| 1. |
- Ekberg, Henrik, et al.
(författare)
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Challenges and considerations in diagnosing the kidney disease in deteriorating graft function.
- 2012
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Ingår i: Transplant international : official journal of the European Society for Organ Transplantation. - : Frontiers Media SA. - 1432-2277. ; 25:11, s. 1119-1128
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Tidskriftsartikel (refereegranskat)abstract
- Despite significant reductions in acute-rejection rates with the introduction of calcineurin inhibitor (CNI)-based immunosuppressive therapy, improvements in long-term graft survival in renal transplantation have been mixed. Improving long-term graft survival continues to present a major challenge in the management of kidney-transplant patients. CNIs are a key component of immunosuppressive therapy, and chronic CNI toxicity has been widely thought to be a major factor in late graft failure. However, recent studies examining the causes of late graft failure in detail have challenged this view, highlighting the importance of antibody-mediated rejection and other factors. In addition, the diagnosis of CNI nephrotoxicity represents a challenge to clinicians, with the potential for over-diagnosis and an inappropriate reduction in immunosuppressive therapy. When graft function is deteriorating, accurately determining the cause of the kidney disease is essential for effective long-term management of the patient. Diagnosis requires a thorough clinical investigation, and in the majority of cases a specific cause can be identified.
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| 2. |
- Paul, Clara, et al.
(författare)
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Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1.
- 2012
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Ingår i: Transplant international : official journal of the European Society for Organ Transplantation. - : Frontiers Media SA. - 1432-2277.
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Tidskriftsartikel (refereegranskat)abstract
- We have recently described the immunosuppressive properties of AR-C117977 and AR-C122982, representatives of a group of compounds identified as inhibitors of lactate transporters (monocarboxylate transporters; MCTs). These compounds demonstrate the potential therapeutic usefulness of inhibiting MCT-1, but their physical and metabolic properties made them unsuitable for further development. We have therefore tried to find analogues with similar immunosuppressive efficacy and a more suitable profile for oral administration. Five analogues of AR-C117977 were synthesised and screened for binding to the transporter, for inhibition of proliferation of both human and rat lymphocytes, for in vivo activity in a model of graft-versus-host (GvH) response in the rat, and in high- and low-responder cardiac transplant models in the rat. There was a good correlation between levels of binding of the five analogues to MCT and their inhibition of lymphocyte proliferation in human and rat cells. Furthermore, activity in both the GvH response and the cardiac transplant models correlated well with the determined concentrations of test compound in plasma. These findings on new analogues of MCT-1 inhibitors have taken us further towards defining the pharmacokinetic properties that may help to identify future drug candidates among inhibitors of MCT-1.
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| 3. |
- Xia, Junjie, et al.
(författare)
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Suppressing memory T cell activation induces islet allograft tolerance in alloantigen-primed mice
- 2010
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Ingår i: Transplant International. - : Frontiers Media SA. - 1432-2277 .- 0934-0874. ; 23:11, s. 1154-1163
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Tidskriftsartikel (refereegranskat)abstract
- P>Memory T cells are known to play a key role in prevention of allograft tolerance in alloantigen-primed mice. Here, we used an adoptively transferred memory T cell model and an alloantigen-primed model to evaluate the abilities of different combinations of monoclonal antibodies (mAb) to block key signaling pathways involved in activation of effector and memory T cells. In the adoptively transferred model, the use of anti-CD134L mAb effectively prevented activation of CD4+ memory T cells and significantly prolonged islet survival, similar to the action of anti-CD122 mAb to CD8+ memory T cells. In the alloantigen-primed model, use of anti-CD134L and anti-CD122 mAbs in addition to co-stimulatory blockade with anti-CD154 and anti-LFA-1 prolonged secondary allograft survival and significantly reduced the proportion of memory T cells; meanwhile, this combination therapy increased the proportion of regulatory T cells (Tregs) in the spleen, inhibited lymphocyte infiltration in the graft, and suppressed alloresponse of recipient splenic T cells. However, we also detected high levels of alloantibodies in the serum which caused high levels of damage to the allogeneic spleen cells. Our results suggest that combination of four mAbs can significantly suppress the function of memory T cells and prolong allograft survival in alloantigen primed animals.
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| 4. |
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| 5. |
- Biglarnia, Ali-Reza, et al.
