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Biomedical subjects

G J Berry

Publications and source records attributed to G J Berry.

At least 19 recordsLinked to original sources
PubMed2005

Giant cell myocarditis: a rare cardiovascular manifestation in a patient with systemic lupus erythematosus.

Giant cell myocarditis (GCM) is a rare form of myocarditis with a median survival of less than one year. It has been reported to occur in patients with various underlying autoimmune diseases; however, no cases of GCM have been described in patients with clear evidence of underlying systemic lupus erythematosus (SLE). The presentation of GCM may mimic that of lupus myocarditis, including an initial response to immunosuppression. Despite initial clinical similarities, lupus myocarditis and GCM are histologically distinct entities with dramatic differences in prognosis. We report herein a patient with a longstanding history of SLE, who presented acutely with myocarditis, responded well to initial immunosuppression and then subsequently died of progressive heart failure that was found to be due to GCM. Endomyocardial biopsy can help define diagnosis and prognosis of lupus patients presenting with myocarditis, and early referral for cardiac transplantation should be considered in patients diagnosed with GCM.

Adult↗
PubMed2002

The pathology of hibernating myocardium.

Myocardial hibernation represents a protective mechanism of muscle preservation in the setting of atherosclerotic coronary artery disease. Long-standing myocardial hypoperfusion leads to diminished myocardial contractility that reverses with improved blood flow after revascularization. The morphologic changes in both animal models and humans are described.

Adaptation, Physiological↗
PubMed2001

Viral serine proteinase inhibitor (SERP-1) effectively decreases the incidence of graft vasculopathy in heterotopic heart allografts.

BACKGROUND: Graft vascular disease (GVD) is the most common cause of late graft failure in solid organ transplantation. Recent studies have shown good efficacy of a novel nontoxic viral-derived serine proteinase inhibitor (SERP-1) in preventing postangioplasty restenosis. The current study was designed to test whether short-term treatment with SERP-1 was effective in reducing the incidence of GVD in a solid organ transplant. METHODS: Piebald-Virol-Glaxo (PVG) donor hearts were transplanted into August-Copenhagen-Irish (ACI) recipients and observed for 90 days. All recipients (n=60) were treated with microemulsion cyclosporine (CsA) 7.5 mg/kg per gavage from day 0 to day 9 and randomized into 4 groups. SERP-1 was given intravenously. Group I received CsA monotherapy; group II, CsA+SERP-1 1 ng/g (postoperative days 0-9); group III, CsA+SERP-1 10 ng/g (postoperative days 0-9); and group IV, CsA+SERP-1 10 ng/g (postoperative days 0-9, 30, and 60). Graft viability was monitored by palpation, and GVD was assessed by morphometry. RESULTS: Two animals in group I rejected their allografts on postoperative days 7 and 14, 1 animal in group II rejected the allograft (postoperative day 31), and none in group III and IV rejected the allografts. At 90 days postoperative, 23.8% of all coronary vessels showed evidence of GVD in group I, 18.4% in group II, 12.9% in group III, and 11.8% in group IV. The difference in incidence of GVD was significant between groups I and III (P<0.05) and groups I and IV (P<0.05). Treatment with SERP-1 was well tolerated, and all animals regained weight quickly postsurgery. CONCLUSIONS: Treatment of allograft recipients with SERP-1 in combination with CsA early after transplantation significantly decreases the incidence of GVD when compared to grafts treated with only CsA. These results demonstrate the clinical potential for this novel serine protease inhibitor to prevent GVD in solid organ transplantation.

Animals↗
PubMed2001

Prolonged inhibition of obliterative airway disease in murine tracheal allografts by brief treatment with anti-leukocyte function-associated antigen-1 (CD11a) monoclonal antibody.

