Biomedical subjects

R D Davis

Publications and source records attributed to R D Davis.

At least 19 recordsLinked to original sources

PubMed2006

Prolonged function of macrophage, von Willebrand factor-deficient porcine pulmonary xenografts.

Porcine von Willebrand factor (vWF) activates human and primate platelets. Having determined the importance of pulmonary intravascular macrophages (PIMs) in pulmonary xenotransplantation, we evaluated whether, in the absence of PIMs, vWF might play a role in pulmonary xenograft dysfunction. Utilizing a left single-lung transplant model, baboons depleted of anti-alphaGal antibodies received lungs from either vWF-deficient (n = 2); MCP-expressing (n = 5); MCP PIM-depleted (n = 5); or vWF-deficient PIM-depleted swine (n = 3). Two out of three of the PIM-depleted, pvWF deficient grafts survived longer than any previously reported pulmonary xenografts, including PIM-depleted xenografts expressing human complement regulatory proteins. Depletion of PIM's from vWF-deficient lungs, like depletion of PIM's from hMCP lungs, resulted in abrogation of the coagulopathy associated with pulmonary xenotransplantation. Thus, in terms of pulmonary graft survival, control of adverse reactions involving pvWF appears to be equally or even more important than is complement regulation using hMCP expression. However, based on the rapid failure of PIM-sufficient, pvWF-deficient pulmonary xenografts, pVWF-deficient pulmonary xenografts appear to be particularly sensitive to macrophage-mediated damage. These data provide initial evidence that vWF plays a role in the 'delayed' (24 h) dysfunction observed in pulmonary xenotransplantation using PIM depleted hMCP organs.

Animals↗

PubMed2006

Comparison of Coapsys annuloplasty and internal reduction mitral annuloplasty in the randomized treatment of functional ischemic mitral regurgitation: impact on the left ventricle.

BACKGROUND: Functional mitral regurgitation is associated with both annular and ventricular distortion. Aggressive reduction annuloplasty for functional mitral regurgitation acts primarily at the annulus, with variable impact on the left ventricle. The Coapsys device externally reshapes the left ventricle to correct functional mitral regurgitation. Left ventricular reshaping was analyzed in a randomized study. METHODS: The RESTOR-MV study randomizes patients with coronary artery disease and functional mitral regurgitation to either reduction annuloplasty and coronary artery bypass grafting (the RA group) or Coapsys annuloplasty and bypass grafting (the CO group). The Coapsys device consists of epicardial pads connected by a cord. It was placed without cardiopulmonary bypass under echocardiographic guidance and sized to reduce annular dimension and improve leaflet coaptation. Internal reduction annuloplasty was performed by device placement. Intraoperative transesophageal echocardiograms were analyzed in 7 patients having reduction annuloplasty and 7 having Coapsys annuloplasty. RESULTS: Baseline mitral regurgitation (0-4 scale) was similar for the RA (3.0 +/- 0.6) and the CO groups (3.0 +/- 0.6). Intraoperative mitral regurgitation was reduced from 2.86 +/- 0.7 to 0.5 +/- 0.7 (P < .01 pre vs post) for the RA group and from 2.64 +/- 0.9 to 05 +/- 0.7 (P < .01 pre vs post) for the CO group. Annular anteroposterior diameter was reduced with both techniques: RA, 3.45 +/- 0.39 to 2.34 +/- 0.37 cm (P < .01 pre vs post); CO, 3.40 +/- 0.27 to 2.85 +/- 0.34 cm (P < .05 pre vs post). Long-axis dimensions were unchanged with both techniques. Short-axis dimensions measured at three levels were significantly reduced only in the CO patients: basal diameter 4.77 +/- 0.58 to 3.58 +/- 0.38 cm (P < .01 pre vs post); mid diameter 4.88 +/- 0.55 to 3.57 +/- 0.43 cm (P < .01 pre vs post); and apical diameter 4.39 +/- 0.46 to 3.38 +/- 0.34 cm (P < .01 pre vs post). CONCLUSIONS: Coapsys and reduction annuloplasty techniques both acutely reduce functional mitral regurgitation and annular dimension. The Coapsys device provided significantly greater left ventricular reshaping than did reduction annuloplasty. Further evaluation will assess the long-term valvular function and ventricular geometric stability associated with both techniques.

