Noninvasive detection of rejection of transplanted hearts with indium - ill - labeled lymphocytes *

To determine whether cardiac transplant rejection can be detected noninvasively with indium-11l (" 'In)-labeled lymphocytes, we studied 11 dogs with thoracic heterotopic cardiac transplants without immunosuppression and five dogs with transplants treated with cyclosporine (10 mg/kg/day) and prednisone (1 mg/kg/day). All were evaluated sequentially with gamma scintigraphy after administration of 150 to 350 ,uCi of autologous "'In-lymphocytes. Technetium-99m-labeled red blood cells (1 to 3 mCi) were used for correction of radioactivity in the blood pool attributable to circulating labeled lymphocytes. Lymphocyte infiltration was quantified as the ratio of indium in the myocardium of the transplant or native heart compared with that in blood (indium excess, IE). Results were correlated with mechanical and electrical activity of allografts and with histologic findings in sequential biopsy specimens. In untreated dogs (n = 11), IE was 15.5 + 7.0 ($D) in transplanted hearts undergoing rejection and 0.4 1.1 in native hearts on the day before animals were killed (p < .01). In dogs treated with cyclosporine and prednisone (n = 5), IE was minimal in allografts during the course of immunosuppression (0.8 ± 0.4) and increased to 22.9 ± 11.1 after immunosuppression was stopped. Scintigraphic criteria of rejection (IE > 2 SD above that in native hearts) correlated with results of biopsies indicative of rejection and appeared before electrophysiologic or mechanical manifestations of dysfunction. Thus infiltration of labeled lymphocytes in allografts, indicative of rejection, is detectable noninvasively by gamma scintigraphy and provides a sensitive approach potentially applicable to clinical monitoring for early detection of rejection and guidance for titration of immunosuppressive measures. Circulation 75, No. 4, 86&876, 1987. CARDIAC TRANSPLANTATION is an increasingly important treatment for end-stage cardiac disease, but rejection continues to be a major complication. Criteria for the presence of rejection fever, atrial arrhythmia, alterations in QRS voltage, leukocytosis, and impaired ventricular performance are insensitive and nonspecific. Thus serial endomyocardial biopsy is required for monitoring patients. Although relatively From the Cardiovascular Division, Department of Internal Medicine, and Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis. Supported in part by NHLBI SCOR in Ischemic Heart Disease HL17646. Address for correspondence: Steven R. Bergmann, M.D., Ph.D., Cardiovascular Division, Washington University School of Medicine, 660 S. Euclid Ave., Box 8086, St. Louis, MO 63110. Received Sept. 12, 1986; revision accepted Jan. 14, 1987. *All editorial decisions for this article, including selection of reviewers and the final disposition, were made by a guest editor. This procedure applies to all manuscripts with authors from the Washington University School of Medicine. safe,' biopsy is an invasive and expensive approach to detecting rejection. Infiltration of lymphocytes is a feature of early rejection.2" We and others have demonstrated the feasibility of detecting early rejection of heterotopic transplants in small laboratory animals with indium11 ("'In) -labeled lymphocytes.`8 Detection of rejection with "'In-leukocytes has also been attempted in patients.9 However, the suitability of this approach for potential clinical applications has not been established. The present study was performed to determine whether rejection of heterotopic cardiac transplants in large animals under conditions simulating those encountered clinically could be detected sensitively and reliably. Erythrocytes labeled with technetium-99m (99Tc) were used as a blood pool tracer for compensation by subtraction of radioactivity attributable to circulating lymphocytes. The subtraction technique is analogous CIRCULATION 868 by gest on A ril 5, 2017 http://ciajournals.org/ D ow nladed from LABORATORY INVESTIGATION-CARDIAC TRANSPLANTATION to one developed in our laboratory for the scintigraphic identification of coronary artery thrombi.i0 ` Each dog was used as its own control with correlative assessments of scintigrams and histopathologic studies in the native and transplanted hearts. Some dogs were treated with immunosuppressive agents to define the utility of scintigraphy for detecting effects of treatment.