BACKGROUND: We have previously shown that anti-leukocyte function-associated antigen (LFA)-1 (CD11a) monoclonal antibody (mAb) prevents acute rejection and produces donor-specific unresponsiveness in murine recipients of heterotopic heart allografts. Here, we investigate the ability of this mAb to prevent the development of obliterative airway disease (OAD) in murine recipients of tracheal allografts. METHODS AND RESULTS: BALB/c tracheae were heterotopically transplanted into C3H mice. OAD developed by day 28 after transplantation and was characterized histologically by a loss of epithelial cell coverage and luminal obliteration of the tracheal allograft with a proliferation of fibrogenic mesenchymal cells, which is a lesion comparable to obliterative bronchiolitis in human lung transplant recipients. Monotherapy with anti-LFA-1 mAb preserved graft epithelium, prevented the development of OAD, and maintained unresponsiveness to donor antigen for more than 42 days after the final mAb administration. CONCLUSION: These findings suggest the potential for anti-LFA-1 mAb therapy to suppress both acute and chronic rejection in clinical lung transplantation.

Animals↗
PubMed2001

Il-18 gene transfer by adenovirus prevents the development of and reverses established allergen-induced airway hyperreactivity.

We examined the role of IL-18 in preventing the development of and in reversing established allergen-induced airway inflammation and airway hyperreactivity (AHR), the cardinal features of asthma. IL-18, which potently induces IFN-gamma, was administered into the respiratory tract as cDNA in a replication-deficient adenovirus (Adv). Treatment of OVA-sensitized mice with the IL-18-expressing Adv reduced allergen-specific IL-4 production, airway eosinophilia, and mucus production, increased IFN-gamma production, and prevented the development of AHR. The effects of the IL-18 Adv treatment were dependent on the presence of IFN-gamma and IL-12. Moreover, administration of the IL-18 Adv to mice with established AHR greatly reduced AHR and IL-4 production and increased IFN-gamma production. These results demonstrate that IL-18, when administered by Adv into the respiratory tract, effectively reduces AHR and replaces an established Th2-biased immune response with a Th1-biased response.

Adenoviridae↗
PubMed2001

CT of noninfectious granulomatous lung disease.

Noninfectious granulomatous diseases of the lung consist of a diverse group of disorders that logically can be subdivided into those with and without associated vasculitis. This article reviews the epidemiologic, clinical, pathologic, and radiologic features of sarcoidosis, hypersensitivity pneumonitis, berylliosis, and the five entities traditionally classified as pulmonary angiitis and granulomatosis.

Diagnosis, Differential↗
PubMed2001

In vivo imaging of acute cardiac rejection in human patients using (99m)technetium labeled annexin V.

Annexin V binds phosphatidylserine moieties on apoptotic cells. This study reports the initial experience at Stanford University Medical Center with 99mTc-labeled annexin V imaging as a noninvasive measure of apoptosis in acute cardiac rejection. Ten cardiac transplant patients had 99mTc Annexin V imaging and endomyocardial biopsy (EMB) performed within 24 h. No complications related to 99mTc annexin V administration occurred. Eight patients had ISHLT grade of acute rejection of 1A or less. Five patients had two or more areas of uptake noted in the right ventricle on imaging studies. Two of these patients had positive biopsies: one patient had grade 2 rejection with two focal uptake areas and another had grade 3A rejection with three foci. An additional five patients had either one or zero hot spot areas and corresponding negative EMBs. 99mTc-annexin V appears to be well tolerated and may identify patients with acute cardiac rejection.

Annexin A5↗
PubMed2001

40-O-(2-hydroxyethyl)-rapamycin attenuates pulmonary arterial hypertension and neointimal formation in rats.

