Effects of the new and highly active immunosuppressant, rapamycin, on lymphoid tissues and cells in vivo.
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Animals↗
Biomedical subjects
M E Billingham
Publications and source records attributed to M E Billingham.
Direct and indirect morphological markers of cocaine toxicity in the human heart.
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Animals↗
Detection of Coxsackievirus B3 RNA in myocardial tissues by the polymerase chain reaction.
Coxsackievirus B3 is a possible etiologic agent in some forms of myocarditis and idiopathic dilated cardiomyopathy. A method for the detection of coxsackievirus B3 RNA was developed using the polymerase chain reaction based on the amplification of a cDNA copy of the positive-strand viral RNA. The fidelity of the method was established in two murine models for coxsackie B3 myocarditis. All cardiac specimens with adequate RNA for study from coxsackie B3-infected mice contained detectable viral RNA, in contrast to none of control specimens from noninfected mice. The sensitivity of the technique was established at approximately 1 to 100 plaque-forming units of virus per gram of tissue, and the specificity was established as limited to the coxsackievirus B3 serotype among nine viruses tested. In patients with myocarditis, one of five specimens contained detectable viral RNA, whereas none of 11 specimens from patients with idiopathic dilated cardiomyopathy or 21 myocardial specimens from patients with a wide variety of other cardiac disorders contained detectable coxsackie B3 viral RNA. The results show that the polymerase chain reaction is a useful means for detecting coxsackie viral RNA and its application should help in the evaluation of hypotheses concerning the infectious etiology of human myocarditis and idiopathic dilated cardiomyopathy.
Amino Acid Sequence↗
Accelerated posttransplant coronary arteriosclerosis in combined heart-lung transplantation.
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Age Factors↗
A mycobacterial 65-kD heat shock protein induces antigen-specific suppression of adjuvant arthritis, but is not itself arthritogenic.
A recombinant (r)65-kD protein from Mycobacterium leprae, at levels far in excess of those present in whole mycobacteria, was unable to induce arthritis. Even when combined with a synthetic adjuvant, CP20961, to mimic the peptidoglycan adjuvant component of the mycobacterial cell wall, the r65-kD protein failed to induce arthritis. Pretreatment with as little as 1 microgram r65-kD protein protected rats against arthritis induced by M. tuberculosis, but this r65-kD protein was markedly less able to protect against arthritis induced by the synthetic adjuvant, CP20961, or type II collagen. The r65-kD protein appears, therefore, to produce an antigen-specific protection against arthritis induced by bacterial cell walls containing the 65-kD protein. Such protection can be overcome, however, by arthritogenic T lymphocytes, suggesting that protection occurs by preventing clonal proliferation of autoreactive T lymphocytes that are induced by the adjuvant properties of mycobacterial cell walls. How the r65-kD protein abrogates this particular adjuvant activity, and the nature of the arthritogenic self antigen(s), remain to be elucidated.
Animals↗
Monoclonal antibodies and arthritis.
Monoclonal antibodies to certain cell surface constituents on lymphocytes, monocytes and macrophages have been administered to Lewis rats with developing, established or adoptively transferred arthritis, to determine any immunomodulatory properties. Anti-CD4 antibodies against helper T-lymphocytes produced a dose related inhibition of developing arthritis; high dose levels completely suppressed all symptoms of arthritis and these rats were resistant to further attempts to induce arthritis. Anti-Ia (MHCII) antibodies also inhibited arthritis in a dose related manner; anti-pan T antibodies delayed the onset of arthritis, but antibodies against CD8 and IL-2 receptor positive cells were without effect. Development of type II collagen-induced arthritis was also inhibited by anti-CD4 treatment. Established arthritis could be temporarily inhibited by anti-CD4 antibodies, but rebound of arthritis invariably occurred after stopping treatment, as is the case with cyclosporin A. Similar results with anti-CD4 antibodies were obtained during treatment of arthritis adoptively transferred by arthritogenic T-lymphocytes. From these experiments it is clear that CD4 positive T-lymphocytes have a major role in the induction of adjuvant arthritis and that interaction between CD4 and Ia bearing cells is important. The rebound of arthritis that occurred after withdrawal of anti-CD4 treatment during established disease infers that cells in addition to helper T-lymphocytes are involved in the chronicity of arthritis, but these remain to be elucidated. These findings are discussed in relation to results with monoclonal antibodies in other models of arthritis and human rheumatoid arthritis; the prospects for human therapy are also discussed.