Aged↗

PubMed2006

Impact of lung transplant operation on bronchiolitis obliterans syndrome in patients with chronic obstructive pulmonary disease.

Previous studies suggest that bilateral (BLT) compared with single lung transplantation (SLT) for patients with chronic obstructive pulmonary disease (COPD) results in improved long-term survival. The effect of transplant operation on bronchiolitis obliterans syndrome (BOS) is unknown. A retrospective study of all lung transplant recipients with pre-transplant diagnoses of COPD at the University of Toronto and at Duke University was performed. Data collected were age, gender, date and type of transplant, acute rejection, survival, presence and time of BOS. 221 (bilateral n = 101, single n = 120) patients met our criteria. Patients with BLT were younger (53.0 vs. 55.3 years; p = 0.034), more likely to be male (56.3% vs. 42.4%; p = 0.039) and more likely to be transplanted at the University of Toronto (79.6% vs. 16.1%; p < 0.001). Freedom from BOS was similar at 1 year post-transplant. However, BLT recipients were more commonly free from BOS 3 years (57.4% vs. 50.7%) and 5 years (44.5% vs. 17.9%) post-transplant (p = 0.024). Survival of BLT was better than SLT recipients at 3 and 5 years post-transplant (BLT vs. SLT: 67.5% vs. 61.1% and 60.7% vs. 34.1%, respectively; p = 0.018). Similar trends on survival were observed after development of BOS. BLT results in lower rates of BOS in patients with COPD that are eligible for both SLT and BLT.

Bronchiolitis Obliterans↗

PubMed2005

A randomized, placebo-controlled trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human beings.

OBJECTIVE: Complement activation has been shown to play a significant role in ischemia-reperfusion injury after lung transplantation. TP-10 (soluble complement receptor 1 inhibitor) inhibits the activation of complement by inactivating C3a and C5a convertases. This was a clinical trial of TP-10 to reduce ischemia-reperfusion injury in lung transplantation. METHODS: In a randomized, double-blinded, multicenter, placebo-controlled trial, 59 patients from four lung transplant programs received TP-10 (10 mg/kg, n = 28) or placebo (n = 31) before reperfusion. This dose achieved 90% complement inhibition for 24 hours, and activity had returned toward normal by 72 hours. RESULTS: At 24 hours, 14 of 28 patients in the TP-10 group (50%) were extubated, whereas only 6 of 31 patients in the placebo group (19%) were (P = .01). The total times on the ventilator and in the intensive care unit both tended to be shorter in the TP-10 group, but these differences did not achieve statistical significance. Among patients requiring cardiopulmonary bypass (n = 5 in placebo group and n = 7 in TP-10 group), the mean duration of mechanical ventilation was reduced by 11 days in the TP-10 group (10.6 +/- 5.0 days vs 21.5 +/- 5.9 days in placebo group, P = .2). Operative deaths, incidences of infection and rejection, and length of hospital stay were not significantly different between the two groups. CONCLUSIONS: Short-term complement inhibition with TP-10 led to early extubation in a significantly higher proportion of lung transplant recipients. The effect of TP-10 was greater among patients undergoing cardiopulmonary bypass, with a large reduction in ventilator days. Complement inhibition thus significantly decreases the duration of mechanical ventilation and could be useful in improving the outcome of lung transplant recipients.

Adolescent↗

PubMed2005

Oral feeding with pig peripheral lymphocytes decreases the xenogeneic delayed type hypersensitivity reaction in galactosyltransferase knockout mice.

