cell traffickng from and presumably to the graft and affect the nature of the host's anti-donor immune response, thereby promoting or inducing long-term acceptance of skin allografts. To test the validity of these hypotheses, we propose the following specific aims:
Specific aim 1. Investigate the effect of treatment with F4-31C and JSM6427 agents on lymphangiogenesis, hemangiogenesis and cell trafficking in mice recipient of a fully allogeneic skin graft.
Specific aim 2. Investigate the influence of lymphangiogenesis blockade using mF4-31C and JSM6427 agents on the alloimmune response to and rejection of fully allogeneic allografts. If successful, this research will provide new insights into the mechanisms underlying the influence of lymhangiogenesis on immune cell trafficking and response in vivo. In addition, it will pave the way for the development of immune-based strategies allowing the storage and successful transplantation of large patches of allogeneic skins for patients with burns and for reconstructive surgery (including face transplants).

Public Health Relevance

In the United States, approximately 2.4 million burn injuries are reported per year, and many of these victims with burns to greater than 25% of their total body surface die. We plan to test a series of compounds which are known to prevent the formation of lymphatic vessels. We hypothesize that these treatments will prevent the migration of donor cells to the host's lymphoid organs and thereby prevent immune rejection of skin grafts. If successful, this research will set the path for the development of biological strategies allowin the storage and successful transplantation of large patches of allogeneic skin for patients with burns and for reconstructive surgery (including face transplants).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI100278-02
Application #
8417661
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2012-03-01
Project End
2014-08-28
Budget Start
2013-03-01
Budget End
2014-08-28
Support Year
2
Fiscal Year
2013
Total Cost
$200,850
Indirect Cost
$75,850
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Kant, Cavit D; Akiyama, Yoshinobu; Tanaka, Katsunori et al. (2015) Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues. J Immunol 194:1364-71
Benichou, Gilles; Tocco, Georges (2013) The road to transplant tolerance is paved with good dendritic cells. Eur J Immunol 43:584-8
Kant, Cavit D; Akiyama, Yoshinobu; Tanaka, Katsunori et al. (2013) Primary vascularization of allografts governs their immunogenicity and susceptibility to tolerogenesis. J Immunol 191:1948-56