Impairment of left ventricular function in combined immune deficiency mice after transfer of peripheral blood leukocytes from patients with myocarditis.

Abstract

Autoimmune mechanisms are suspected to play an important role in the pathogenesis of human myocarditis. In order to evaluate the significance of autoimmune leukocytes for the development of human myocarditis (MC) and subsequent heart failure, we transferred 15 x 10(6) or 50 x 10(6) peripheral blood leukocytes (PBLs) from patients with immunohistologically proven MC and impaired left ventricular function into severe combined immune deficiency (SCID) mice that possess neither B nor T lymphocytes. PBLs from seven patients and five healthy controls were transferred into three SCID mice each by intraperitoneal injection. After 60 days human PBLs could be demonstrated in the peripheral blood of SCID mice, representing up to 10% of peripheral blood mononuclear cells. Likewise, human immunoglobulins were present in all transfused SCID mice (up to 3 mg.ml-1 IgG and IgM); however, autoantibodies against the adenine nucleotide translocator, a myocardial autoantigen, were only present in the mice receiving PBLs from patients with MC. Infiltrating human lymphocytes were also only found in the hearts of SCID mice having received PBLs from MC patients, but not in those receiving PBLs from normal controls. When we measured the slope of the left ventricular pressure pulse by direct puncture under ether anaesthesia, we found it to be decreased (dp/dt = 1750 +/- 194 mmHg.s-1 in mice receiving PBLs from MC patients, compared with mice receiving PBLs from controls (dp/dt = 2456 +/- 92 mmHg.s-1 or receiving no transfusion (dp/dt = 2576 +/- 142 mmHg.s-1. These results demonstrate that the impairment of the ventricular function seen in patients with MC can be transferred to SCID mice by transfer of PBLs. This proves the significance of autoimmune mechanisms for the pathogenesis of MC.