Pneumonectomized rats develop pulmonary hypertension (PH) and pulmonary vascular neointimal formation 4 wk after monocrotaline (MCT) administration. Male Sprague-Dawley rats were injected with MCT (60 mg/kg) on Day 7 after left pneumonectomy. Three groups (n = 5) received 40-O-(2-hydroxyethyl)-rapamycin (RAD, 2.5 mg/kg/d, by gavage): Group PMR(5-35) from Day 5 to Day 35, Group PMR5-14 from Day 5 to Day 14, and Group PMR15-35 from Day 15 to Day 35. By Day 35, rats that received vehicle had higher mean pulmonary arterial pressures (Ppa = 41 +/- 3 mm Hg) (p < 0.001), right ventricular systolic pressures (Prv,s = 45 +/- 2 mm Hg) (p < 0.01), and right ventricle/(left ventricle plus septum) (0.55 +/- 0.05) (p = 0.028) than rats in Groups PMR5-35 (Ppa = 25 +/- 3 mm Hg, Prv,s = 32 +/- 7 mm Hg, RV/LV&S = 0.42 +/- 0.06) and PMR5-14 (Ppa = 29 +/- 4 mm Hg, Prv,s = 30 +/- 5 mm Hg, RV/LV&S = 0.43 +/- 0.07). Pulmonary arterial neointimal formation (quantified by a vascular occlusion score) was more severe in vehicle-treated rats (1.93 +/- 0.03) than in Groups PMR5-14 (1.56 +/- 0.27) and PMR(5-35) (1.57 +/- 0.1) (p < 0.01). RAD attenuates the development of MCT-induced pulmonary arterial hypertension in the pneumonectomized rat.

Animals↗
PubMed2000

Zinc-mediated reduction of apoptosis in cardiac allografts.

BACKGROUND: Apoptosis is thought to occur during immune-mediated acute rejection of cardiac allografts. In vitro studies have shown that zinc inhibits the activity of the proapoptotic enzyme caspase-3. We hypothesized that ZnCl(2) would reduce acute cardiac rejection in vivo via the blockade of caspase-3-dependent apoptosis. (99m)Tc-labeled annexin V was used to measure apoptosis in cardiac allografts through nuclear imaging. Annexin V binds to phosphatidylserines, which are externalized to the outer membrane of apoptotic cells. METHODS AND RESULTS: Twenty-seven PVG rat hearts were transplanted heterotopically into the abdomen of untreated ACI rats as controls (group 1). Fifteen were scanned and euthanized on postoperative day 4, and 12 were assessed for graft survival. Group 2 and 3 rats (n=15 each) received 1 and 5 mg/kg ZnCl(2) BID IP, respectively. Nine of each of these groups were scanned and euthanized on postoperative day 4, and 6 were studied for allograft survival. Group 4 rats (n=3) received isografts. Region-of-interest analysis demonstrated a dose-dependent reduction in (99m)Tc annexin uptake in ZnCl(2)-treated allografts: 2.43+/-0.37% for group 1, 1. 97+/-0.41% for group 2, 1.21+/-0.47% for group 3, and 0.55+/-0.19% for group 4 (ANOVA, P:=0.001). Graft survival times of 6.4+/-1.7, 9. 3+/-3.0, and 11.5+/-3.4 days for groups 1, 2, and 3, respectively, were also observed (ANOVA, P:=0.001). Caspase-3 activity in the allografts showed a 3.7-fold reduction in group 3 animals compared with group 1 animals (P:=0.004). CONCLUSIONS: Apoptosis that occurs in acute cardiac allograft rejection is reduced with ZnCl(2) in a dose-dependent manner via caspase-3 inhibition.

Animals↗
PubMed2000

Epithelial re-growth is associated with inhibition of obliterative airway disease in orthotopic tracheal allografts in non-immunosuppressed rats.

BACKGROUND: Because epithelial cells are targets of alloimmune injury leading ultimately to airway obliteration, we tested whether epithelial re-growth could prevent obliterative airway disease (OAD) in orthotopic tracheal allografts. METHODS: Brown Norway tracheal segments were orthotopically transplanted into nonimmunosuppressed Lewis rats. Allografts were removed on days 2-10 (n=13), 30 (n=4), and 60 (n=5) for histology, computerized morphometry (obliteration), and immunohistochemical detection of mononuclear cells, smooth muscle alpha-actin, and tissue phenotype. Normal tracheas, host tracheas, and heterotopically transplanted allografts served as controls. RESULTS: Orthotopic allografts removed on days 2-10 exhibited epithelial damage and re-growth and mononuclear cell infiltration. On days 30 and 60, partially ciliated cuboidal or attenuated epithelium completely covered the lumen. Although mononuclear cells declined, numerous T cells with a high CD4/CD8 ratio were found in the epithelium till day 60. Orthotopic allograft epithelium expressed donor phenotype on day 7, but recipient phenotype on days 30 and 60. Despite subepithelial alpha-actin positive myofibroblast proliferation, obliteration did not progress from day 7 to 30 and 60 (35, 30, and 33%, respectively). Although more than in normal or host tracheas, the obliteration in orthotopic allografts on days 30 and 60 was significantly less (P<0.001) than in heterotopic allografts. CONCLUSIONS: We describe, for the first time, longterm patency of fully histoincompatible orthotopic tracheal allografts in nonimmunosuppressed rats. Despite acute alloimmune injury and induction of myofibroblast proliferation, epithelial re-growth from the host limited the progression of OAD, thus emphasizing the role of epithelium in the control of airway obliteration.