(författare)
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Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation
- 2011
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 24:8, s. e61-e66
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Tidskriftsartikel (refereegranskat)abstract
- We describe the presumably first intentional ABO-incompatible deceased-donor kidney and pancreas transplantation with a severe antibody-mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement-related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.
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| 6. |
- Felldin, Marie, et al.
(författare)
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The antibody response to pandemic H1N1 2009 influenza vaccine in adult organ transplant patients.
- 2012
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Ingår i: Transplant international : official journal of the European Society for Organ Transplantation. - : Frontiers Media SA. - 1432-2277. ; 25:2, s. 166-71
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Tidskriftsartikel (refereegranskat)abstract
- Limited data are available regarding antibody response and the safety of the monovalent influenza A H1N1/09 vaccine for immunocompromised patients. In this study, the humoral response to this vaccine in solid organ transplant (SOT) recipients and healthy individuals was evaluated. Eighty-two SOT recipients and 28 healthy individuals received two doses of the influenza A H1N1/09 AS03 adjuvanted vaccine containing 3.75mg of haemagglutinin at a 3- to 4-week interval. Serum samples were drawn at baseline and 3-4weeks after the first and second vaccine doses. Seroprotective titres were measured with a haemagglutination inhibition. After the first dose seroprotective titres were observed in 69% of the SOT patients and in 96% of the healthy controls (P=0.006), and increased after the second dose to 80% and 100%, respectively (P=0.003). All controls and 77% of the SOT recipients achieved a ≥4-fold titre rise after the first immunisation (P=0.005). The vaccine was well tolerated and no acute rejection was observed. Influenza A H1N1/09 vaccine elicited a protective antibody response in the majority of SOT recipients, but the response was lower when compared with controls. A second dose significantly improved vaccine immunogenicity in SOT recipients. (ClinicalTrials.gov number: NCT01254955).
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| 7. |
- Kakabadze, Zurab, et al.
(författare)
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Long-term engraftment and function of transplanted pancreatic islets in vascularized segments of small intestine
- 2011
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 24:2, s. 175-183
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Tidskriftsartikel (refereegranskat)abstract
- This study evaluated the potential of vascularized small intestinal segments for pancreatic islet transplantation. Islets isolated from Lewis rats were transplanted into diabetic syngeneic recipients. Segments of small intestine were prepared by denudation of the mucosal layer prior to implantation of pancreatic islets into the segments. Animal groups were established to determine engraftment, survival and function of islets transplanted into either intestinal segments or portal vein over up to 60 days. We found transplantation of functionally intact pancreatic islets into small intestinal segments was well tolerated. Transplanted islets were rapidly engrafted in intestinal segments as demonstrated vascularization and expression of insulin and glucagon throughout the 60-day duration of the studies. Transplantation of islets restored euglycemia in diabetic rats, which was similar to animals receiving islets intraportally. Moreover, animals treated with islet transplants showed normal responses to glucose challenges. Removal of graft-bearing intestinal segments led to recurrence of hyperglycemia indicating that transplanted islets were responsible for improved outcomes. Therefore, we concluded that vascularized intestinal segments supported reorganization, survival and function of transplanted islets with therapeutic efficacy in streptozotocin-treated diabetic rats. The approach described here will be appropriate for studying islet biogenesis, reorganization and function, including for cell therapy applications.
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| 8. |
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| 9. |
- van Keimpema, Loes, et al.
(författare)
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Excellent survival after liver transplantation for isolated polycystic liver disease: an European Liver Transplant Registry study.
- 2011
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Ingår i: Transplant international : official journal of the European Society for Organ Transplantation. - : Frontiers Media SA. - 1432-2277. ; 24:12, s. 1239-45
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Tidskriftsartikel (refereegranskat)abstract
- Patients with end-stage isolated polycystic liver disease (PCLD) suffer from incapacitating symptoms because of very large liver volumes. Liver transplantation (LT) is the only curative option. This study assesses the feasibility of LT in PCLD. We used the European Liver Transplant Registry (ELTR) database to extract demographics and outcomes of 58 PCLD patients. We used Kaplan-Meier survival analysis for survival rates. Severe abdominal pain (75%) was the most prominent symptom, while portal hypertension (35%) was the most common complication in PCLD. The explantation of the polycystic liver was extremely difficult in 38% of patients, because of presence of adhesions from prior therapy (17%). Karnofsky score following LT was 90%. The 1- and 5-year graft survival rate was 94.3% and 87.5%, while patient survival rate was 94.8% and 92.3%, respectively. Survival rates after LT for PCLD are good.
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