Animals↗
Pathologic changes in the long-term transplanted heart: a morphometric study of myocardial hypertrophy, vascularity, and fibrosis.
Myocyte hypertrophy and myocardial fibrosis have been observed in transplanted human hearts, and both could potentially have an adverse effect on long-term cardiac function. There has been some concern that distant donor heart procurement and cyclosporine treatment increase the risk of these changes, but their incidence and severity have not been documented quantitatively in large numbers of cardiac transplant recipients. We used light microscopic morphometric methods to estimate myocardial collagen volume fraction and myocyte width in right ventricular endomyocardial biopsies from 95 recipients at 3 years posttransplantation, and electron microscopic stereology to estimate myocardial vascularity and myocyte myofibril content in 40 recipients, also at 3 years posttransplantation. We compared those with locally and distantly procured donor hearts (mean ischemic time 160 minutes) and cyclosporine versus noncyclosporine immunosuppression. Controls were pretransplant right ventricular biopsies from 20 donor hearts which were free of heart disease. We found no significant differences in myocardial collagen volume fractions. Myocyte hypertrophy was typical of all the transplant biopsies (mean myocyte width 20.2 microns, SD 3.0 in all transplants versus 11.8 microns, SD 2.2 in controls, P less than 0.001), but distant donor procurement and cyclosporine had no significant effect. There were significant reductions of myofibril volume fraction in the transplants, which raises the possibility of gradual decompensation in some patients. There were no significant differences in myocardial vascularity, although a few patients were well below the control range. We conclude that distant donor heart procurement, with ischemic times averaging less than 3 hours, and cyclosporine treatment are not responsible for significant hypertrophy or fibrosis in most transplants. Hypertrophy is typical of the transplanted heart, and it is possible that associated abnormalities might have an effect on cardiac function in some long-term survivors.
Adult↗
Endocardial infiltrates in human heart transplants: a serial biopsy analysis comparing four immunosuppression protocols.
Endocardial mononuclear cell infiltrates were studied in 2,350 consecutive biopsies from 172 patients over a period ranging from 4 to 16 months post cardiac transplantation. The patients, otherwise unselected, were equally subdivided into four groups based upon the specific type of maintenance immunosuppression used. This was to allow for comparison of the effects of four separate commonly used recipient immunosuppression protocols, which could potentially influence the characteristics of the infiltrates. With azathiaprine-corticosteroid immunosuppression, endocardial infiltrates in otherwise normal biopsies were exceedingly rare, very minor, and invariably unifocal. Mild and moderate rejection were associated with a highly significant stepwise increase in incidence, prominence, and multifocality of endocardial infiltrates. In contrast, with each of the three cyclosporine-based recipient immunosuppression protocols which were evaluated, approximately 15% of biopsies with no evidence of rejection were associated with endocardial infiltrates. There was a wide range of variation in the prominence of the endocardial infiltrates present. Multifocal infiltrates were frequently encountered, the incidence of which was exclusively dependent upon the specific cyclosporine-based immunosuppression protocol used. With mild and with moderate rejection there was a significant stepwise increase in overall biopsy incidence of all endocardial infiltrates in each of the three groups, although there was no variation in relative prominence of the infiltrates, or in incidence of multifocality when biopsies without rejection were compared. The presence of conspicuous vascular spaces within endocardial infiltrates and significant extension of the infiltrates into the adjacent myocardium, with or without associated myofiber necrosis, were characteristic features of the most prominent endocardial infiltrates in all three cyclosporine-based immunosuppression groups. This constellation of changes has sometimes been referred to as "Quilty" effect. The relative incidence with which these particular features were encountered in association with endocardial infiltrates did not vary with rejection category of the biopsies. This study has shown that the presence of all forms of endocardial infiltrates, in the absence of concomitant rejection, is a characteristic manifestation of cyclosporine-based recipient immunosuppression, regardless of the specific protocol and cyclosporine dosage schedule. Under azathiaprine-based immunosuppression, endocardial infiltrates are almost invariably associated with rejection. It is postulated that cyclosporine-related endocardial mononuclear cell infiltration, in the absence of overt rejection, may result from a low level alloimmune response secondary to fluctuations in cyclosporine drug levels or related factors, and that the incidence with these infiltrates occur can be augmented during acute rejection episodes when the strength of the recipient immune response is magnified.
