Early detection of rejection and assessment of cyclosporine therapy by 111In antimyosin imaging in mouse heart allografts.

Abstract

BACKGROUND. Mice (n = 58) with abdominal heterotopic heart transplants were studied to examine the effectiveness of 111In-labeled antimyosin scintigraphy in the detection of rejection and to determine the consequence of cyclosporine therapy on the results. METHODS AND RESULTS. Allografts from B10D2 donors were transplanted into B6AF1 recipients. Of the 49 allografted mice, 19 were treated with cyclosporine (15 mg/kg.day). Nine isografted mice served as controls. Scintigraphy was performed by injecting 100 muCi 111In antimyosin monoclonal antibody 2-15 days after transplantation. An increase in the ratio of percent dose of antimyosin injected per gram (% dose/g) of the grafted heart (G) to that of the autologous heart (A) (G/A) as well as the increasing percent dose per gram of antimyosin in the grafts reflected the severity of histopathological rejection regardless of the presence or absence of cyclosporine. Scintigraphic images demonstrated unequivocally intense accumulation of 111In in rejected allografts as confirmed by histologically demonstrable myocyte necrosis. The G/A ratio in allografted mice with mildly deteriorated mechanical activity (4.2 +/- 1.0, mean +/- SD) was greater than that in mice with normal contractility (1.8 +/- 0.7) (p less than 0.001), and the necrosis correlated with this modest decline in mechanical function could be scintigraphically identified. Of mice with normally contracting allografts, the G/A ratio was greater in animals with demonstrated myocyte necrosis (2.6 +/- 0.5) than in those without necrosis (1.5 +/- 0.5) (p less than 0.001). In contrast, isografted mice or a subset of allografted mice treated with cyclosporine and not showing evidence of rejection did not manifest any significant change in G/A ratio, nor did they have scintigrams positive for rejection as late as 15 days after transplantation. CONCLUSIONS. These findings suggest that antimyosin scintigraphy is a sensitive and early indicator of cardiac transplant rejection and that it could be useful as a noninvasive method for assessing the efficacy of cyclosporine treatment.

Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy

“…The role of antibodies to vimentin leading to accelerated cardiac rejection has also been demonstrated in a recent study using a mouse model (43). Furthermore, imaging studies have suggested that anti-MYO Abs could be used as a predictor of transplant survival (44). While the role of anti-MYO and anti-VIM Abs in the development of rejection (mostly chronic) following HTx have been demonstrated in studies with small patient cohorts, we have demonstrated these findings in a large group of human heart transplant patients who developed acute AMR and CAV, with a concomitant immune response to self antigens, MYO and VIM in the early and late post-HTX period respectively (42, 45).…”

Implication for transglutaminase 2-mediated activation of β-catenin signaling in neointimal vascular smooth muscle cells in chronic cardiac allograft rejection

“…In the isograft group, BALB/c (H-2 d ) mice were used as donors and recipients (N=3). Hearts were transplanted into the abdomen of the recipients as primary vascularized grafts by the microvascular technique previously described by Isobe et al 27 Graft survival was monitored by daily palpation. All of the cardiac allografts functioned up to 8 weeks (confirmed visually at the time of harvest).…”

Gene Therapy for Heart Transplantation‐Associated Coronary Arteriosclerosisa

“…They were housed in plastic cages with free access to food and water. Donor hearts were heterotopically transplanted into recipient mice as described before 11,12. DBA/2 mice were used as donors and B10.D2 as recipients.…”