(Circulation. 1996;93:111-119.)
© 1996 American Heart Association, Inc.
Articles |
Lysis of Adult Ventricular Myocytes by Cells Infiltrating Rejecting Murine Cardiac Allografts
Presented in part at the 2nd International Symposium of Heart Failure, Geneva, Switzerland, May 29, 1993, and the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8, 1993, and published in abstract form in Circulation (1993;88:I-41).
From the Division of Cardiology and Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City.
Correspondence to William H. Barry, MD, Division of Cardiology, University of Utah Health Sciences Center, 50 N Medical Dr, Salt Lake City, UT 84132.
Background Immunologic mechanisms that mediate myocardial cell injury during rejection are not fully understood. We therefore investigated whether cells that infiltrate rejecting cardiac allografts are capable of directly injuring myocytes and whether this injury resembles that produced by cytotoxic T lymphocytes (CTLs) that are generated in a mixed lymphocyte reaction (MLR).
Methods and Results Heart-infiltrating cells (HICs) were isolated from murine heterotopic BALB/c cardiac allografts undergoing rejection 6 to 8 days after transplantation into C57BL/6 mice. An in vitro model system of cultured adult murine ventricular myocytes was developed to facilitate investigation of cell-mediated myocyte injury. Isolated adult myocytes were incubated with either HICs or MLR effector cells, and myocyte death was quantified by counting the number of rod-shaped myocytes excluding trypan blue. The frequency of donor-reactive CTLs was similar in the HIC and MLR populations, as assessed by limiting dilution analysis. However, HICs were less efficient at killing donor-strain myocytes than were MLR cells. CTL-mediated cell lysis occurred by 6 hours, whereas myocyte injury produced by HICs was more gradual, with considerable cytotoxicity occurring between 12 and 24 hours. Furthermore, whereas MLR cells lysed only donor-strain myocytes, HIC lysed donor, third-party, and syngeneic myocytes. Treatment of MLR cells and HICs with anti-CD8 antibody plus complement produced a much greater inhibition of MLR cytotoxicity than of HIC cytotoxicity.
Conclusions These data demonstrate that only a small component of myocyte injury mediated by allograft-infiltrating cells can be ascribed to CTLs within the infiltrating cell population. These findings suggest that cell types associated with a delayed-type hypersensitivity response, as well as CTLs, cause myocyte injury during cardiac rejection.
Key Words: cells • rejection • transplantation • lymphocytes
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