Recently, a potentially lethal pattern of vascular rejection has been described in heart transplant patients treated with cyclosporine. The purpose of this study was to identify potential immune mechanisms responsible for the development of coronary vascular injury associated with acute rejection. Our hypothesis was that changes in histocompatibility (MHC) expression induced by immunosuppressive therapy with cyclosporine plays an important role in directing an immune response to the arterial bed. With the ACI to Lewis allograft model, we compared the histology and immunohistology of both unmodified allograft rejection at days 2, 3, and 4 after transplantation, and allograft rejection modified by pretreatment with cyclosporine. Both models exhibit histologic evidence of early rejection before extensive myocyte necrosis is seen. Unmodified early rejection develops rapidly and is associated with dense MHC class I antigen expression on both myocytes and venous endothelium. Cyclosporine-modified rejection develops more slowly and is characterized by an arterial vasculitis. This modified pattern of rejection is associated with increased myocardial expression of MHC class II antigens with the arterial bed preferentially expressing increased MHC antigens. It is interesting to speculate that in the setting of a slower developing rejection process, the preferential expression of MHC antigens within the arterial bed produces a delayed-type hypersensitivity response directed toward either the endothelium and/or adjacent MHC class II expressing myocytes. A prolonged periarterial and intraluminal inflammatory reaction may then produce a true vasculitis, which may be detrimental to the survival of the graft.

Animals↗

PubMedDate not supplied

Differences in the pathogenesis of first-set allograft rejection and acute xenograft rejection as determined by sequential morphologic analysis.

To examine the pathogenesis of unmodified heart xenograft and allograft rejection, a sequential morphologic analysis was undertaken. Heterotopic cardiac allografts and xenografts were performed by implanting donor hearts into the abdomen of Lewis rats. Xenograft donors were Golden Syrian hamsters and allograft donors were ACI rats. Both xenografts and allografts were excised and examined by light microscopy at specific postoperative intervals. Allograft rejection was found to be a cell-mediated process, beginning with interstitial infiltrates and perivascular cuffing, which progressed to focal myocyte necroses. Ultimately, complete replacement of the myocardium by mononuclear cells was noted in fully rejected hearts. Xenograft rejection was markedly different. Although xenograft rejection was characterized first by interstitial mononuclear cell infiltrates, unlike allografts there was only minimal progression of cellular rejection. Instead, subsequent rejection was characterized by marked interstitial edema and arteriolar vasculitis and thrombosis, leading to extensive infarcts and hemorrhage in fully rejected hearts. Fibrinoid arteriolar changes and the rapid development of edema in the absence of significant cellular infiltrate suggest that cytotoxic antibodies alter xenograft vascular permeability. These data suggest that humoral immunity is largely responsible for acute concordant xenograft rejection, whereas first-set allograft rejection is mainly a cell-mediated process.

Animals↗

PubMedDate not supplied

Arteriolar vasculitis on endomyocardial biopsy: a histologic predictor of poor outcome in cyclosporine-treated heart transplant recipients.

The histologic pattern of severe, potentially lethal cardiac rejection in transplant recipients who are treated with cyclosporine may be difficult to distinguish from mild or moderate rejection. The purpose of this study was to determine whether specific histologic abnormalities seen on endomyocardial biopsy could identify which histologic patterns of rejection are associated with progression to graft dysfunction or graft failure. We performed a blinded, retrospective analysis of endomyocardial biopsies from our initial 19 transplant recipients. Group 1 was composed of five patients who developed graft failure or dysfunction after transplantation. Group 2 was composed of the remaining 14 patients with normal hemodynamics and function at heart catheterization 1 year after transplantation. Seventeen histologic parameters were semiquantitatively graded, and comparisons between the two groups were made with the Student's t test. Of the 17 parameters, only arteriolar vasculitis was significantly increased in group 1 versus group 2 biopsies (p = 0.002). Arteriolar vasculitis was identified in four of five patients in group 1 and was unique to group 1. Of 53 group 1 biopsies, eight patients had foci of arteriolar vasculitis and were seen up to 88 days before graft failure. Therefore the finding of arteriolar vasculitis on endomyocardial biopsy may identify high risk rejection episodes in transplant recipients who are treated with cyclosporine.

Adult↗

PubMedDate not supplied

Supratentorial cartilaginous tumors. (A report of 2 cases).

Explore the source record for details and available documents.

Adult↗

PubMedDate not supplied

Cellular and molecular mechanisms of human cardiac myocyte injury after transplantation.

