Severe Acute Vascular Rejection Research Articles

Early Administration of FTY720 Prevents Chronic Airway as Well as Vascular Destruction in Experimental Rat Lung Transplantation

BackgroundChronic rejection (CR) in terms of bronchiolitis obliterans (BO) and vascular sclerosis (VS) still represents the major obstacle for pulmonary graft survival in the medium and long term course after lung transplantation (LTX). Aside from nonspecific stimuli, early acute rejection (AR) seems to be causative especially in cases of a late diagnosis or inadequate treatment. This study investigated the effects of FTY720, a new immunosuppressant that promotes lymphocyte sequestration into lymph nodes and Peyer's patches, on the development of CR after experimental LTX. MethodsA total of 50 rats underwent allogenic (F344-to-WKY) and syngenic (WKY-to-WKY) left LTX. Group 1 animals had no treatment. Group 2 animals were administered FTY720 (3 mg/kg body weight per day) at the maximum time of AR (day 14) and continued up to day 100 after LTX. Group 3 animals were treated with the same dosage of FTY720 from day 0 to 100. The grades of AR and CR were classified according to the criteria of the International Society for Heart and Lung Transplantation. ResultsWithin 14 days after allogenic LTX, all nontreated rats developed early AR followed by severe CR with VS and BO. Similar data were observed for FTY720 treatment of existing AR (group 2). Only early administration of FTY720 (at the time of LTX) significantly reduced the proportion of animals with severe acute vascular rejection (P < .001). However, all of these allografts showed high-grade acute airway inflammation. After long-term application, the chronic inflammatory response was absent; none of the allografts developed BO and VS. ConclusionOnly application of FTY720 immediately after LTX prevented lymphocyte recirculation and lung injury.

Impact of the severity of acute rejection in the early phase after rat lung transplantation on the effectiveness of mycophenolate mofetil to treat chronic allograft rejection

Prevention and treatment of bronchiolitis obliterans (BO) after lung transplantation (LTX) remains disappointing. The high prevalence and the critical detection of early mild acute lung rejection aggravated optimum immunosuppressive therapy. In this study, two hypotheses were investigated: (i) mycophenolate mofetil (MMF) prevented the development of BO after rat LTX. (ii) The effectiveness of MMF depended on the degree of acute rejection (AR) at the time of drug initiation. A rat model of left lung allo-transplantation (Fisher 344 to Wistar Kyoto) was used to evaluate the basic effect of MMF (30 mg/kg body weight per day) on the development BO. MMF therapy began on Days 0, 7 and 14 after transplantation characterizing different degree of AR of the allograft at the time of drug initiation and ended on Day 60 after transplantation. Non-treated animals were used as controls. Histopathological alterations were analysed according to the International Society for Heart and Lung Transplantation (ISHLT). MMF treatment of allografts with high-grade AR (ISHLT-A3-4/B2R; from Day 14 to 60) failed. All animals developed vascular fibrosis and BO. Promising long-term outcome was shown after treatment of mild to moderate acute rejecting of allografts (MMF from Day 7 to 60). The proportion of animals with high grade acute airway inflammation was significantly reduced (33%; P<0.05). All animals were free of BO and chronic vascular alterations (90%). MMF (Day 0-60) significantly reduced the proportion of animals with severe acute vascular rejection and high grade airway inflammation (17 and 0%, respectively; P<0.05, each). None of the animals treated with MMF from Day 0 to 60 developed chronic rejection (CR). MMF significantly reduced AR and CR after rat LTX. However, only allografts with no or mild AR at the time of drug initiation benefited from MMF treatment. In addition, the appearance of early signs of fibroproliferative alterations in the airway structures might prevent a successful long-term outcome.

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.

MEAN XENOGRAFT SURVIVAL OF 14,6 DAYS IN A SMALL GROUP OF HDAF-TRANSGENIC PIG HEARTS TRANSPLANTED ORTHOTOPICALLY INTO BABOONS

O55 Aims: In a discordant orthotopic xenotransplantation (oXHTx) 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 (IS) regimen consisting of ERL (Novartis Pharma AG, Basel), 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 titres of xenoreactive antibodies (XNAb) served as recipients. Serological and hemodynamic parameters were measured. Finally myocardial tissue was sampled for histological and immunohistochemical examinations. Results: First baboon had an acute graft failure after 1 h due to preservation injury. The second died after 11.1 d because of acute renal. The third died after 13.1 days from an ileus. The fourth baboon had continuously excellent cardiac function (mean echocardiographical ejection fraction: 69.2%), but died on day 20 due to anemia. Corrected mean xenograft survival (excluding first baboon because of technical failure) was 14.6+/−2.6 days. XNAb decreased on 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 IS drug combination (Neoral, ERL, steroids and several single small doses of CyP). An optimum “fine-tuning” of IS is required to achieve the best risk-benefit ratio.

Doppler signal quantitation in renal allografts: comparison in normal and rejecting transplants, with pathologic correlation.

Quantitative duplex Doppler sonography was performed in 55 renal transplant patients during 54 independent episodes of acute rejection, three episodes of chronic rejection, three episodes of acute tubular necrosis (ATN), and 23 occasions of normal graft function. Doppler signals were obtained from four arterial sites in each kidney. Nine patients, in whom signals were absent, were subsequently shown at nephrectomy to have absence of perfusion resulting from severe acute vascular rejection. In each patient with graft dysfunction, biopsy or nephrectomy was performed within 24 hours of the Doppler study. Arterial Doppler signals were quantified using a pulsatility index (PI). Acute rejection produced a significantly higher PI at each arterial site. Receiver-operator characteristics suggest that signals obtained from the segmental arteries are most sensitive to these changes. With a threshold PI of 1.5, the sensitivity of this technique for detection of acute renal allograft rejection is 75%; the specificity is 90%. In acute vascular rejection, the same PI yields a sensitivity of 79% and specificity of 90%. With a cutoff PI of 1.8, a specificity of 100% can be achieved.

Cytomegalovirus glomerulopathy: A controversial lesion

Seven autopsies performed on immunosuppressed bone marrow transplant recipients who died with documented herpes virus infection were reviewed. The kidneys were studied by light and electron microscopy and revealed no pathological findings, specifically no glomerulopathy or tubular interstitial nephritis. Seven renal biopsies performed on kidney transplant recipients in whom a diagnosis of cytomegalovirus glomerulopathy was entertained were also studied. These patients exhibited clinical parameters suggestive of cytomegalovirus infection. Three patients had subsequent nephrectomies and two showed severe acute vascular rejection. The one kidney without demonstrable acute vascular rejection was negative for cytomegalovirus on culture. Three additional patients improved or stabilized their renal function under therapy for rejection. Light, electron microscopic and immunofluorescent studies, although confirmatory of endothelial cell damage, did not substantiate active cytomegalovirus renal infection in these patients. An additional group of fifteen children with disseminated cytomegalovirus infection revealed no evidence of glomerulopathy. Finally, two kidney transplant recipients with proven cytomegalovirus infection (one with associated tubular interstitial nephritis) also showed no glomerular alterations. It is the author's opinion that the entity that has been considered as cytomegalovirus glomerulopathy probably represents rejection, either a peculiar anti-endothelial type of rejection or a protracted, early, or partially resolved acute vascular rejection without residual or identifiable acute vascular rejection changes in the tissue sampled.