Chronic Cardiac Transplant Arteriopathy in Mice:Relationship of Alloantibody, C4d Deposition and Neointimal Fibrosis

Abstract

Murine heterotopic cardiac allografts were used to reveal some of the fundamental interrelationships between donor-specific alloantibodies (DSA), chronic transplant arteriopathy (CTA) and capillary C4d deposition. B10.BR recipients of B10.A hearts developed transient DSA and C4d deposition that peaked on day 7 and became undetectable at day 56 while CTA developed progressively. Male cardiac grafts in female recipients showed similar degrees of CTA at day 56 but never developed DSA or C4d deposition, indicating that T cell-mediated mechanisms are sufficient to produce CTA. Passive transfer of monoclonal IgG2a anti-H-2Kk into B6.RAG1 KO recipients of B10.BR hearts over 14–28 days led to progressive CTA. If treatment was stopped on day 14, lesions showed little progression and had no C4d deposition or detectable DSA on day 42. If treatment was stopped on day 28 when the lesions were fully developed, no regression occurred over the next 28 days, even though C4d deposition and circulating antibody became undetectable. Therefore, a minimum threshold of antibody exposure is needed to cause CTA. Once the CTA develops, C4d may become negative after DSA disappears. Thus, serial samples are needed in clinical studies to ascertain the relevance of alloantibody to the lesions of chronic graft rejection. Murine heterotopic cardiac allografts were used to reveal some of the fundamental interrelationships between donor-specific alloantibodies (DSA), chronic transplant arteriopathy (CTA) and capillary C4d deposition. B10.BR recipients of B10.A hearts developed transient DSA and C4d deposition that peaked on day 7 and became undetectable at day 56 while CTA developed progressively. Male cardiac grafts in female recipients showed similar degrees of CTA at day 56 but never developed DSA or C4d deposition, indicating that T cell-mediated mechanisms are sufficient to produce CTA. Passive transfer of monoclonal IgG2a anti-H-2Kk into B6.RAG1 KO recipients of B10.BR hearts over 14–28 days led to progressive CTA. If treatment was stopped on day 14, lesions showed little progression and had no C4d deposition or detectable DSA on day 42. If treatment was stopped on day 28 when the lesions were fully developed, no regression occurred over the next 28 days, even though C4d deposition and circulating antibody became undetectable. Therefore, a minimum threshold of antibody exposure is needed to cause CTA. Once the CTA develops, C4d may become negative after DSA disappears. Thus, serial samples are needed in clinical studies to ascertain the relevance of alloantibody to the lesions of chronic graft rejection.