Importance of donor- and recipient-derived selectins in cardiac allograft rejection.
The selectins expressed on activated endothelial cells (E- and P-selectin), leukocytes (L-selectin), and platelets (P-selectin) play crucial roles in the rolling and tethering of leukocytes. We explored the importance of donor and recipient selectins in acute and chronic cardiac allograft rejection using mice deficient in all three selectins (ELP-/-). In BALB/c recipients, survival of fully allomismatched hearts from ELP-/- C57BL/6 donors was almost double that of wild-type grafts. In ELP-/- cardiac allografts, mononuclear cell infiltration and vasculitis of intramyocardial coronary arteries were significantly reduced. Interestingly, ELP-/- grafts were rejected similarly in both the presence and the absence of recipient selectins, and both wild-type and ELP-/- recipients promptly rejected wild-type hearts. Alternative adhesive molecules such as alpha4beta7 integrin may compensate for the lack of selectins and may mediate rejection in ELP-/- recipients. Chronic rejection was evaluated in a major histocompatibility complex (MHC) class II mismatch model using C57BL/6.C-H2(bm12) mice. While lack of selectins in recipients did not offer protection against chronic rejection, luminal stenosis of coronary arteries in ELP-/- grafts was markedly diminished. In conclusion, donor-derived selectins contribute to the development of both acute and chronic cardiac allograft rejection, and targeting donor selectins may open novel therapeutic approaches in clinical transplantation.
Izawa
Atsushi
A
Transplantation Research Center, Brigham & Women's Hospital, Boston, Massachusetts 02115, USA.
Ueno
Takuya
T
Jurewicz
Mollie
M
Ito
Toshiro
T
Tanaka
Katsunori
K
Takahashi
Masafumi
M
Ikeda
Uichi
U
Sobolev
Olga
O
Fiorina
Paolo
P
Smith
Rex Neal
RN
Hynes
Richard O
RO
Abdi
Reza
R
D000818:Animals; D015815:Cell Adhesion Molecules / Q000502:physiology; D023921:Coronary Stenosis / Q000209:etiology; D006084:Graft Rejection / Q000209:etiology*; D006085:Graft Survival / Q000502:physiology; D016027:Heart Transplantation / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019087:Selectins / Q000502:physiology*; D014019:Tissue Donors
D015815:Cell Adhesion Molecules; D019087:Selectins