PURPOSE: Oral tolerance induction has shown promising results in experimental allotransplantation models but is not well investigated in xenotransplantation. We investigated the possibility to induce tolerance against pig peripheral lymphocytes (pPBL) in galactosyltransferase knockout mice (gal -/-), which produce antibodies against Galalpha1-3Gal. MATERIAL AND METHODS: Female (gal -/-) mice 6 to 8 weeks old weighing 35 to 40 g (n = 10) were fed orally every third day five times with 2 x 10(7) isolated, viable pPBL, or with phosphate-buffered saline (PBS) only (n = 7). They were then immunized subcutaneously on day 0 with a subcellular lysate from 4 x 10(7) isolated, viable pPBL. On day 13, 25 microL of a subcellular lysate corresponding to 1 x 10(7) isolated, viable pPBL was injected in the right dorsal foot pad, and the delayed type hypersensitivity (DTH) reaction was calculated after 24 hours by subtracting the swelling response from 25 microL PBS in the left footpad. Anti-Galalpha1-3Gal immunoglobulin IgG and IgM antibody titers were measured in the serum before oral feeding and at day 14. RESULTS: The DTH reaction of the pPBL fed mice was 0.07 +/- 0.05 mm vs 0.57 +/- 0.23 mm for the controls (P < .001). No significant differences in anti Gal alpha1-3 Gal IgG and IgM antibody titers were seen. CONCLUSIONS: This study demonstrates for the first time that oral delivery of pPBL can counteract the indirect T-cell reaction against xenogeneic subcellular antigens from pPBL. These observations warrant further investigation in immunologically modified mice and perhaps in primate models of xenotransplantation.

Administration, Oral↗

PubMed2002

Laparoscopic antireflux surgery in the lung transplant population.

BACKGROUND: Lung transplantation has emerged as a viable therapeutic option for patients with a variety of end-stage pulmonary diseases. As immediate posttransplant surgical outcomes have improved, the greatest limitation of lung transplantation remains chronic allograft dysfunction. Gastroesophageal reflux disease (GERD) with resultant aspiration has been implicated as a potential contributing factor in allograft dysfunction. GERD is prevalent in end-stage lung disease patients, and it is even more common in patients after transplantation. We report here on the safety of laparoscopic fundoplication surgery for the treatment of GERD in lung transplant patients. METHODS: Eighteen of the 298 lung transplants performed at Duke University Medical Center underwent antireflux surgery for documented severe GERD. The safety and benefit of laparoscopic fundoplications in this population was evaluated. RESULTS: The antireflux surgeries included 13 laparoscopic Nissen fundoplications, four laparoscopic Toupets, and one open Nissen (converted secondary to extensive adhesions). Two of the 18 patients reported recurrence of symptoms (11%), and two others reported minor GI complaints postoperatively (nausea, bloating). There were no deaths from the antireflux surgery. After fundoplication surgery, 12 of the 18 patients showed measured improvement in pulmonary function (67%). CONCLUSIONS: GERD occurs commonly in the posttransplant lung population. Laparoscopic fundoplication surgery, when indicated, can be done safely with minimal morbidity and mortality. In addition to the resolution of reflux symptoms, improvement in pulmonary function may be seen in this population after fundoplication. Lung transplant patients with severe GERD should be strongly considered for antireflux surgery.

Adolescent↗

PubMed2001

Safety of aerosolized amphotericin B lipid complex in lung transplant recipients.

BACKGROUND: Fungal infections remain an important cause of morbidity and mortality in lung transplant recipients. Aerosolized amphotericin B lipid complex (ABLC) may be more efficacious than conventional amphotericin B in the prevention of fungal infections in animal models, but experience with aerosolized ABLC in humans is lacking. METHODS: We conducted a prospective, noncomparative study designed to evaluate safety of aerosolized ABLC in lung or heart-lung transplant recipients. RESULTS: A total of 381 treatments were administered to 51 patients. Complete spirometry records were available for 335 treatments (69 in intubated patients, 266 in extubated patients). ABLC was subjectively well tolerated in 98% of patients. Pulmonary mechanics worsened by 20% or more posttreatment in less than 5% of all treatments. There were no significant adverse events related to study medication in any patient, and 1-year survival for all enrolled patients was 78%. CONCLUSION: Administration of nebulized ABLC is safe in the short-term and well-tolerated in lung transplant recipients. Additional prospective, randomized studies are needed to determine the efficacy of aerosolized ABLC alone or in conjunction with systemic therapies in the prevention of fungal infections in lung transplant recipients.