Biopsy↗
Collagen profile in the transplanted heart.
To substantiate the finding of interstitial myocardial fibrosis in the transplanted heart and to characterize the collagen profile of the transplanted heart, we studied endomyocardial biopsy specimens from 30 heart transplants and four heart-lung transplants at 1 to 82 months after transplantation. Indirect immunofluorescent techniques with affinity-purified antibodies for collagen types I, III, IV, and V were used. The degree of interstitial collagen present was scored. The amount of type I collagen was increased in transplants from distant donors (mean ischemia time, 154 minutes) compared with those from on-site donors (mean ischemic time, 59 minutes): collagen scores 1.1 and 1.7, respectively (P less than .01). There was a trend toward a positive correlation, not statistically significant, between cyclosporine dose and collagen III deposition (r = .35), collagen IV (r = .38), and collagen V (r = .56). There was a negative correlation between number of rejection episodes and mean cyclosporine dose (r = -.41) and amount of collagen III (r = -.42) or collagen IV (r = -.42). No correlations were found between collagen deposition and any other variables studied. These results confirm the mixed nature of the collagen deposited and suggest that some fibrosis is related to cyclosporine administration rather than to the number of prior healed rejection episodes.
Adult↗
The safety and utility of endomyocardial biopsy in infants, children and adolescents.
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Adolescent↗
Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro.
The anthracycline antibiotic doxorubicin produces a characteristic myopathy in cardiac muscle that limits its use in cancer therapy. We have shown in cultured neonatal rat cardiac muscle cells that doxorubicin treatment resulted in a rapid, selective decrease in the expression of muscle-specific genes, which preceded other changes characteristic of doxorubicin cardiomyopathy. Doxorubicin selectively and dramatically decreased the levels of mRNA for the sarcomeric genes, alpha-actin, troponin I, and myosin light chain 2, as well as the muscle-specific, but nonsarcomeric M isoform of creatine kinase. However, doxorubicin did not affect nonmuscle gene transcripts (pyruvate kinase, ferritin heavy chain, and beta-actin). Actinomycin D, an inhibitor of DNA-dependent RNA polymerase, did not show a similar selective decrease of muscle-specific mRNAs but, rather, produced a nonspecific, dose-dependent decrease of muscle and nonmuscle transcripts. The doxorubicin effect on muscle gene expression was limited to cardiac muscle; cultured skeletal myocytes were resistant to the effects of doxorubicin at 100-fold greater doses than those causing changes in mRNA levels in cardiac muscle cells. These effects of doxorubicin were reproduced in vivo; rats injected with doxorubicin showed a dose-dependent decrease in the levels of mRNAs for alpha-actin, troponin I, myosin light chain 2, and M isoform of creatine kinase in cardiac but not skeletal muscle. These selective changes in gene expression in cardiocyte cultures and cardiac muscle precede classical ultrastructural changes and may explain the myofibrillar loss that characterizes doxorubicin cardiac injury.
Actins↗
In situ hybridization studies for viral nucleic acids in heart and lung allograft biopsies.
In situ hybridization has been shown to be a useful technique for the identification of specific viruses in pathologic tissues. The authors studied 313 lung and 164 heart biopsies from 20 heart-lung recipients to assess its utility in this clinical setting, employing biotinylated probes for the cytomegalovirus, herpes simplex, and adenovirus genomes. Twenty-five lung biopsies and one heart biopsy had detectable cytomegalovirus DNA by in situ hybridization. As compared to histopathology, in situ hybridization had a sensitivity of 85% and a specificity of 99%. None of the biopsies had detectable herpes simplex or adenovirus by either in situ hybridization or routine histopathology. In situ hybridization studies may be of greatest use when the results of conventional histopathology are equivocal and in the patients with radiologic or clinical evidence of pulmonary disease.
