Ischemia-reperfusion injury accelerates human antibody-mediated transplant vasculopathy.
Background. The pathogenesis of transplant vasculopathy (TV) is a multifactorial process. We hypothesized that ischemia-reperfusion injury and antibody-mediated damage contribute to the development of TV.Methods. Human vessels were procured from nine separate donors undergoing cardiac surgery and stored in saline solution on ice until transplantation. BALB/c Rag2-/-IL-2Rgamma-/- mice were transplanted with a human vessel graft on day 0. Purified anti-human leukocyte antigen class I antibody (W6/32), isotype control antibody, or saline was injected into recipient mice weekly until day 42, at which point the degree of intimal expansion (IE) of vessels was assessed by histologic analysis.Results. We found that a prolonged cold ischemia time (6-12 hr) alone did not induce IE. In mice that received antibody where vessels were transplanted within 6 hr of procurement, no IE was observed. By contrast, in vessels exposed to more than 6 hr cold ischemia, both W6/32 antibody (30.4%T6.9%) and isotype control antibody(39.5%T6.0%) promoted significant IE (P<0.05 vs. saline [12.4%T1.7%]). Importantly, the isotype control antibody did not cross-react with human tissue. Interestingly, the number of mouse Fc-receptor-positive cells was significantly increased in human vessels exposed to more than 6 hr cold ischemia but only in the presence of antibody (P<0.05).Conclusions. Antibody, regardless of its specificity, may promote IE in human vessels that are injured through cold ischemia via interaction with Fc-receptor-positive cells. This highlights the importance of controlling the degree of cold ischemia in clinical transplantation in an effort to reduce the risk of TV development.
Ryoichi
R
Goto
Fadi
F
Issa
Sebastiaan
S
Heidt
David
D
Taggart
Kathyrn J
KJ
Wood
D000818:Animals; D000918:Antibody Specificity; D001808:Blood Vessels / Q000276:immunology / Q000293:injuries* / Q000637:transplantation*; D050377:Cold Ischemia / Q000009:adverse effects; D005260:Female; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology*; D006680:HLA Antigens; D006801:Humans; D007518:Isoantibodies / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications* / Q000276:immunology*; D014019:Tissue Donors; D014183:Transplantation, Heterologous; D017539:Tunica Intima / Q000276:immunology / Q000473:pathology
D006680:HLA Antigens; D007518:Isoantibodies; D017452:Receptors, IgG