Adult↗

PubMed2001

Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection.

BACKGROUND: Although the use of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection in heart and kidney allograft recipients, its role in lung transplantation remains controversial. Therefore, we conducted a randomized, prospective, open-label, multicenter study in lung transplant recipients to determine whether MMF decreases episodes of acute allograft rejection when compared with azathioprine (AZA). METHODS: Between March of 1997 and January of 1999, 81 consecutive lung transplant recipients from two centers were prospectively randomized to receive cyclosporine, corticosteroids, and either 2 mg/kg per day of AZA or 1 g twice daily of MMF. The primary study endpoint was biopsy-proven acute allograft rejection over the first 6 months posttransplant. Secondary endpoints included clinical rejection, cytomegalovirus (CMV) infection, adverse events, and survival. Surveillance bronchoscopies were performed at 1, 3, and 6 months, or if clinically indicated. Pathologists interpreting the biopsy results were blinded to the randomization. Results were analyzed according to intention-to-treat. Between group comparisons of means and proportions were made by using two sample t tests and Fisher's exact tests, respectively. Six-month survival was calculated by the Kaplan-Meier method and compared by the log rank test. RESULTS: Thirty-eight patients were prospectively randomized to receive AZA, and 43 MMF. The incidence of biopsy proven grade II or greater acute allograft rejection at 6 months was 58% in the AZA group and 63% in the MMF group (P=0.82). The 6-month survival rates in the MMF and AZA groups were 86% and 82%, respectively (P=0.57). Rates of CMV infection and adverse events were not significantly different between the two groups. CONCLUSIONS: Acute rejection rates and overall survival at 6 months are similar in lung transplant recipients treated with either MMF- or AZA-based immunosuppression.

Acute Disease↗

PubMed2001

Hapten-induced primary and memory humoral responses are inhibited by the infusion of anti-CD20 monoclonal antibody (IDEC-C2B8, Rituximab).

Blocking the elicited humoral immune response has proven useful in treating individuals with autoimmune disorders or those who are at risk of developing antibodies which might be pathologic, e.g., transplant patients. Unfortunately, humoral immunity has evaded efforts at ablation and those therapies aimed at ameliorating it have resulted in only partial success. In addition, some of the current anti-humoral therapies not only target B-cells but also cross-react with other elements of immune response, making these therapies nonspecific. Thus there is a need in the clinical arena for specific anti-humoral therapies. Here we report the impact of infusion of a chimeric monoclonal, an anti-CD20 IgG, on the primary humoral and memory response against a simple hapten (DNP) in a nonhuman primate model. Anti-CD20 IgG interfered with the elicited humoral response and with the memory response when administered prior to antigen exposure. Furthermore, we provide evidence that anti-CD20 blocks the humoral response by eliminating those B-cells capable of responding to the hapten.

Animals↗

PubMed2001

Immune complex formation after xenotransplantation : evidence of type III as well as type II immune reactions provide clues to pathophysiology.

Rejection of renal and cardiac xenografts is initiated when natural antibodies of the recipient bind to donor endothelium, activating complement on the surface of endothelial cells. Pulmonary xenotransplants, however, reveal less evidence of antibody binding and complement activation and, in contrast to other xenografts, fare worse when the complement of the graft recipient is depleted. Accordingly, we asked whether distinct immunochemical reactions might occur after xenotransplantation of the lung and what implications such reactions might have for pulmonary pathophysiology. Analysis of serum from baboons after transplantation with porcine lungs revealed complexes containing baboon IgM and porcine von Willebrand factor. The baboon IgM in these complexes was specific for Galalpha1-3Gal. Immune complexes were also seen, albeit to a lesser extent, in the serum of kidney and heart xenotransplant recipients. Deposits of porcine von Willebrand factor and baboon C3 were detected in livers and spleens of transplanted baboons. These results indicate pulmonary xenotransplantation eventuates in formation of immune complexes and in the deposition of those complexes at distant sites. Immune complex formation could explain the peculiar fate of xenoreactive antibodies after pulmonary xenotransplantation and might contribute to the pathophysiology of the lung and systemic changes not previously considered a complication of xenotransplantation.

