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Biomedical subjects

B Reichart

Publications and source records attributed to B Reichart.

At least 397 records · Page 22Linked to original sources
PubMedDate not supplied

Combining the hDAF transgene with the GP IIb/IIIa inhibitor tirofiban improves heart performance and reduces myocardial damage following hyperacute rejection in an ex vivo perfusion model.

Xenograft rejection is associated with vascular injury resulting at least in part from platelet activation, and rejected xenografts invariably demonstrate intravascular thrombosis. Assuming that complement activation is a major determinant of humoral immune reactions bringing about platelet-endothelial cell interactions, we tested the effects of the specific platelet glycoprotein IIb/IIIa inhibitor tirofiban in combination with the human decay accelerating factor (hDAF) transgene on hyperacute rejection of pig hearts. Four groups were studied in a working heart-perfusion model. Pig hearts transgenic for hDAF and nontransgenic pig hearts were perfused with human blood containing tirofiban or with unmodified human blood. Cardiac output, stroke work index, and creatine phosphokinases were measured for the evaluation of the extent of myocardial damage. Consumption of complement components was determined. Endothelial deposition of fibrin and intravascular thrombosis were evaluated. Tirofiban improved cardiac output and stroke work index of nontransgenic pig hearts and was able to further increase hemodynamic function of hDAF transgenic pig hearts. Low levels of creatine phosphokinases also revealed a cardioprotective effect of tirofiban. However, a further extension of the survival of hDAF transgenic pig hearts could not be achieved, although tirofiban prolonged beating time of nontransgenic pig hearts. Tirofiban was able to reduce the consumption of complement components independently of hDAF. Intravascular evidence of fibrin and thrombosis tended to be particularly reduced by the combination of tirofiban and hDAF. Thus, the application of tirofiban together with hDAF improves the performance of pig hearts by reducing myocardial damage and intravascular thrombosis.

Acute Disease↗
PubMedDate not supplied

Mean xenograft survival of 14.6 days in a small group of hDAF-transgenic pig hearts transplanted orthotopically into baboons.

INTRODUCTION: In a discordant orthotopic xenotransplantation model (pig-to-baboon) donor pigs expressing human decay accelerating factor (hDAF) as a regulator of complement activity were used to prevent hyperacute xenograft rejection (HXR). We investigated a modified immunosuppressive therapy consisting of ERL080 (Novartis Pharma AG, Base, Switzerland), cyclosporin A (Neoral), steroids, and a cyclophosphamide (CyP) induction protocol with several reduced doses to prevent acute vascular rejection (AVR). METHODS: Donor hearts were harvested from hDAF-transgenic pigs (18.8 +/- 2.6 kg, Imutran Ltd., a Novartis Pharma AG Company). Four adult baboons (25.6 +/- 2.7 kg) with high titers of xenoreactive antibodies (XAb) served as recipients. Serological and hemodynamic parameters were measured. Finally, myocardial tissue was sampled for histological and immunohistochemical examinations. RESULTS: In the first baboon, an acute graft failure occurred after 1 hour due to preservation injury. The second succumbed after 11.1 day due to an acute renal failure. The third died after 13.1 days of an ileus. The fourth baboon had continuously excellent cardiac function (mean echocardiographic ejection fraction, 69.2%), but succumbed on day 20 due to anemia. Corrected mean xenograft survival (excluding the first baboon because of a technical failure) was 14.6 +/- 2.6 days. XAb decreased after day 3 to constantly low levels (<1:64 titer) after CyP induction. White blood cell count decreased from 10.3 +/- 0.8 to 0.9 +/- 0.3 G/L after day 3. Macroscopically and histologically no typical signs of HXR or severe AVR could be detected. CONCLUSIONS: These results confirm that hDAF transgen blocks HXR in this life-supporting model. AVR was prevented by using a modified quadruple immunosuppressive drug combination (Neoral, ERL080, steroids, and several small single doses of CyP). An optimum "fine-tuning" of immunosuppression is required to achieve the best risk-benefit ratio.