Animals↗
PubMed2000

Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates.

BACKGROUND: Current immunosuppressive protocols fail to prevent chronic rejection often manifested as graft vascular disease (GVD) in solid organ transplant recipients. Several new immunosuppressants including sirolimus, a dual function growth factor antagonist, have been discovered, but studies of drug efficacy have been hampered by the lack of a model of GVD in primates, as a prelude to clinical trials. As described earlier, we have developed a novel non-human primate model of GVD where progression of GVD is quantified by intravascular ultrasound (IVUS). METHODS: Twelve cynomolgus monkeys underwent aortic transplantation from blood group compatible but mixed lymphocyte reaction-mismatched donors. To allow the development of GVD in the allograft, no treatment was administered for the first 6 weeks. Six monkeys were treated orally with sirolimus from day 45 after transplantation to day 105. RESULTS: Progression of GVD measured as change in intimal area from day 42 to 105 was halted in sirolimus-treated monkeys compared to untreated monkeys (P<0.001, general linear model). On day 105, the intimal area +/- SEM was 3.7+/-1.0 and 6.4+/-0.5 mm2, respectively (P<0.05, t test). The magnitude of allograft intimal area on day 105 correlated inversely with sirolimus trough levels (R2=0.67, P<0.05). Regression of the intimal area was seen in four of six sirolimus-treated monkeys, which was significantly different from the untreated monkeys (P<0.05). CONCLUSIONS: Our results in the first non-human primate model of GVD showed that treatment with sirolimus not only halted the progression of preexisting GVD but also was associated with partial regression. Sirolimus trough blood levels were correlated with efficacy. Therefore, sirolimus has the potential to control clinical chronic allograft rejection.

Actins↗
PubMed2000

Immunosuppressive therapies for the prevention and treatment of obliterative airway disease in heterotopic rat trachea allografts.

BACKGROUND: Obliterative bronchiolitis remains a major long-term complication after lung transplantation. Using a reproducible model of heterotopically transplanted rat tracheas, this study examined the role of several novel immunosuppresive compounds to prevent and reverse obliterative airway disease in these animals. METHODS: Brown Norway rat trachea were transplanted into the greater omentum of Lewis (allografts) or Brown Norway (isografts) animals. Recipient animals were treated with rapamycin, cyclosporine, 15-deoxyspergulin, mycophenolate mofetil, or leflunomide from day 0, 7, or 14 until day of graft removal, either day 28 or 50. Trachea segments were evaluated for degree of lumenal occlusion, as well as percent and type of lumen epithelial cell coverage. RESULTS: All untreated allografted tracheas obliterated completely, although isografts appeared patent with normal respiratory epithelium when they were removed. Leflunomide, rapamycin, and cyclosporine effectively prevented obliteration when treatment was initiated at day 0, with rapamycin showing continued efficacy when initiated as late as day 7. 15-deoxyspergulin and mycophenolate mofetil failed to consistently inhibit obliteration with any treatment schedule. An inverse correlation was found between epithelial coverage and degree of obliteration, and was especially pronounced in grafts from cyclosporine-treated animals. CONCLUSIONS: Immunosuppressive drug therapy will inhibit airway obliteration, but efficacy sharply diminishes if initiation of treatment is delayed. Efficacy also varies among immunosuppressive compounds, and results indicate those drugs that enable epithelial regrowth most effectively inhibit airway graft obliteration.