Adenoviridae↗
Transesophageal echocardiography and its potential for esophageal damage.
The purpose of this study was to determine whether the pressure produced by contact between a transesophageal echocardiography (TEE) probe and the esophagus was sufficient to cause esophageal damage. The authors studied the effects of sustained contact and associated surface pressure on the esophagus by a TEE probe in anesthetized dogs and humans. Contact pressure between the tip of the probe and the esophageal wall in dogs was measured using a previously described flat balloon of Silastic fitted to the end of a TEE probe and the recording system calibrated with a mercury manometer. In the dog studies, the probe was inserted, maximally flexed, and its position fixed for 4, 6, 8, and 12 h. The maximum surface pressure generated by contact between a probe and the esophageal wall was 10 mmHg. Subsequent pathologic studies failed to reveal either gross or microscopic evidence of tissue damage. The same system was used in short-term patient studies with the surface contact pressure transducer connected to a Camino Catheter 420 Digital Pressure Monitor. In five of six patients contact pressure was less than 17 mmHg despite maximal rotation of the TEE controls. However, one of the six patients developed very high contact pressure, up to 60 mmHg, between the probe and the esophagus. This patient had no history of esophageal disease but did have intrathoracic pathology.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Histamine mediates myocardial damage by an H1 mechanism independent of coronary blood flow.
Administration of histamine to rabbits may result in myocardial damage similar to that produced by catecholamines and the anthracycline antibiotics. To explore the mechanisms involved in histamine-mediated myocardial damage, conscious New Zealand white rabbits were pretreated with H1 and H2 receptor blocking agents, alone and in combination, and then administered histamine. Coronary artery blood flow was measured with radiolabeled microspheres in rabbits that received histamine alone, and in those that received an H1 blocking agent and histamine. Rabbits that received an H1 blocking agent had a significant reduction in morphological injury which was scored as follows: grade 1, minimal or no injury; grade 2, moderate; and grade 3, severe injury (mean pathology score = 1.1 +/- 0.28 for histamine alone vs. 0.06 +/- 0.06 with H1 receptor blockade, p less than 0.05). Animals pretreated with H2 receptor blockade (mean pathology score = 1.2 +/- 0.49) were not protected against morphological injury. Coronary blood flow decreased in animals that received histamine alone: control = 2.61 +/- 0.38 vs. 1.80 +/- 0.30 ml/min/g (p less than 0.05), and in animals pretreated with H1 blockade; control = 3.29 +/- 0.34 vs. 1.91 +/- 0.28 ml/min/g (p less than 0.01). We conclude that histamine-mediated myocardial damage appears to be mediated by the H1 receptor system and that this appears to be independent of initial changes in global coronary blood flow.
Animals↗
Induction of donor-specific unresponsiveness to cardiac allografts in rats by pretransplant anti-CD4 monoclonal antibody therapy.
In the present report a monoclonal antibody designated OX-38 directed against the rat CD4 molecule was tested for its ability to prolong the survival of heterotopic vascularized rat heart allografts transplanted across major histocompatibility barriers. Fluorescence-activated cell-sorter analysis showed that administration of OX-38 selectively depleted 80-95% of CD4+ cells from peripheral blood of treated rats. The immunosuppressive effects of OX-38 in vivo were verified by suppression of an antibody response against OX-38 itself as a heterologous protein immunogen. Recipient rats received OX-38 antibody as a single agent given in pretransplant regimens. Nine of 12 treated rats have maintained heterotopic abdominal heart allografts for greater than 175 days. Control rats that did not receive antibody therapy rejected their grafts within 14 days. Rats that maintained heart allografts for greater than 100 days accepted second donor strain hearts but rejected third-party heart grafts transplanted into the femoral space. Anti-CD4-induced allograft unresponsiveness persisted for at least 90 days following surgical removal of donor tissue and retransplantation of a second donor-matched heart. These results indicated that transient, pretransplant therapy with monoclonal antibodies directed against the CD4+ lymphocyte induced specific, long-lasting unresponsiveness to fully MHC-mismatched cardiac allografts in rats without additional immunosuppression.