Animals↗

PubMed2001

Myocardial function in hearts with transgenic overexpression of the G protein-coupled receptor kinase 5.

BACKGROUND: Chronic heart failure is associated with impairment of the myocardial beta-adrenergic receptor (beta-AR) system. In this study, the effects of G protein-coupled receptor kinase 5 (GRK5) overexpression on myocardial performance were directly assessed in the hearts of transgenic mice using an isolated work-performing murine heart preparation and computerized analysis of functional data. METHODS: A controlled experimental study was performed to evaluate cardiac function in both transgenic mice with a 30-fold overexpression of GRK5 (n = 9, 23 to 29 g) and littermate controls (n = 10, 22 to 29 g). Preload-dependent cardiac output, contractility, stroke work, stroke volume, and heart rate were compared between the two groups. RESULTS: Significant decreases in preload-dependent cardiac output and contractility were observed in the mice with GRK5 overexpression when compared with control group mice and occurred in association with significant decreases in stroke work and stroke volume. There was no significant difference in the average heart rate between the two groups. CONCLUSIONS: These data suggest that GRK5 upregulation may be partially responsible for alterations in myocardial function in chronic heart failure.

Animals↗

PubMed2001

Evidence for polyreactive xenoreactive antibodies in the repertoire of human anti-swine antibodies: the 'next' humoral barrier to xenotransplantation?

The xenoreactive nature of anti-Galalpha1-3Gal antibodies, and to a lesser extent, polyreactive antibodies, has been characterized by a number of investigators. With the advent of therapies that avoid hyperacute xenograft rejection due to anti-Galalpha1-3Gal antibodies coupled with the possible development of Galalpha1-3Gal deficient swine, the Galalpha1-3Gal antigen may soon cease to be a barrier to xenotransplantation. With this in mind, the potential xenoreactive nature of polyreactive antibodies was investigated using several approaches. The levels of polyreactive antibodies from the serum of newborn (n = 2) and adult (n = 4) baboons undergoing pulmonary xenotransplantation were evaluated. Depletion of 95% and 94% of total serum IgM, without any decrease in albumin levels, was observed in the newborn baboons. This finding indicates that the IgM present at birth and germ line polyreactive IgM was adsorbed by the xenografts. The depletion of polyreactive antibodies (43-83% reduction of anti-DNP IgM) from adult baboons was also observed following pulmonary xenotransplantation or immunoadsorption therapy plus pulmonary xenotransplantation. Additional experiments using human cord serum indicated that most human polyreactive IgM were adsorbed by pig lung homogenate and that the human polyreactive IgM bound approximately two-fold more to immobilized pig lung antigens than to immobilized human lung antigens. These findings indicate that germline polyreactive antibodies are, for the most part, xenoreactive. These data suggest that polyreactive antibodies, although autoreactive, may be more xenoreactive than autoreactive.

2,4-Dinitrophenol↗

PubMed2001

Prognostic value of serum carcinoembryonic antigen levels in patients who undergo lung transplantation.

