Antibody to CD18 reduces neutrophil and T lymphocyte infiltration and vascular cell adhesion molecule-1 expression in cardiac rejection.
Most antirejection therapies target immune activation but may not reduce leukocyte infiltration into the graft. The leukocyte integrin CD18 has been shown to be important for leukocyte migration in vitro. We postulated that antibody blockade of CD18 might reduce the migration of different leukocyte subpopulations into myocardium during rejection. Using a rabbit model, we evaluated the effect of a monoclonal antibody to CD18 on the infiltration of neutrophils (polymorphonuclear leukocytes [PMNs]), T lymphocytes, and macrophages into cardiac grafts. In addition, vascular cell adhesion molecule-1 (VCAM-1) expression was assessed to determine the relationship between leukocyte infiltration and VCAM-1 expression, an unblocked alternate adhesion pathway. Donor hearts from Stauffland rabbits were transplanted heterotopically into the cervical position of New Zealand White recipients. Recipient rabbits received either monoclonal antibody to CD18 daily without other immunosuppression (n=51), saline injections as placebo controls (n=52), or nonfunctional isotype-matched antibody (n=4). Recipient rabbits were killed at 1 hr, 6 hr, 24 hr, 3 days, and 7 days after transplantation (10-12 rabbits per group at each time point). PMNs, T lymphocytes, and macrophages were differentiated by routine staining and immunocytochemistry, respectively, and quantified as the number of cells per standardized field. VCAM-1 expression was examined immunocytochemically in 30 treated and 30 control transplanted hearts. Monoclonal antibody to CD18 significantly reduced the infiltration of PMNs and T lymphocytes into myocardium during rejection, but did not affect the infiltration of macrophages. Blocking the CD18/intercellular adhesion molecule-1 adhesion pathway also resulted in a decrease in VCAM-1 expression, which correlated in time with the reduction in T lymphocyte infiltration.
Akimoto
H
H
Department of Surgery, University of Washington, Seattle, Washington 98195, USA.
McDonald
T O
TO
Weyhrich
J T
JT
Thomas
R
R
Rothnie
C L
CL
Allen
M D
MD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D018821:CD18 Antigens / Q000502:physiology*; D006084:Graft Rejection; D016027:Heart Transplantation; D009206:Myocardium / Q000473:pathology*; D009504:Neutrophils / Q000502:physiology*; D011817:Rabbits; D013601:T-Lymphocytes / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis*
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D019010:Vascular Cell Adhesion Molecule-1