The role of CD11b/CD18 mediated neutrophil adhesion in complement deficient xenograft recipients.
Hyperacute rejection (HAR) of discordant xenografts is dependent on local complement activation. The formation of a functional complex of the complement components C5b-9 (membrane attack complex, MAC) causes endothelial injury and activation leading to coagulation and inflammation. In PVG rats which selectively lack the C6 component of complement, the MAC complex is not formed, whereas early split products of the complement cascade are produced normally. We reported previously that HAR is averted in C6 deficient xenograft recipients, and that subsequent accelerated acute rejection (AAR) can be delayed by inhibition of CD11b/CD18 (Mac-1) dependent neutrophil adhesion using leumedin, a member of a novel class of anti-inflammatory agents. Here we report the in vivo effects of a dose-response study using 2 new members of another class of Mac-1 directed agents designated nactins. Discordant cardiac xenografts from Hartley guinea pigs were heterotopically grafted into PVG(C6-) and PVG(C6+) rats. Experimental animals were divided into 3 groups receiving leumedin (group 1) or nactin (groups 2 and 3). Control animals received intravenous saline solution only. All C6(+) rats rejected their grafts hyperacutely within 10 to 15 min, irrespective of mode or dosage of treatment. C6 deficient controls rejected grafts within 17.7 +/- 3.5 h (n = 10). Treatment with leumedin/nactin prolonged graft survival up to 61.0 +/- 4.7 h (n = 4-6), with dose dependent differences in effectiveness among the 3 compounds tested. Histology showed that treatment was associated with less edema, hemorrhage, and neutrophil infiltrate at 2, 6, and 12 h. The marked decrease in hemorrhage seen in nactin-treated animals may reflect an interaction of Mac-1 with blood coagulation factors. Our data confirm that the neutrophil adhesion pathway is involved in AAR, especially when complement mediated injury due to MAC is restricted.
Jakobs
F M
FM
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore 21205, USA.
Davis
E A
EA
Qian
Z
Z
Liu
D Y
DY
Baldwin
W M
WM
Sanfilippo
F
F
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D001779:Blood Coagulation Factors / Q000187:drug effects; D018845:CD11 Antigens / Q000276:immunology*; D018821:CD18 Antigens / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000187:drug effects / Q000276:immunology; D003165:Complement System Proteins / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival; D006168:Guinea Pigs; D016027:Heart Transplantation / Q000276:immunology*; D006470:Hemorrhage / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D011919:Rats, Inbred Strains; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001779:Blood Coagulation Factors; D018845:CD11 Antigens; D018821:CD18 Antigens; D015938:Complement Membrane Attack Complex; D007166:Immunosuppressive Agents; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D003165:Complement System Proteins; D007930:Leucine