Animals↗
Rapid histological changes in endomyocardial biopsy specimens after myocarditis.
The course and response to treatment in acute lymphocytic myocarditis are conventionally monitored by endomyocardial biopsy performed every 3-12 weeks. A patient with a short history (five days) of acute myopericarditis of unknown aetiology presented in cardiogenic shock with evidence of severe systolic dysfunction on the echocardiogram. The initial biopsy specimen showed histologically unequivocal myocarditis. Repeat endomyocardial biopsy after four days of treatment with steroids and azathioprine showed substantial histological improvement, a reduction in cellular infiltrate and myocardial necrosis, and interstitial fibrosis. Serial biopsies at 2 weeks and then 1, 2, 4, 5, 8, and 14 months after the initial biopsy showed progressive clearing of cellular infiltrate, increasing interstitial fibrosis, and compensatory myocyte hypertrophy by 4 months. At 14 months scattered lymphocytes persisted but myocyte abnormalities had resolved completely. The patient remained symptom free and systolic function was normal during this recovery period. Early endomyocardial biopsy (within one week of diagnosis) may yield useful histological information on the response to treatment in patients with myocarditis. It may not be necessary to wait the customary 3-4 weeks to repeat the biopsy. This case shows the chronology of histological changes and emphasises that a return to normal myocardial function may precede resolution of the histological abnormalities, which may persist in part or may resolve totally after the acute episode.
Acute Disease↗
Mildly dilated congestive cardiomyopathy. Use of prospective diagnostic criteria and description of the clinical course without heart transplantation.
Prognosis in classically described dilated congestive cardiomyopathy has been reported to be related to ventricular size. Mildly dilated congestive cardiomyopathy (MDCM) has been defined as end-stage heart failure of unknown etiology (New York Heart Association class IV, left ventricular ejection fraction less than 30%), occurring with neither typical hemodynamic signs of restrictive myopathy nor significant ventricular dilatation (less than 15% above normal range). The present study includes follow-up in 12 nontransplant patients. In the first 4 months after diagnosis, two patients improved and are living, and two showed cardiac dilation and clinical deterioration and died. Six of the remaining eight with persistent MDCM died (four with intractable heart failure and two, sudden deaths) without change in ventricular size before death, despite medical therapy over 20 +/- 8 months. Eight comparable transplanted patients with persistent MDCM demonstrated improved total survival by life table analysis (p less than 0.05). A family history of congestive cardiomyopathy was found in nine of 16 patients (56%) with persistent MDCM. Nontransplant patients were older (p less than 0.02), but other findings were similar in the two groups. Endomyocardial biopsies available in 14 of 16 cases showed little or no myofibrillar loss in spite of severe hemodynamic impairment. The degree of myofibrillar loss did not correlate with hemodynamic parameters but showed good correlation with left ventricular size, that is, five of six patients with no myofibrillar loss had normal ventricular size, whereas all eight patients with mild myofibrillar loss had mild cardiomegaly (p less than 0.002). Our current experience suggests a somewhat variable but negative prognosis after prospective diagnosis of MDCM, with poor survival in patients with persistence of the original diagnostic features during follow-up. Preservation of heart size in MDCM is probably related to lack of significant myofibrillar loss. Thus, irrespective of heart size or myofibrillar preservation on biopsy, heart transplantation should be strongly considered in MDCM if signs of severe cardiac dysfunction persist despite therapy.
Adult↗
The pathology of transplanted hearts.
In summary, cardiac transplantation offers an excellent chance of long-term survival and functional rehabilitation for the carefully selected patient with end-stage cardiac disease. At this time, the morphological index of acute rejection by endomyocardial biopsy is still the only reliable one. For the future, it is hoped that a satisfactory consensus on grading systems for the biopsy can be worked out so that better correlations with treatment can be made. It is also to be hoped that a reliable noninvasive technique can be found to monitor acute rejection, particularly for children and infants. Lastly, one of the most important priorities in heart transplantation is to produce the exact etiology, pathology, and prevention of graft coronary disease.
Biopsy↗