Anil Dangi1, Irma Husain1, Collin Z Jordan1, Shuangjin Yu2, Naveen Natesh3, Xiling Shen3,4, Jean Kwun5,6, Xunrong Luo7,6. 1. Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina. 2. Division of Organ Transplantation, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 3. Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, North Carolina. 4. Terasaki Institute, Los Angeles, California. 5. Department of Surgery, Duke University School of Medicine, Durham, North Carolina. 6. Duke Transplant Center, Duke University School of Medicine, Durham, North Carolina. 7. Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina xunrong.luo@duke.edu.
Abstract
BACKGROUND: In kidney transplantation, early allograft inflammation impairs long-term allograft function. However, precise mediators of early kidney allograft inflammation are unclear, making it challenging to design therapeutic interventions. METHODS: We used an allogeneic murine kidney transplant model in which CD45.2 BALB/c kidneys were transplanted to CD45.1 C57BL/6 recipients. RESULTS: Donor kidney resident macrophages within the allograft expanded rapidly in the first 3 days. During this period, they were also induced to express a high level of Ccl8, which, in turn, promoted recipient monocyte graft infiltration, their differentiation to resident macrophages, and subsequent expression of Ccl8. Enhanced graft infiltration of recipient CCR8+ T cells followed, including CD4, CD8, and γδ T cells. Consequently, blocking CCL8-CCR8 or depleting donor kidney resident macrophages significantly inhibits early allograft immune cell infiltration and promotes superior short-term allograft function. CONCLUSIONS: Targeting the CCL8-CCR8 axis is a promising measure to reduce early kidney allograft inflammation.
BACKGROUND: In kidney transplantation, early allograft inflammation impairs long-term allograft function. However, precise mediators of early kidney allograft inflammation are unclear, making it challenging to design therapeutic interventions. METHODS: We used an allogeneic murine kidney transplant model in which CD45.2 BALB/c kidneys were transplanted to CD45.1 C57BL/6 recipients. RESULTS: Donor kidney resident macrophages within the allograft expanded rapidly in the first 3 days. During this period, they were also induced to express a high level of Ccl8, which, in turn, promoted recipient monocyte graft infiltration, their differentiation to resident macrophages, and subsequent expression of Ccl8. Enhanced graft infiltration of recipient CCR8+ T cells followed, including CD4, CD8, and γδ T cells. Consequently, blocking CCL8-CCR8 or depleting donor kidney resident macrophages significantly inhibits early allograft immune cell infiltration and promotes superior short-term allograft function. CONCLUSIONS: Targeting the CCL8-CCR8 axis is a promising measure to reduce early kidney allograft inflammation.
Authors: Denise J Lo; Tim A Weaver; David E Kleiner; Roslyn B Mannon; Lynn M Jacobson; Bryan N Becker; S John Swanson; Douglas A Hale; Allan D Kirk Journal: Transplantation Date: 2011-01-15 Impact factor: 4.939
Authors: Sabina A Islam; Daniel S Chang; Richard A Colvin; Mike H Byrne; Michelle L McCully; Bernhard Moser; Sergio A Lira; Israel F Charo; Andrew D Luster Journal: Nat Immunol Date: 2011-01-09 Impact factor: 25.606
Authors: Anil Dangi; Naveen R Natesh; Irma Husain; Zhicheng Ji; Laura Barisoni; Jean Kwun; Xiling Shen; Edward B Thorp; Xunrong Luo Journal: JCI Insight Date: 2020-10-15