BACKGROUND: Potential candidates for lung transplantation undergo a rigorous evaluation before transplant. Serum carcinoembryonic antigen (CEA) levels are used as a screening tool for occult malignancy in many lung transplant centers. We reviewed the pre-transplant CEA levels in lung transplant recipients in our institution to determine their prognostic significance. MATERIALS AND METHODS: We performed a retrospective database review of the first 200 patients that had undergone lung or heart-lung transplant at our institution (dates were 1/20/92-7/25/98). Data extracted included CEA levels (in ng/ml) at the time of lung transplant evaluation, demographic data, and survival. Patients had one of the following diagnoses: alpha-1-anti-trypsin deficiency, cystic fibrosis, chronic obstructive pulmonary disease, Eisenmenger's syndrome, idiopathic pulmonary fibrosis, primary pulmonary hypertension, sarcoidosis, or other. RESULTS: After excluding re-transplants, CEA results were available for 174 of 193 (90.2%) patients. CEA levels were elevated in 85 patients (48.9%) with a mean value of 3.15 +/- 2.55 (normal < 2.5). Solid organ cancers developed in 6 patients, at a median follow-up of 27.5 months after transplant. Their mean pre-transplant CEA level was similar to the rest of the group (3.52 +/- 2.05). Pre-transplant CEA levels did not predict post-transplant survival. Patients with idiopathic pulmonary fibrosis had the highest pre-transplant CEA levels, whereas patients with primary pulmonary hypertension and Eisenmenger's syndrome had the lowest (5.36 +/- 4.59, 0.83 +/- 0.56, and 1.43 +/- 0.81, respectively; p = 0.0001). CONCLUSIONS: CEA levels are high in patients with end-stage lung disease, especially IPF. Their levels appear to be a marker of the underlying disease and do not predict the post-transplant survival or development of malignancy.

Adult↗

PubMed2001

Comparison of survival after mitral valve replacement with biologic and mechanical valves in 1139 patients.

OBJECTIVE: We sought to compare 10-year survival in patients after mitral valve replacement with biologic or mechanical valve prostheses. METHODS: Retrospective survival analysis was performed on data from 1139 consecutive patients older than 18 years of age undergoing mitral valve replacement with Carpentier-Edwards (n = 495; Baxter Healthcare Corp, Irvine, Calif) or St Jude Medical (n = 644; St Jude Medical, Inc, St Paul, Minn) prostheses. RESULTS: The 10-year survival was not statistically different between the patients receiving Carpentier-Edwards valves and those receiving St Jude Medical valves (P =.16). Adjusted survival estimates at 2, 5, and 10 years were 82% +/- 2% (95% confidence intervals, 79%-85%), 69% +/- 2% (95% confidence intervals, 64%-73%), and 42% +/- 3% (95% confidence intervals, 37%-48%), respectively, for the Carpentier-Edwards group and 83% +/- 2% (95% confidence intervals, 80%-86%), 72% +/- 2% (95% confidence intervals, 69%-76%), and 51% +/- 3% (95% confidence intervals, 45%-58%), respectively, for the St Jude Medical group. Predictors of worse survival after mitral valve replacement are older age, lower ejection fraction, presence of class IV congestive heart failure, coronary artery disease, renal disease, smoking history, hypertension, concurrent other valve surgery, and redo heart surgery. CONCLUSION: Choice of biologic or mechanical prosthesis does not significantly affect long-term patient survival after mitral valve replacement.

Age Factors↗

PubMed2001

Influenza pneumonia in lung transplant recipients: clinical features and association with bronchiolitis obliterans syndrome.

Influenza infection is increasingly recognized to cause significant morbidity and mortality in the community, especially in pediatric patients and elderly persons. Influenza infection, however, has not been well described among thoracic organ transplant recipients. We provide the first detailed clinical, radiographic, and histologic description of influenza pneumonia among three lung transplant recipients. The presentation varied considerably among the three patients and, in some cases, was atypical for influenza. Despite treatment, a persistent decline in pulmonary function occurred in all three patients after the acute illness. Interestingly, on follow-up biopsy specimens, each patient had histologic evidence of acute rejection and/or obliterative bronchiolitis. Additional research, therefore, is needed to clarify the relationship between influenza infection, acute rejection, and obliterative bronchiolitis.

Biopsy, Needle↗

PubMed2001

Exposure of hooded capuchin monkeys (Cebus apella cay) to a rabid bat at a zoological park.