Animals↗
PubMedDate not supplied

Combination of hDAF-transgenic pig hearts and immunoadsorption in heterotopic xenotransplantation of immunosuppressed baboons.

INTRODUCTION: Hyperacute xenograft rejection (HXR) and acute vascular rejection (AVR) after xenotransplantation are triggered by xenoreactive antibodies (XAb) and an activated complement cascade. In a heterotopic (abdominal) xenotransplantation model we combined immunoadsorption (IA, Ig-Therasorb column) and a quadruple immunosuppressive drug therapy in recipient baboons with donor pig hearts transgenic for human decay accelerating factor (hDAF). METHODS: According to XAb titers between 6 and 14 cycles of IA were performed preoperatively in 4 recipient baboons (18.6 +/- 2.5 kg). Hearts of hDAF-transgenic donor pigs (6.1 +/- 1.1 kg, Imutran Ltd., a Novartis Pharma AG Company, Basel, Switzerland) were heterotopically transplanted using the abdominal technique in baboons. Immunosuppression consisted of cyclophosphamide (CyP) induction therapy, ERL080 (Novartis Pharma AG), cyclosporin A (CyA, Neoral), and steroids. Blood levels of mycophenolate, CyA, immunoglobulins (Ig), anti-pig-antibodies, complement factors, and cardiac enzymes were determined. Abdominal electrocardiography (ECG), echocardiography, and palpation were used for monitoring of the pig hearts. Myocardial tissue specimens were examined using immunohistochemistry, light microscope (LM), and electron microscope (EM). RESULTS: Ten cycles of IA alone removed 78% of XAb and accordingly IgM, IgG, IgA, complement C3, and C4. None of the xenografts was hyperacutely rejected, but xenograft failure occurred after 5.0 +/- 1.3 days (range, 2.4-8.0 days) because of an AVR associated with a rapid XAb increase within 24 hours. White blood cell count (10.3 +/- 2.2 G/L) showed a maximum of 13.1 +/- 2.1 (day 1) and constant levels (1.4 +/- 0.3-2.1 +/- 1.3 G/L) between day 3 and 6. Histology (LM/EM) showed massive hemorrhage, necrosis, and vascular thrombi as signs of AVR. CONCLUSION: Although HXR was prevented by using IA and hDAF-transgenic donor hearts, AVR was not avoided due to insufficient immunosuppressive regimen used and a missed postoperative IA treatment as a result of an inefficient control of XAb production.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Improvement of lung preservation -- from experiment to clinical practice.

BACKGROUND: Reperfusion injury represents a severe early complication following lung transplantation. Among the pathogenetic factors, the high potassium content of Euro-Collins(reg) solution is discussed. MATERIAL AND METHODS: In a pig model of orthotopic left-sided lung transplantation we investigated the effect of Euro-Collins solution (EC: n = 6) versus low potassium dextran (LPD: Perfadex: n = 6). Sham-operated (n = 6) animals served as control. Transplant function, cellular energy metabolism and endothelial morphology served as parameters. In a clinical investigation, 124 patients were evaluated following single (EC: n = 31; LPD n = 37) or double (EC: n = 17; LPD n = 39) lung transplantation, whose organs where preserved with EC (n = 48) or LPD (n = 76). Duration of ischemia, duration of ventilation and stay on ICU were registered. Primary transplant function was evaluated according to AaDO(2) values. Cause of early death (30 days) was declared. RESULTS: Experimental results: After flush with EC and 18 h ischemia, a reduction of tissue ATP content (p < 0.01 vs inital value and LPD) was noted. Endothelial damage after ischemia was severe (p < 0.05 vs control), paO(2) was significantly decreased. CLINICAL RESULTS: In the LPD group, duration of ischemia was longer for the grafts transplanted first (SLTx and DLTx: p = 0.0009) as well as second (2. organ DLTx: p = 0.045). Primary transplant function was improved (day 0: SLTx: p = 0.0015; DLTx: p = 0.0095, both vs EC). Duration of ventilation and stay on ICU were shorter (n.s.). Reperfusion injury-associated death was reduced from 8% (EC) to 0 (LPD). CONCLUSION: In experimental lung preservation, LPD lead to an improved graft function. These results were confirmed in clinical lung transplantation. Clinical lung preservation, therefore, should be carried out by use of LPD.

