Complement Independent Antibody‐Mediated Endarteritis and Transplant Arteriopathy in Mice

Abstract

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.

Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association With Antibody-Mediated Rejection

“…Experimental studies have provided direct linkage of circulating antibodies, and chronic graft pathology was shown in experimental models in which passive transfer of MHC antibodies could initiate the chronic arterial lesions in mice. Immunodeficient SCID or RAG-/-mice that were given repeated doses of anti-class I alloantibodies developed fibrous intimal thickening of coronary arteries (arteriosclerosis) in cardiac allografts (28). Taken together, these animal models suggest that alloantibodies to HLA class I or II expressed by endothelium may cause a variety of effects on heart transplants, ranging from acute but also supporting the existence of chronic rejection with a phenotype of microcirculation inflammation and arteriosclerosis lesions (28).…”

“…Immunodeficient SCID or RAG-/-mice that were given repeated doses of anti-class I alloantibodies developed fibrous intimal thickening of coronary arteries (arteriosclerosis) in cardiac allografts (28). Taken together, these animal models suggest that alloantibodies to HLA class I or II expressed by endothelium may cause a variety of effects on heart transplants, ranging from acute but also supporting the existence of chronic rejection with a phenotype of microcirculation inflammation and arteriosclerosis lesions (28). This is consistent with our results, showing that a number of patients had indolent and previously unrecognized ABMR occurring years before allograft failure and also operating in a substantial (47.5%) fraction of failing allografts.…”

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

“…15 In contrast to acute AMR, activation of the classic complement pathway does not seem to be critical for the development of chronic AMR lesions. The first evidence supporting this concept was in the study by Colvin and coworkers, 16 which transplanted immunodeficient RAG knockout mice with allogenic heart. Colvin and coworkers 16 observed that a passive transfer of noncomplement binding DSAs was sufficient enough to promote allograft vasculopathy.…”

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology

“…Note that the extent of i‐IFTA is not analogous to the Banff total inflammation score, the latter representing the sum of inflammation in scarred and nonscarred areas of the cortex. Consequently, it was decided to modify the Banff 2007 criteria by adding a statement (Table 3, category 4), reflecting findings that lesions of transplant arteriopathy may represent chronic active ABMR 42 as well as TCMR—also shown in experimental studies 43—and that chronic active TCMR may also be manifest in the tubulointerstitial compartment.…”