On 27 May 1999, a big brown bat (Eptesicus fuscus) was discovered on an island exhibit at the Denver Zoo that contained a troop of 15 hooded capuchin monkeys (Cebus apella cay). The monkeys were attacking the bat when it was discovered. The bat was collected and humanely euthanatized without direct handling and submitted to the Colorado Department of Public Health and Environment Virology Laboratory for rabies evaluation. The monkeys had not been vaccinated against rabies virus. The next day, the laboratory confirmed that the bat was positive for rabies. The recommendations from the Colorado Department of Public Health and Environment and the Centers for Disease Control and Prevention were to euthanatize the monkeys or quarantine them and comply with the human nonvaccinated postexposure protocol. A 1-ml dose of a killed rabies vaccine was administered i.m. in the hip on each of days 2, 7, 12, 19, and 33 postexposure, and a single dose of human rabies immune globulin was administered i.m. 5 days postexposure. Blood was collected under anesthesia in order to evaluate the immune response after rabies vaccination from six monkeys 5 days postexposure, six monkeys 19 days postexposure (five of the six monkeys were the same monkeys bled 5 days postexposure), 15 monkeys 67 days postexposure, and 13 monkeys approximately 1 yr postexposure. All of the monkeys developed and maintained levels of rabies virus neutralizing antibody above 0.05 IU/ml by 67 days postexposure. Although a serologic titer of 0.05 IU/ml indicates an adequate human response after rabies vaccination, no similar information is available for nonhuman primates. To date, none of the monkeys has succumbed to rabies.

Animals↗

PubMed2000

The role of anti-Galalpha1-3Gal antibodies in acute vascular rejection and accommodation of xenografts.

BACKGROUND: A major impediment to the transplanting of porcine organs into humans is the susceptibility of porcine organs to acute vascular rejection, which can destroy a vascularized xenograft over a period of hours to days. Acute vascular rejection of porcine-to-primate xenografts is thought to be triggered by binding of xenoreactive antibodies to the graft. We tested whether antibodies, binding to Galalpha1-3Gal epitopes in porcine tissue, initiate this phenomenon. METHODS AND RESULTS: Specific depletion of anti-Galalpha1-3Gal antibodies from the blood of baboons, using extracorporeal perfusion of separated plasma through columns of Sepharose beads covalently linked to the antigenic trisaccharide, Galalpha1-3Galbeta1-4GlcAc, averted the development of acute vascular rejection in porcine organs transgenic for human decay-accelerating factor and CD59. More importantly, after immunodepletion was stopped and Gala1-3Gal antibodies were allowed to return, these same organs continued to function and remained pathologically normal and thus seemed to achieve a state of accommodation. CONCLUSION: These results demonstrate that anti-Galalpha1-3Gal antibodies cause acute vascular rejection and suggest that depletion of these antibodies leads to accommodation of the donor cardiac xenograft and could supply an important model for additional study.

Acute Disease↗

PubMed2000

Beta(2)-adrenergic and several other G protein-coupled receptors in human atrial membranes activate both G(s) and G(i).

Cardiac G protein-coupled receptors that couple to Galpha(s) and stimulate cAMP formation (eg, beta-adrenergic, histamine, serotonin, and glucagon receptors) play a key role in cardiac inotropy. Recent studies in rodent cardiac myocytes and transfected cells have revealed that one of these receptors, the beta(2)-adrenergic receptor (AR), also couples to the inhibitory G protein Galpha(i) (activation of which inhibits cAMP formation). If beta(2)ARs could be shown to couple to Galpha(i) in the human heart, it would have important ramifications, because levels of Galpha(i) increase with age and in failing human heart. Therefore, we investigated whether beta(2)ARs in the human heart activate Galpha(i). By photoaffinity labeling human atrial membranes with [(32)P]azidoanilido-GTP, followed by immunoprecipitation with antibodies specific for Galpha(i), we found that Galpha(i) is activated by stimulation of beta(2)ARs but not of beta(1)ARs. In addition, we found that other Galpha(s)-coupled receptors also couple to Galpha(i), including histamine, serotonin, and glucagon. When coupling of these receptors to Galpha(i) is disrupted by pertussis toxin, their ability to stimulate adenylyl cyclase is enhanced. These data provide the first evidence that beta(2)AR and many other Galpha(s)-coupled receptors in human atrium also couple to Galpha(i) and that abolishing the coupling of these receptors to Galpha(i) increases the receptor-mediated adenylyl cyclase activity.

Adenylate Cyclase Toxin↗