Adult↗
PubMedDate not supplied

Correlation between mononuclear infiltration and changes in VASP phosphorylation patterns after heterotopic cardiac transplantation in the rat.

Chronic cardiac transplant vasculopathy still remains the major cause of late graft failure after the 1st postoperative year, with iNOS playing a central role in the progression of this disease. Since VASP, a recently identified microfilament-associated protein in smooth muscle cells, endothelial cells, and platelets, is phosphorylated by cyclic nucleotide dependent protein kinases, changing amounts of NO-producing mononuclear infiltration cells during cardiac rejection are supposed to change platelet VASP phosphorylation patterns. We investigated whether platelet VASP Ser(157) phosphorylation (VASP shift) after coronary passage of rat cardiac allografts correlates with graft infiltration. The Lew-F344 heterotopic rat cardiac transplantation model was used. Native hearts and grafts were harvested 3-150 days after transplantation and were used for Langendorff perfusion. The platelet VASP shift after native heart and graft perfusion was identified. Additional iNOS stimulation and iNOS inhibition were achieved pharmacologically. Immunohistology revealed graft mononuclear infiltration. Platelet VASP Ser(157) and Ser(239) phosphorylation significantly increased after coronary passage of native hearts and grafts (p < 0.01). Though platelet VASP Ser(157) phosphorylation failed to directly express graft infiltration, we showed a significant correlation between changes of platelet VASP shift and extent of grafts' mononuclear infiltration after competitive iNOS inhibition (p < 0.01). The platelet VASP shift is modified during coronary perfusion, and this modification correlates with mononuclear infiltration in the graft. This emphasizes the influence of mononuclear infiltration cells on microfilamental structures of the cytoskeleton in adjacent cells.

Animals↗
PubMedDate not supplied

Bridging to transplant: allogeneic heart transplantation after xenografting.

Xenografting seems to be a solution to use to bridge time intervals when desperately needed allograft cannot be obtained. A following allograft was never ventured. Nine dogs (weight, 20 to 25 kg; age, 2 years) underwent right cervical heart transplantation. Donors were silver foxes (3 to 4 kg). The animals were treated by triple-drug therapy consisting of cyclosporine, methylprednisolone, and azathioprine in clinical dosages. For control, six recipients received only allogeneic hearts and the identical immunosuppression. After rejection of the xenograft, a second allogeneic heart was anastomosed subsequently to the same right cervical vessels. Routine histologic and immunohistologic examinations were performed. Thromboxane B2 and 6-keto-prostaglandin F1 alpha were determined daily in peripheral blood. After final rejection the sensitization of the recipient was controlled by hemagglutination test. Survival time of the xenografts was 9.6 +/- 1.2 days; the subsequent allogeneic hearts under the same therapy beat for 4.5 +/- 5.0 days. The average survival time of control hearts was 18 +/- 1.9 days. The five hyperacute second allografts showed signs of humoral rejection by absence of inflammation. The release of thromboxane B2 was different in hyperacute, accelerated, or cellular rejection. In contrast to the long-functioning grafts, thromboxane B2 persisted during hyperacute rejection at a high level. However, 6-keto-prostaglandin F1 alpha showed no significant differences between longtime survivors and hyperacute rejecting hearts. After xenogeneic transplantation, all recipients showed hemagglutinating titers between 1:4 and 1:16. Allogeneic grafts have a different kinetics of rejection after xenogeneic heart transplantation compared with control hearts. Thromboxane B2 seems to be an important mediator in hyperacute rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