Animals↗
PubMed2000

Prevention of acute allograft rejection in nonhuman primate lung transplant recipients: induction with chimeric anti-interleukin-2 receptor monoclonal antibody improves the tolerability and potentiates the immunosuppressive activity of a regimen using low doses of both microemulsion cyclosporine and 40-O-(2-hydroxyethyl)-rapamycin.

BACKGROUND: In previous studies of cynomolgus monkey lung allograft recipients, we demonstrated significant immunosuppressive efficacy but reduced tolerability after combined treatment with high doses of microemulsion cyclosporine (CsA) and SDZ RAD (40-O-(2-hydroxyethyl)-rapamycin). The current study was designed to compare efficacy and tolerability of a combination of low-dose CsA and high-dose SDZ RAD (CTL group) to triple therapy using the chimeric anti-interleukin-2 (IL-2) receptor (CD25) monoclonal antibody (mAb) basiliximab (anti-IL-2 receptor mAb) for induction therapy (basiliximab: 5 mg intravenously on days 0 and 4) plus low-dose CsA and low-dose SDZ RAD for maintenance immunosuppression (CD25 group). CsA and anti-IL-2 receptor mAb are drugs that reduce cytokine synthesis and block IL-2-mediated lymphocyte stimulation, respectively. SDZ RAD blocks lymphocyte stimulation by other cytokines (e.g., IL-15) that are not inhibited by anti-IL-2 receptor mAb. METHODS: Twelve unilateral lung transplants were performed. Recipients were observed for 49 days by daily weight assessment, hemograms, blood chemistries, radiographs, and lung biopsies. Monkeys were euthanized before day 49 in the event of excessive weight loss (>25%) or organ failure. Target CsA trough levels were 100-200 ng/ml. Target SDZ RAD trough levels in the CTL group (no mAb) were 20-40 ng/ml, and 10-20 ng/ml in the CD25 group. RESULTS: None of the monkeys in the CD25 group needed to be euthanized early due to signs of drug toxicity. In contrast, four monkeys in the CTL group were sacrificed on days 28-35 as a result of excessive weight loss (n=3) and renal functional impairment (n=1). Three recipients in the CD25 group were euthanized on days 36, 38, and 46 as a result of persistent high fever associated with severe rejection. The median animal survival in the CTL group was 32 vs. 46 days in the CD25 group (P<0.04). The only two long-term survivors in the CTL group showed moderate rejection at day 49. The median rejection scores at day 14 (A0) and day 28 (A2) were identical in the two groups, despite the fact that the mean SDZ RAD trough level was significantly lower in the CD25 group (CTL: 38+/-3 ng/ml, CD25: 18+/-2 ng/ml, P<0.0001). After basiliximab levels fell below the minimum therapeutic level (1 mg/ml) on day 28, the median rejection score at day 49 increased to A4 in the CD25 group. CONCLUSION: This is the first study to combine an anti-IL-2 receptor mAb with a drug from the rapamycin class plus CsA. Our study shows that induction therapy with basiliximab enabled SDZ RAD blood levels to be significantly reduced, which led to improved tolerability without the penalty of increased rejection.

Animals↗
PubMed2000

The role of respiratory epithelium in a rat model of obliterative airway disease.

BACKGROUND: The etiology and pathogenesis of obliterative bronchiolitis after lung transplantation remain to be fully elucidated. Using a rat model of heterotopically transplanted trachea grafts, we have examined the role airway epithelium plays in obliterative airway disease (OAD). METHODS: Rat trachea isografts were denuded of epithelium by protease digestion. Grafts were inoculated either with or without native airway epithelial cells and transplanted into the omentum of recipient animals. RESULTS: Airway epithelium removal resulted in OAD in denuded isogeneic trachea grafts. Reseeding of the denuded grafts with epithelial cells significantly reduced airway obliteration from 78% to 22% luminal occlusion. CONCLUSIONS: Non-immune-mediated injury will cause OAD, and epithelial cell replacement in denuded isografts can significantly reduce the fibrotic progression of the disease.

Animals↗