BACKGROUND: Fetal human cardiac myocytes or a cell line derived from fetal human cardiac myocytes, termed W1, even after experimental induction of "normal" levels of major histocompatibility complex class I and II antigens, fail to induce the activation of primary allogeneic responses. Therefore, our laboratory has investigated the ability of such MHC-expressing cardiac myocytes to induce secondary alloproliferative responses or to serve as target cells for cytotoxic T lymphocytes. METHODS: Cloned CD4+ and CD8+ T-cell lines having specificity for major histocompatibility complex class I and II molecules expressed by the fetal human cardiac myocytes and the W1 cell line were used in standard proliferation and cytotoxicity assays. RESULTS: Our data show that none of the 19 HLA-DR3 (beta 1 0301)- or HLA-DR15 (beta 1 1501)-specific CD4+ cloned T-cell lines reacted with HLA-DR3- or DR15-expressing W1 or fetal human cardiac myocytes. However, these CD4+ T cells did react, as expected, with similar HLA-DR3/DR15-expressing homozygous typing cells. Of the 16 cloned CD8+ cytotoxic T lymphocytes with specificity for HLA-A2 and the 12 with specificity for HLA-A1, only two of each showed weak cytotoxicity against interferon gamma-pretreated HLA-A2 and A1-expressing W1 and fetal human cardiac myocytes, respectively. Each cloned cytotoxic T lymphocytes line, however, was very effective against HLA-A2 and A1-expressing homozygous typing cells. Although the IFN-gamma-induced W1 and fetal human cardiac myocytes were not susceptible to cytotoxic T lymphocytes-mediated lysis, they were capable of inhibiting specific cytotoxic T lymphocytes function as defined by cold target inhibition studies. CONCLUSIONS: These data suggest that peptide-allo major histocompatibility complex presented by human cardiomyocytes is recognized by T cells and the these lymphocyte/myocyte interactions lead to immunologic ignorance.

CD4-Positive T-Lymphocytes↗

PubMedDate not supplied

Neutrophil adhesion inhibition prolongs survival of cardiac allografts with hyperacute rejection.

Hyperacute rejection results in rapid destruction of a cardiac allograft and is characterized by infiltration of neutrophils into the donor organ. We sought to ameliorate this response by using a potent inhibitor of neutrophil adhesion to vascular endothelium, NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy) carbonyl]-L-leucine) and determine its effect on long-term graft survival and histology. This compound specifically prevents recruitment of neutrophils at inflammatory foci by inhibiting upregulation of the CD11b/CD18 adhesion molecule located on the neutrophil surface. Lewis rats were presensitized by three serial ACI rat skin grafts placed 10 days apart. ACI rat hearts were heterotopically transplanted into Lewis recipients 10 to 14 days after the final skin graft. Group I (n = 15) was treated with a 10 mg/kg intravenous bolus of NPC 15669 before reperfusion, followed by 3 mg/kg over 30 minutes. Group II (n = 13) was given saline vehicle intravenously. Two allografts in each group were harvested at 5, 15, 30, and 60 minutes, and the remainder were followed to cessation of graft function. Early 5- to 60-minute allograft histologic findings revealed focal interstitial hemorrhage, edema, and contraction-band necrosis associated with neutrophil infiltration in group II. Group I had significant reduction of all parameters at the earliest time points. Graft survival was significantly increased in group I, 89.2 +/- 20.3 hours (mean +/- SD) compared to 27 +/- 17 hours in group II (p < 0.0001). End-stage rejection was characterized by extensive neutrophil infiltrate and hemorrhage in group II; group I grafts had a predominantly mononuclear cell infiltrate with rare neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Complications of endomyocardial biopsy in heart transplant patients.

Despite the increasing use of alternative techniques, endomyocardial biopsy remains the primary method for diagnosing cardiac allograft rejection. Improved patient longevity and an increasing number of transplantation centers are resulting in an increase in the number of biopsies performed. Although endomyocardial biopsy is usually considered a safe procedure, no large studies of the risks of endomyocardial biopsy specifically in the transplant population have been undertaken. To determine the risk of endomyocardial biopsy in these patients, we reviewed 2454 endomyocardial biopsies performed from January 1983 to December 1990 in 133 cardiac allograft patients at our institution. At the time of each endomyocardial biopsy, a worksheet was completed detailing the patient's interval history, the site of vascular introduction, the number of attempts, the number of specimens, and any complications encountered. A total of 74 (3.0%) complications occurred. Fifty-six (2.3%) complications were associated with catheter insertion, including carotid puncture (1.8%), vasovagal reaction (0.1%), and prolonged bleeding (0.4%). Complications during biopsy included arrhythmias (0.25%) and conduction abnormalities (0.2%). In addition, we observed five episodes (three patients) of allergic reaction to a reusable bioptome and one case of pacemaker dislodgement. All complications were without significant long-term sequelae. In contrast to the cardiomyopathy population, no ventricular perforations or deaths occurred. Thus although endomyocardial biopsy has some risk, it continues to be a safe and effective way of monitoring rejection.

Adult↗