Complement independent antibody-mediated endarteritis and transplant arteriopathy in mice.
Complement fixation, as evidenced by C4d in the microvasculature, is a widely accepted criterion of antibody-mediated rejection. Complement fixation has been shown to be essential in acute antibody-mediated rejection, but its role in chronic rejection has not been addressed. Previous studies showed that passive transfer of complement fixing monoclonal IgG2a anti-H-2Kk into B6.RAG1-/- KO recipients of B10.BR hearts led to progressive chronic transplant arteriopathy (CTA) over 14-28 days, accompanied by C4d deposition. The present studies were designed to test whether complement was required for these lesions. We report that a noncomplement fixing donor-specific alloantibody (DSA, monoclonal IgG1 anti-H-2Kk) injected into B6.RAG1-/- KO recipients of B10.BR hearts also promotes CTA, without C4d deposition. Furthermore, a passive transfer of DSA (monoclonal IgG2a anti-H-2Kk) initiated endarteritis followed by CTA in B6.RAG1-/- mice genetically deficient in the third component of complement (RAG1-/-C3-/-). These studies indicate that antibody to class I MHC antigens can trigger chronic arterial lesions in vivo without complement participation, in contrast to acute antibody-mediated rejection. This pathway may be relevant to C4d-negative chronic rejection sometimes observed in patients with DSA, and argues that lack of C4d deposition does not exclude antibody-mediated chronic rejection.
Hirohashi
T
T
Transplantation Division, Department of Surgery, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.
Uehara
S
S
Chase
C M
CM
DellaPelle
P
P
Madsen
J C
JC
Russell
P S
PS
Colvin
R B
RB
D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001158:Arteries / Q000473:pathology*; D015935:Complement C4b / Q000235:genetics*; D003165:Complement System Proteins / Q000378:metabolism*; D018450:Disease Progression; D004692:Endarteritis / Q000276:immunology*; D006321:Heart / Q000502:physiology; D016027:Heart Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000235:genetics*; D013997:Time Factors
D000906:Antibodies; D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d; D003165:Complement System Proteins